DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .1
Status of Claims
Claims 15-19, 25-33 and 37-47 are pending and under examination. The pending claims are directed to a method of treating NASH (Nonalcoholic steatohepatitis) by administering Lanifibranor2 and Firsocostat3.
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Response to Arguments
Applicant's arguments filed Dec 11 2025 have been fully considered but they are not persuasive. The rejection of claims 15-19, 25-33 and 37-44 under 35 U.S.C. 103 as being unpatentable over Loomba et al., Gastroenterology, Elsevier Inc, US, vol. 155, no. 5, 31 Oct. 2018, and Sven et al. Contemporary Clinical Trials, 98 (available online Oct 2020) 106170, p. 1-11, in view of WO 2018/193006 A1 (WO 006) ,is maintained and applied to new claims 45-47.
In the Attorney responses dated Feb 4 2025 and Dec 11 2025, the Attorney response references and quotes a Rule 132 Declaration (identified as the “Wettstein Declaration”). At the time of this office action and after an inspection of the incoming document history, it appears a copy of the Wettstein Declaration was not submitted.
Accordingly, the Examiner can only be address those comments referenced by Applicant’s Attorney in the Dec 11 2025 response per se. If the Examiner is mistaken in this belief and a copy has been submitted, clarification of when the Declaration was submitted to the PTO is requested. Otherwise a copy of the Rule 132 is requested.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicants are advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 15-19, 25-33 and 37-41 are rejected under 35 U.S.C. 103 as being unpatentable over Loomba et al., "GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers In Patients with Nonalcoholic Fatty Liver Disease", Gastroenterology, Elsevier Inc, US, vol. 155, no. 5, 31 Oct. 2018, and Sven et al. “A randomised, double-blind, placebo-controlled, multi-centre, dose-range, proof-of-concept, 24-week treatment study of lanifibranor in adult subjects with non-alcoholic steatohepatitis: Design of the NATIVE study,” Contemporary Clinical Trials, 98 (available online Oct 2020) 106170, p. 1-11, in view of WO 2018/193006 A1 (WO 006). Loomba, Sven and WO 006 have been previously cited by the Examiner.
Claim 37 is a method of treating non-alcoholic fatty liver disease (NAFLD) or a complication thereof, which comprises administering to a patient in need thereof an effective amount of lanifibranor and an effective amount of firsocostat.
Regarding claim 37 with the limitation of a combination comprising (i) lanifibranor, and (ii) firsocostat, and the treatment of NAFLD, Loomba discloses the treatment of NAFLD with the compound firsocostat (therein identified as GS-0976, a known acetyl coenzyme carboxylase (ACC) inhibitor), see abstract and title. Loomba discloses firsocostat was tested in a phase 2 clinical trial patients with NAFLD, aged 18-25 years, including hepatic steatosis (i.e., non-alcoholic hepatic steatosis, aka NASH), see section Methods, page 1464, column 2.
Loomba teaches an oral firsocostat 5 or 20 mg dosage form, See Study Design section, page 1464, column 2. Loomba teaches Serum TIMP-1 and acylcarnitines were suppressed in treated patients, where patients who received firsocostat had significant reductions in hepatic steatosis, fibrosis markers and plasma acylcarnitines. Id.
Loomba teaches measured reductions in fibrosis serum markers and liver injuries, are representative in treatment of NALFD/NASH, such as the noninvasive Enhanced Liver Fibrosis (ELF) test and its components, such asTIMP1, procollagen III N-terminal peptide [PIII-NP], and hyaluronic acid. See Loomba page 1465, column 1, first paragraph. 4 Serum markers of liver injury and function, including ALT, aspartate aminotransferase, bilirubin, g-glutamyl transferase, and alkaline phosphatase were also collected, Id. 5
Although Loomba teaches firsocostat to treat NAFLD/NASH, where various blood chemistry biomarkers are measured, Loomba does not teach a combination with the PPAR (peroxisome Proliferator-Activated Receptors) agonist lanifibranor for the treatment of NAFLD/NASH in a subject in need.
However, a person having ordinary skill in the art (PHOSITA) would have a reasonable expectation of success in arriving at the claimed invention because 1) both ACC inhibitor compounds such as firsocostat and lanifibranor PPAR agonists are known to treat NAFLD/NASH, and precursor conditions that lead to hepatic fibrosis and cirrhosis and 2) such a suggestion to do so is noted in the art by virtue of the fact both Loomba and Sven address the same biomarkers and same blood chemistry values in the study of these two compounds to treat the same disease/conditions of NAFLD/NASH, where a teaching and suggestion to combine PPAR inhibitors and ACC inhibitors are known.
Regarding these points of obviousness, Sven teaches dosage forms of lanifibranor administered with food (i.e., orally dosed forms) in daily doses of 800 mg or 1200 mg for 24 weeks, see page 5, column 2, Section 2.4 Dosing rationale. Lanifibranor acts on 3 different PPAR isotypes (a pan PPAR agonist) that address the different components of disease as demonstrated in preclinical models, see abstract.
Similar to Loomba, Sven discloses NAFLD is defined by the presence of hepatic steatosis in the absence of significant alcohol consumption and includes its more severe and potentially progressive subtype, NASH, see page 2, column 1 first paragraph, Introduction. Sven discloses PPAR agonists such as lanifibranor, exert positive metabolic and anti-fibrotic effects in animal models, page 2, column 1. Sven discloses that NASH can progress to hepatic fibrosis and liver cirrhosis, where PPAR plays a central role in the regulation of glucose and lipid metabolism and of the inflammatory and fibrogenic pathways in liver and in other organs that all contribute to NASH pathogenesis, see abstract.
Sven discloses that in its phase 2b study of NASH patients (NATIVE), that lanifibranor demonstrated improving portal hypertensin and hepatic fibrosis in an experimental rat model of advanced chronic liver disease, see page 2, column 2, as well as summarizing various other studies noting its preventive effects in rodent animal models of liver or other organ fibrosis, Id.
Similar to Loomba, Sven discloses lanifibranor was noted to normalize various liver fibrotic markers such as TIMP1, see page 3, column 2. Further, Sven teaches other biomarkers listed as notable in Loomba such as TIMP1, and hyaluronic acid, See page 7, column 1. Sven also notes the measurement of the same/similar blood chemistry levels (as Loomba) of AST/ALT, alkaline phosphatase and total bilirubin, see page 6, column 2, Section 2.10. Safety assessments.
The basis to combine the teachings of a PPAR inhibitor as per Sven (lanifibranor) with a ACC inhibitor (firsocostat per Loomba) to treat NAFLD/NASH is not only established by Loomba and Sven, but also taught in the prior art where, WO 006 is directed to combinations (combinations products also) of a PPAR agonist compound (elafibranor) with an anti-NASH, anti-fibrotic or anti-cholestatic agent (in particular GS-0976, aka firsocostat, the ACC inhibitor), see claims 1-2 and 5. WO 006 discloses treatment of various subjects in need such as NAFLD, NASH (hepatic steatosis) and various liver fibrotic conditions and cirrhosis. See claim 12.
More particularly, WO 006 discloses the PPAR agonist compound (elafibranor) in combination with GS-0976, aka firsocostat specifically, see page 23, lines 20-23. See also Figure 10 (page 39 description of combinations with firsocostat aka GS-0976), Figure 16 (page 41 description); page 49, line noting synergy of PPAR agonist with firsocostat aka GS-0976; and Example 4, page 57, starting at line 30.
This teaching of a PPAR agonist with firsocostat, provides the PHOSITA a rationale to look towards WO 006 in combination with Loomba and Sven, as all are directed to these classes of compounds (PPAR agonist and ACC inhibitors, such as firsocostat aka GS-0976) for the treatment of the same population of patients in need afflicted with NASH/NAFLD.
Accordingly, as both Loomba and Sven, respectively, disclose and provide a rationale to treat NAFLD/NASH with firsocostat (ACC inhibitor) and lanifibranor (PPAR agonist), a PHOSITA, noting the common blood and chemistry markers AND where a PPAR and ACC inhibitor synergistic combination is known, would combine the two in a combination product and/or method of combination treatment. Per MPEP 2144.06.6
As both drugs are known to be used for the treatment for NAFLD/NASH, and the art explicitly teaches synergy of such a combination of PPAR inhibitor and ACC inhibitor (firsocostat), it is prima facie obvious to combine them to treat the same patient population in need, suffering from the same disease, whether as a pharmaceutical combination product (separate components), or as a single formulation administered simultaneously. See also the basis established by WO 006 making it known that PPAR and ACC inhibitors are known to synergistically treat NAFLD/NASH.
A PHOSITA following the teachings of Loomba, would have found it prima facie obvious to combine treatment of NAFLD/NASH with firsocostat (ACC inhibitor) with the teachings of Sven, the treatment of these diseases with lanifibranor, especially as both references teach the reliance of TIMP1, AST/ALT, alkaline phosphatase and total bilirubin, as measurement of the effectiveness of said treatment in view of WO 006 and where a PPAR and ACC inhibitor synergistic combination is known to treat NASH/NAFLD.
Regarding claim 15 and the limitations therein, such as treatment of a complication of NAFLD like NASH, steatosis, steatohepatitis, liver fibrosis/cirrhosis/failure caused by NASH, etc., as discussed above, both Loomba and Sven teach the treatment of these NAFLD complications. See first page 1463 and abstract of Loomba and Sven abstract.
Regarding claims 16-17 and the limitations of simultaneous and separate administration, WO 006 teaches the simultaneous and separate administration of the PPAR agonist component (i) and firsocostat aka GS-0976 (ii), see page 34, lines 13-17.
Regarding claim 18 where the claimed combination is administered over a period of time, WO 006 teaches administration over time periods of the combination performed daily or even several times a day, if necessary, see page 35, line 27.
Regarding the limitation of claim 19 where firsocostat and lanifibranor are in a first and second distinct pharmaceutical composition, this taught by both Loomba and Sven as noted above.
Regarding claim 25 where the PPAR agonist and firsocostat aka GS-0976 are combined into a single formulation, WO 006 discloses the PPAR agonist component (i) and firsocostat aka GS-0976 (ii) are combined in the same single formulation and separate formulations, see page 34, lines 8-12.
Regarding claims 26-33 and the limitations therein, such as treatment of a complication of NAFLD like NASH, steatosis, steatohepatitis, liver fibrosis/cirrhosis/failure caused by NASH, etc., as discussed above, both Loomba and Sven teach the treatment of these NAFLD complications. See first page 1463 and abstract of Loomba and Sven abstract.
With regard to claim 32 in particular and the complication of cardiovascular disease of NASH/NAFLD, Sven teaches this complication, see page 2, column 1.
With regard to claim 33 in particular and the complication of hepatocellular carcinoma of NASH/NAFLD, Sven teaches this complication, see page 2, column 1.
Regarding claims 38-39 and the limitation of lanifibranor of about 400 mg to about 1200 mg, about 800 mg to about 1,000 mg, Sven teaches dosage forms of lanifibranor to administered with food (i.e., orally dosed forms) in daily doses of 800 mg or 1200 mg for 24 weeks, see page 5, column 2, Section 2.4 Dosing rationale. See MPEP 2144.05.
Regarding claims 40-41 and the limitation of wherein firsocostat dose is, about 5 mg to about 40 mg, about 5 mg to about 20 mg, Loomba teaches a pharmaceutical composition/product of firsocostat as an oral dosage form of 5 or 20 mg, See Study Design section, page 1464, column 2. See MPEP 2144.05.
Claims 42-47 are rejected under 35 U.S.C. 103 as being unpatentable over Loomba et al., Gastroenterology, Elsevier Inc, US, vol. 155, no. 5, 31 Oct. 2018, US 20210300913A1 (US Pub 913) and Sven et al., Contemporary Clinical Trials, 98 (available online Oct 2020) 106170, p. 1-11, in view of WO 2018/193006 A1 (WO 006). US Pub 913, Loomba, Sven and WO 006 have been previously cited by the Examiner.
Claims 42 is directed to a method of treating non-alcoholic fatty liver disease (NAFLD) or a complication thereof, which comprises administering to a patient in need thereof an effective amount of a deuterated form of lanifibranor and an effective amount of firsocostat.
Regarding claim 42, Loomba discloses the treatment of Non-alcoholic fatty liver disease (NAFLD) with the compound firsocostat (therein identified as GS-0976, a known acetyl coenzyme carboxylase (ACC) inhibitor), see abstract and title. Loomba discloses firsocostat was tested in a phase 2 clinical trial patients with NAFLD, aged 18-25 years, including hepatic steatosis (i.e., non-alcoholic hepatic steatosis, aka NASH), see section Methods, page 1464, column 2.
Loomba teaches an oral firsocostat 5 or 20 mg dosage form, See Study Design sec., p. 1464, col. 2. Loomba teaches Serum TIMP-1 and acylcarnitines were suppressed in treated patients who received firsocostat had significant reductions in hepatic steatosis, fibrosis markers and plasma acylcarnitines, Id.
Loomba teaches fibrosis serum markers and liver injuries, whose measured reduction would be representative in treatment of NALFD/NASH, such as the noninvasive Enhanced Liver Fibrosis (ELF) test and its components (TIMP1, procollagen III N-terminal peptide [PIII-NP], and hyaluronic acid). See Loomba page 1465, column 1, first paragraph. 7 Serum markers of liver injury and function including ALT, aspartate aminotransferase, bilirubin, g-glutamyl transferase, and alkaline phosphatase also were collected, Id. 8
Although Loomba teaches firsocostat to treat NAFLD/NASH, as noted by the various biomarkers above, as per claim 37, Loomba does not teach a combination with the PPAR (peroxisome Proliferator-Activated Receptors) agonist lanifibranor in deuterated form, for the treatment of NAFLD/NASH in a subject in need.
However, a person having ordinary skill in the art (PHOSITA) would have a reasonable expectation of success in arriving at the claimed invention because 1) both ACC inhibitor compounds such as firsocostat and lanifibranor PPAR agonists are known to treat NAFLD/NASH, precursor conditions that lead to hepatic fibrosis and cirrhosis and 2) such a suggestion to do so is noted in the art by virtue of the fact both Loomba and Sven address the same biomarkers and same blood chemistry values in the study of these two compounds to treat the same disease/conditions of NAFLD/NASH, where a teaching and suggestion to combine PPAR inhibitors and ACC inhibitors are known..
Regarding these points of obviousness, Sven teaches dosage forms of lanifibranor administered (i.e., orally dosed forms) in daily doses of 800 mg or 1200 mg for 24 weeks, see page 5, column 2, Section 2.4 Dosing rationale. Lanifibranor acts on 3 different PPAR isotypes (a pan PPAR agonist) that address the different components of disease as demonstrated in preclinical models, see abstract.
Similar to Loomba, Sven discloses NAFLD is defined by the presence of hepatic steatosis in the absence of significant alcohol consumption and includes its more severe and potentially progressive subtype, NASH, see page 2, column 1 first paragraph, Introduction. Sven discloses PPAR agonists such as lanifibranor, exert positive metabolic and anti-fibrotic effects in animal models, page 2, column 1. Sven discloses that NASH can progress to hepatic fibrosis and liver cirrhosis, where PPAR plays a central role in the regulation of glucose and lipid metabolism and of the inflammatory and fibrogenic pathways in liver and in other organs that all contribute to NASH pathogenesis, see abstract.
Sven discloses that in its phase 2b study of NASH patients (NATIVE), that lanifibranor demonstrated improving portal hypertensin and hepatic fibrosis in an experimental rat model of advanced chronic liver disease, see page 2, column 2, as well as summarizing various other studies noting its preventive effects in rodent animal models of liver or other organ fibrosis, Id.
Similar to Loomba, Sven discloses lanifibranor was noted to normalize various liver fibrotic markers such as TIMP1, see page 3, column 2. Further, Sven teaches other biomarkers listed as notable in Loomba such as TIMP1, and hyaluronic acid, See page 7, column 1. Sven also notes the measurement of the same/similar blood chemistry levels (as Loomba) of AST/ALT, alkaline phosphatase and total bilirubin, see page 6, column 2, Section 2.10. Safety assessments. Note that Sven does not teach the “deuterated form” of lanifibranor as required by claim 42, but it would routine for a PHOSITA to optimize treatment of NAFLD/NASH with a deuterated form of lanifibranor, as these forms are known in the art.
Regarding claim 42 and the limitation of a deuterated form lanifibranor for the treatment of NAFLD, US 913 teaches deuterated forms of lanifibranor, specifically for the treatment of fibrotic disease. See abstract. US Pub 913 teaches lanifibranor is particular for its use as a PPAR receptor antagonist for the treatment of non-alcoholic steatohepatitis (NASH) a form of the class of fibrotic disease, NAFLD as required by claim 42. See also claims 1, 6-8, 12, 13 and 15-17, directed to deuterated lanifibranor and methods of treating a fibrotic disease such as NASH (therein identified as non-alcoholic steatohepatitis).
The basis to combine the teachings of a PPAR inhibitor as per Sven (lanifibranor) with a ACC inhibitor (firsocostat per Loomba and deuterated form as per US Pub 913) to treat NAFLD/NASH is not only established by Loomba and Sven, but also taught in the prior art where, WO 006 is directed to combinations (combinations products also) of a PPAR agonist compound (elafibranor) with an anti-NASH, anti-fibrotic or anti-cholestatic agent (in particular GS-0976, aka firsocostat, the ACC inhibitor), see claims 1-2 and 5. WO 006 discloses treatment of various subjects in need such NAFLD, NASH (hepatic steatosis) and various liver fibrotic conditions and cirrhosis. See claim 12.
More particularly, WO 006 discloses the PPAR agonist compound (elafibranor) in combination with GS-0976, aka firsocostat specifically, see page 23, lines 20-23. See also Figure 10 (page 39 description of combinations with firsocostat aka GS-0976), Figure 16 (page 41 description); page 49, line noting synergy of PPAR agonist with firsocostat aka GS-0976; and Example 4, page 57, starting at line 30.
This teaching of a PPAR agonist with firsocostat aka GS-0976, provides the PHOSITA a rationale to look towards WO 006 in combination with Loomba and Sven, as all are directed to these classes of compounds (PPAR agonist and ACC inhibitors, such as firsocostat aka GS-0976) for the treatment of the same population of patients in need afflicted with NASH/NAFLD.
Accordingly, as Loomba, Sven, US Pub 913 and WO 006, disclose and provide a rationale to treat NAFLD/NASH with firsocostat (ACC inhibitor) and a deuterated form of lanifibranor (PPAR agonist), a PHOSITA, noting the common blood and chemistry markers, would combine the two in a combination product and/or method of combination treatment. See MPEP 2144.06 (Art Recognized Equivalence; Combination of Equivalents Known for Same Purpose)
As both drugs are known to be used for the treatment for NAFLD/NASH, it is prima facie obvious to combine them into treat said same patient population in need, suffering from the same disease, whether as a pharmaceutical combination product (separate components), or as a single formulation administered simultaneously. See also the basis established by WO 006 making it known that PPAR and ACC inhibitors are known to synergistically treat NAFLD/NASH.
A PHOSITA following the teachings of Loomba, would have found it prima facie obvious to combine treatment of NAFLD/NASH with firsocostat (ACC inhibitor) with the teachings of Sven and US Pub 913, the treatment of these diseases with a deuterated form of lanifibranor, especially as Loomba and Sven references teach the reliance of TIMP1, AST/ALT, alkaline phosphatase and total bilirubin, as measurement of the effectiveness of said treatment, where it would be obvious to use deuterated forms of lanifibranor as per US Pub 913, where WO 006 teaches combinations of PPAR and ACC inhibitors for the treatment of NAFLD/NASH.
Regarding claim 43 and the limitations therein, such as treatment of a complication of NAFLD like NASH, steatosis, steatohepatitis, liver fibrosis/cirrhosis/failure caused by NASH, etc., as discussed above, both Loomba and Sven teach the treatment of these NAFLD complications. See first page 1463 and abstract of Loomba and Sven abstract.
Claim 44 claims wherein the complication of NAFLD is NASH. Loomba discloses acetyl coenzyme carboxylase inhibitors such as firsocostat was tested in a phase 2 clinical trial patients with NAFLD, aged 18-25 years, also inclusive of hepatic steatosis (i.e., non-alcoholic hepatic steatosis, aka NASH), see section Methods, page 1464, column 2. Similar to Loomba, Sven discloses NAFLD is defined by the presence of hepatic steatosis in the absence of significant alcohol consumption and includes its more severe and potentially progressive subtype, NASH, see page 2, column 1 first paragraph, Introduction. Similarly, US Pub 913 teaches treatment of NASH with a deuterated form of lanifibranor, see paragraph 2 and claims 1, 6-8, 12, 13 and 15-17.
Claims 45-47 are directed to methods wherein the deuterated form of lanifibranor is administered at a daily dose of from about 400 mg to about 1,200 mg and firsocostat is administered at a daily dose of from about 5 mg to about 40 mg, or lanifibranor at about 800 mg to about 1,000 mg and firsocostat at 5 mg to about 40 mg
Regarding claims 45-47, Sven teaches dosage forms of lanifibranor to administered with food (i.e., orally dosed forms) in daily doses of 800 mg or 1200 mg for 24 weeks, see page 5, column 2, Section 2.4 Dosing rationale. Loomba teaches a pharmaceutical composition/product of firsocostat as an oral dosage form of 5 or 20 mg, See Study Design section, page 1464, column 2. See MPEP 2144.05.
RESPONSE TO ATTORNEY ARGUMENTS:
As stated above, while the previous office actions have addressed the Attorney response remarks quotes regarding the submitted Declaration by Inventor Dr. Guillaume Wettstein, as detailed above, a copy of the Declaration could not be found in the prosecution history by the Examiner. At this point, the Examiner will address the Attorney response’s direct quotes form this document quoting the Declaration.
The Attorney response states the Examiner errs by ignoring Sections 6.1 and 6.2 of the Declaration, where such reference to the paragraphs are to rebut the prima facie case and not argue the prima facie case has not been established.
In summary, Section 6.1 is said to provide background with both decreases in hepatic fat and improvements with hepatic steatosis, inflammation and fibrosis, where Section 6.2 notes decreases in hepatic fat AND improvement in hepatic steatosis, inflammation and fibrosis.
Because a copy of the Declaration is not in the prosecution history, the Examiner is reproducing those Declaration sections referenced by the response.
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The Attorney response argues that nothing in the prima facie case of obviousness would suggest that combining the two compound would provide the result of a decrease in hepatic fat AND an improvement in hepatic steatosis, inflammation and fibrosis (i.e., unexpected results) especially when the two compounds have different mechanisms of action.
In response, Applicant argues Sections 6.1 and 6.2 are intended to rebut the prima facie case of obviousness as established by MPEP 2144.06, prima facie obvious to combine two known equivalents, citing to In re Kerkhoven. Initially, it is noted the Examiner did not find the Wettstein Declaration in the prosecution history and Applicant is required to file it in order to rely upon its findings.
On the other hand, assuming Examiner error for not finding the Declaration in the prosecution history and the Declaration was filed, those sections referenced by the Attorney response will be addressed as below.
Once the prima facie case has been established and rebuttal evidence submitted per a Rule 132 Declaration, per MPEP 716 rebuttal evidence must be objective to be considered, such as comparative evidence.
Further per MPEP 716.01(d), evidence supporting patentability must be weighed against evidence supporting a prima facie case.
Further per MPEP 716.02(a) and 716.02(c) declaration must be unexpected and weighed against expected evidence.
Further per MPEP 716.02(d), declaration evidence must be commensurate in scope with the claimed invention.
With regard to the reference to decreases in hepatic fat (liver triglycerides, hepatic fatty acid levels and hepatic total cholesterol), Applicant’s response argues that it has results (Table 1) noting that additive combined data of both firsocostat and lanifibranor is unexpected when compared to monotherapy of each individually.
It would not be unexpected to a PHOSITA that combination therapy would result in lower hepatic fat acids, cholesterol and triglycerides, despite the statement that both compounds work under different mechanisms of action.
Per In re Kerkhoven and MPEP 2144.06, a PHOSITA would expect with a reasonable expectation of success a reduction in fatty liver by the two drugs known to treat NAFLD. Declaration evidence must be weighed against the prima face case. See MPEP 716.01(d).
Elaboration of doses to support Table 1 (and amendment of claims to support the doses) would be convincing to overcome the prima facie case.
With regard to Table 2 and the steatosis, inflammation and Fibrosis score, it is noted that the steatosis and inflammation score demonstrate an additive effect of firsocostat and lanifibranor being more effective than vehicle or monotherapy of either, were per MPEP 2144.06, it would be prima facie obvious to combine two compounds known for the same purpose.
In contrast, with regard to fibrosis score of Table 2,both firsocostat and lanifibranor monotherapy are said to demonstrate scores equivalent to non-active vehicle carrier, 0.9, where the combination of firsocostat and lanifibranor yields a value of 0.3. At first this data appears to be statistically significant.
However, it is noted that Table 2 does not recite doses of any of the monotherapy or combination therapy. Without the proper context of dosing of the monotherapy or combination therapy, it is unknown how significant this data is. Further, no context is provided with regard to fibrosis scores in terms liver health or lack thereof, in terms of fatty liver disease. While the fibrosis score of the combination is significantly lower than the score of the vehicle or monotherapy, context regarding how a score of 0.3 in terms of fatty liver status would relate to overall treatment of NAFLD or complications thereof. See MPEP 716.01(d); MPEP 716.02(a) and 716.02(c) . Further, the method of claim 37 for treating NAFLD or a complication thereof is broader than the lowering of fibrosis score in vehicle animal subject as argued by the Attorney response. See MPEP 716.02(d).
In rebutting the Examiner’s statements regarding the requirement that the evidence be commensurate in scope the claimed invention, the response states “the claimed compounds are used in effective amounts for treatment of non-alcoholic fatty liver disease (NAFLD) or a complication thereof to a patient in need of such treatment. Thus, the dosage is not undefined but defined in terms of an amount that effectively treats NAFLD.” The response argues claim 37 does not have to be defined by specific dose to match those of the experiments set out in the Declaration. This argument is also applied to claim 42 and where the response to points to new claims 45-47 which recites doses. The Attorney response argues that the claimed daily doses of lanifibranor (800-1200mg) and firsocostat (5 and 20 mg) were used in clinical trials.
With regard to the statement that the claimed “effective doses” claimed do not have to be defined by specific dose to match those experiments set out in the Declaration, evidence and/or disclosure of those specific experimental doses, along with corresponding statements to demonstrate how these correlate to a claimed “effective dose” to treat NAFLD and complications thereof would advance the prosecution of the claimed invention.
The Attorney response argues that C57BL6/J mice used in its experiments is a well-recognized mouse to model human disease. The Examiner agrees. The Attorney response states it does not deny that NAFLD can progress to NASH, but rather that its bullet point (ii) is state that just a fibrosis model alone is not conclusive that a combination of elafibranor with GS-0976 (aka firsocostat), (where the combination is noted to be anti-fibrotic) would have an effect going beyond an anti-fibrotic one.
In response, the Examiner maintains its position that, a PHOSITA would have a reasonable expectation of success in treating NAFLD where the prior art teaches an antifibrotic effect of the elafibranor GS-0976 (aka firsocostat) combination.
Conclusion and Correspondence
In summary, no claims are allowed. 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 WILLIAM LEE whose telephone number is (571)270-3876. The examiner can normally be reached M-F.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Adam C. Milligan can be reached at (571) 270-7674. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/WILLIAM Y LEE/Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
1 This application claims earliest priority to European Application EP 20306394.6 filed on 11/17/2020. Foreign priority is acknowledged based upon the certified copies of papers required by 37 CFR 1.55.
2 Lanifibranor
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1-(6-Benzothiazolylsulfonyl)-5-chloro-1H-indole-2-butanoic acid (ACI)
5-Chloro-1-[(6-benzothiazolyl)sulfonyl]-1H-indole-2-butanoic acid
IVA 337
3 Firsocostat
CAS Reg. No. 1434635-54-71,4-Dihydro-1-[(2R)-2-(2-methoxyphenyl)-2-[(tetrahydro-2H-pyran-4-yl)oxy]ethyl]-α,α,5-trimethyl-6-(2-oxazolyl)-2,4-dioxothieno[2,3-d]pyrimidine-3(2H)-acetic acid (ACI)
(R)-2-(1-(2-(2-Methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,2-dihydrothieno[2,3-d]pyrimidin-3(4H)-yl)-2-methylpropanoic acid
2-[1-{(2R)-2-(2-methoxyphenyl)-2-[(oxan-4-yl)oxy]ethyl}-5-methyl-6-(1,3-oxazol-2-yl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl]-2-methylpropanoic acid
GS 0976, GS-ACC, GS-Y, ND 630, NDI 010976
4 Serum markers of liver injury and function including ALT, aspartate aminotransferase, bilirubin, g-glutamyl transferase, and alkaline phosphatase also were collected, Id. Change from baseline in serum levels of cytokeratin 18 M30 and M65 fractions were measured as indicators of hepatocellular apoptosis and necrosis,. See Loomba page 1465, column 1, first paragraph.
5 Loomba also noted changes from baseline in serum levels of cytokeratin 18 M30 and M65 fractions were measured as indicators of hepatocellular apoptosis and necrosis,. See Loomba page 1465, column 1, first paragraph.
6 MPEP 2144.06 Art Recognized Equivalence for the Same Purpose, I. Combining Equivalents Known for the Same Purpose.
It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980) (citations omitted)
7 Serum markers of liver injury and function including ALT, aspartate aminotransferase, bilirubin, g-glutamyl transferase, and alkaline phosphatase also were collected, Id. Change from baseline in serum levels of cytokeratin 18 M30 and M65 fractions were measured as indicators of hepatocellular apoptosis and necrosis,. See Loomba page 1465, column 1, first paragraph.
8 Loomba also noted changes from baseline in serum levels of cytokeratin 18 M30 and M65 fractions were measured as indicators of hepatocellular apoptosis and necrosis,. See Loomba page 1465, column 1, first paragraph.