DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 5/27/2025 has been entered.
AIA Status of the Claims
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Arguments
Applicant’s arguments, filed 5/27/2025, have been fully considered.
Applicant traverses the rejection of claims under 35 U.S.C. 103(a). Applicant’s arguments are summarized as follows:
(a) Applicant argues that, as amended, the claimed method comprises active steps that are not taught by the prior art of record;
(b) Applicant argues that the previously presented step of twice- or thrice-weekly administration of miricorilant for at least twelve weeks is not taught or suggested by the prior art of record;
(c) Applicant argues that the prior art of record does not teach that reducing miricorilant administration to only twice-weekly or thrice-weekly administration would be effective to reduce liver fat in a patient; and
(d) Applicant argues that the prior art of record is not substantially identical to the instantly claimed method.
Regarding (a): Applicant “notes that claim 1 [and claim 11], as amended, includes active steps, including active steps of measuring baseline liver fat content by [MRI-PDFF]; identifying a patient having a baseline liver fat content greater than about 5%; determining a baseline level of ALT or of AST or both; and determining a baseline liver volume; among other active steps” (Applicant Arguments, Page 6). As argued by Applicant, “the pending claims include elements of active steps that are not found, and are not suggested, in the cited references” (Applicant Arguments, Page 7).
The rejection of claims under 35 U.S.C. 103(a) has been modified to address these new limitations.
Regarding (b): Applicant argues that “Belanoff lacks twice- or thrice-weekly administration of miricorilant for at least twelve weeks” (Applicant Arguments, Page 10). Although Applicant acknowledges that Belanoff et al teach that “[t]he state of the art allows the clinician to determine the dosage regimen for each individual patient” (Paragraph 0135), further discussing tailoring administration “depending on the dosage and frequency as required and tolerated by the patient” (Paragraph 0136), Applicant points to Paragraph 0136 which goes on to state that:
“[t]hus, in one embodiment, the pharmaceutical formulations for oral administration nof the compound of the present invention is in a daily amount of between about 0.5 to about 20 mg per kilogram of body weight per day. In an alternative embodiment, dosages are from about 1 mg to about 4 mg per kg of body weight per patient per day”
As argued by Applicant, “Belanoff is clearly discussing daily administration” (Applicant Arguments, Page 10).
The argument is not found persuasive. At the outset, 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 (CCPA 1981); In re Merck & Co., 800 F.2d 1091 (Fed. Cir. 1986).
Furthermore, Belanoff et al clearly discuss tailoring administration “depending on the dosage and frequency as required and tolerated by the patient” (Paragraph 0136). Although Paragraph 0136 only provides examples in which the dosage is modified and does not provide examples wherein the frequency of said dosage is modified does not, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (see In re Susi, 440 F.2d 442 (CCPA 1971); see also In re Gurley, 27 F.3d 551 (Fed. Cir. 1994), “A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use”; and In re Fulton, 391 F.3d 1105 (Fed. Cir. 2004), “The prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed”).
Regarding (c): Applicant next argues that “Belanoff discusses daily miricorilant administration” and that “nothing in Belanoff, or in Goodman & Gilman, nor in their combination, suggests that reducing miricorilant administration to only twice-weekly or thrice-weekly administration, would be effective to reduce liver fat in a patient” (Applicant Arguments, Page 8).
Yet, as discussed in the previous Action (Paragraphs 34-38) and reiterated below, it is necessarily the case that the prima facie obvious administration of miricorilant taught by the prior art – in the same amount and according to the same regimen to the same patient population having a baseline liver fat content of a patient greater than about 5% of liver tissue as measured by MRI-PDFF to treat the same condition therein as instantly claimed – would necessarily reduce the amount of the patient’s liver fat, as measured by MRI-PDFF, as compared to the patient’s baseline liver fat content as measured by MRI-PDFF.
Applicant, however, argues that “inherency can contribute to obviousness only when the inherent feature would have been expected by skilled artisans at the time of invention. If a property was hidden or unappreciated at the time, it generally cannot be used retroactively to argue obviousness” (Applicant Arguments, Page 9).
The argument is not found persuasive. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the time of invention, but only that the subject matter is in fact inherent in the prior art reference (see Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003), rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency; see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004), “the fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention”; Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed.Cir.1999), “If a product that is offered for sale inherently possesses each of the limitations of the claims, then the invention is on sale, whether or not the parties to the transaction recognize that the product possesses the claimed characteristics”; Atlas Powder Co. v. Ireco, Inc., 190 F.3d 1342, 1348-49, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999), “Because ‘sufficient aeration’ was inherent in the prior art, it is irrelevant that the prior art did not recognize the key aspect of [the] invention.... An inherent structure, composition, or function is not necessarily known”).
Regarding (d): Applicant argues that “the combination of cited references… lacks suggestion that… miricorilant administration must be twice-weekly or thrice-weekly… and thus fails to provide methods that are substantially identical to the present claims” (Applicant Arguments, Page 11) to support the conclusion that the prior art method would
The argument is not found persuasive. 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 (CCPA 1981); In re Merck & Co., 800 F.2d 1091 (Fed. Cir. 1986). In the instant case, the combination of prior art teach the same method of treating a fatty liver disease comprising administering the same agent, miricorilant, in the same amount and according to the same dosing regimen, to the same patient population having the same baseline liver fat content of greater than about 5% of liver tissue as measured by the same technique, MRI-PDFF, as instantly claimed.
For all of the foregoing reasons, Applicant’s arguments are not found persuasive.
Claim Objections
Claim 1 is objected to for the following reason:
Claim 1 recites the step of “[m]easuring a baseline liver fat content of a patient by MR-PDFF” which should recite the step of “[m]easuring a baseline liver fat content of a patient by MRI-PDFF”.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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 1-4, 6-7, 10-14, 16-17 and 20-22 are rejected under 35 U.S.C. 103(a) as being unpatentable over Belanoff et al (US 2019/0151318; of record) in view of Goodman & Gilman’s The Pharmacological Basis of Therapeutics (11th Edition, Pages 14-22, 2006; of record), Caussy et al (Hepatology 68:763-772, 2018) and Tang et al (Abdom Imaging 40:26-37, 2015).
As amended, claim 1 is drawn to a method of treating a fatty liver disorder (more specifically, NAFLD (claim 3), even more specifically NASH (claim 4)) in a patient suffering therefrom – said patient suffering from a baseline amount of liver fat content greater than about 5% of liver tissue as measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) and having (i) a baseline level of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) and (ii) a baseline liver volume – the method comprising:
measuring a baseline liver fat content of a patient by MRI-PDFF;
identifying a patient having a baseline liver fat content greater than about 5% of liver tissue;
determining a baseline level of alanine aminotransferase (ALT) and/or of aspartate aminotransferase (AST) as well as a baseline liver volume in said patient identified as having a baseline liver fat content greater than about 5% of liver tissue;
administering (orally (claim 7)) to said identified patient thrice-weekly doses, for at least twelve weeks (more specifically, in doses of about 75 mg, about 100 mg, or about 150 mg (claim 10)) of (E)-6-4-(4-phenylcyclohexyl)-5-(3-trifluoromethylbenzyl)-1H-pyrimidine-2,4-dione (aka miricorilant) having the following structure:
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effective to:
reduce said amount of the patient’s liver fat, as measured by MRI-PDFF, as compared to the patient’s baseline liver fat content as measured by MRI-PDFF; and
treat said fatty liver disorder.
Claim Interpretation:
Regarding the recitation of administering miricorilant “effective to reduce said amount of the patient’s liver fat, as measured by MRI-PDFF, as compared to the patient’s baseline liver fat content as measured by MRI-PDFF” - as currently drafted, while the claim requires that administering miricorilant thrice-weekly for at least twelve weeks to the subject suffering from a fatty liver disorder bring about a reduction in amount of the patient’s liver fat, as measured by MRI-PDFF, as compared to the patient’s baseline liver fat content as measured by MRI-PDFF, the claim does not require the active step of measuring and determining said reduction in liver fat content, including by using MRI-PDFF.
Basis of the Rejection:
Belanoff et al teach the “treatment of fatty liver disease using a class of pyrimidinedione cyclohexyl compounds” (Abstract), wherein:
“the fatty liver disease is… nonalcoholic steatohepatitis (NASH)” (Paragraph 0064) in which “[a]n individual’s liver may be considered to be steatotic when a biopsy reveals at least 5-10% w/w fatty deposits” (Paragraph 0091), further noting that “[i]n an individual suspected of having… NASH, baseline testing of serum may include measuring or determining levels of AST [and/or] ALT” (Paragraph 0087) and “[r]adiological methods such as… magnetic resonance imaging (MRI)… can be used to detect NAFLD” (Paragraph 0088); and
the pyrimidinedione cyclohexyl compound is most preferably the glucocorticoid receptor (GR) modulator miricorilant (Paragraph 0104).
As further taught by Belanoff et al, “[t]he compounds of the present invention can be… administered in a wide variety of oral… dosage forms” (Paragraph 0118) wherein “[t]he quantity of active component in a unit dose preparation may be… most typically 10 mg to 500 mg” (Paragraph 0134). More particularly, Belanoff et al teach “formulations for oral administration” wherein “dosages are from about 1 mg to about 4 mg per kg of body weight per patient per day” (Paragraph 0136) which, based on an average adult weight of about 60 kg to 80 kg, entails a dosage of about 60 mg to about 320 mg per day.
Additionally, Belanoff et al teach that the “[e]fficacy of treatment may be determined by a reduction in one or more… clinical manifestations of a disease as well as any of the tests described… for diagnosis” (Paragraph 0093).
Specifically, Belanoff et al teach:
administering miricorilant daily for 6 weeks to mice results in a reduction of liver fat accumulation by about 60% (Paragraphs 0171-0177, Example 3; see also Figure 4 (compare HF-6wks group (i.e., Group 3 (Paragraph 0175)) with HF-118335-6 wks group (i.e., Group 4 (Paragraph 0176))); and
administering miricorilant daily for 3 weeks to mice results in a reduction of liver fat by about 50% and treats fatty liver disorder (Paragraphs 0171-0177, Example 3; see also Figure 4 (compare HF-6wks group (i.e., Group 3 (Paragraph 0175)) with HF-118335 rev group (i.e., Group 5 (Paragraph 0177))).
As such, the method of Belanoff et al differs from the instantly claimed method in the following ways:
(a) Belanoff et al teach measuring a baseline liver fat content of a patient via MRI and identifying a patient having a baseline liver fat content greater than about 5% of liver tissue but do not teach measuring said baseline liver fat content by MRI-PDFF;
(b) Belanoff et al teach determining a baseline level of alanine aminotransferase (ALT) and/or of aspartate aminotransferase (AST) in said patient but do not teach determining a baseline liver volume in said patient; and
(c) Belanoff et al teach daily administration of miricorilant for a period of 6 weeks but do not teach thrice-weekly administration for a period of at least twelve weeks.
Yet, as to (a): as taught by Caussy et al, “therapeutic trials in NASH require liver biopsy to establish an initial diagnosis of NASH and to document response. However, biopsy is an expensive and invasive procedure that carries potential risks” and, as such, “[n]oninvasive, reliable, accurate, safe, and quantitative biomarkers are needed as an alternative to liver biopsy” (Page 763, Column 2 to Page 764, Column 1). As further taught by Caussy et al, “MRI-PDFF is a quantitative imaging biomarker that enables accurate, repeatable, and reproducible quantitative assessment of liver fat over the entire liver” and “is emerging as one of the leading noninvasive quantitative biomarkers suitable as a surrogate to liver biopsy for assessing treatment response in a subset of NASH trials” (Page 764, Column 1).
Accordingly, based further on Caussy et al, it would have been prima facie obvious to measure the baseline liver fat content of the subject to be treated according to the method of Belanoff et al using MRI-PDFF. At the outset, the simple substitution of one known method for measuring baseline liver fat content in patients suffering from NAFLD/NASH for another known method for measuring baseline liver fat content in patients suffering from NAFLD/NASH is prima facie obvious. Moreover, it would have been obvious to specifically utilize MRI-PDFF in the method of Belanoff et al in order to obtain “accurate, repeatable, and reproducible quantitative assessment of liver fat over the entire liver”, as taught by Caussy et al, with a reasonable expectation of success.
As to (b): as taught by Tang et al, “[t]he hallmark feature of NAFLD is steatosis, the presence of intra-hepatocellular fat vacuoles” and “virtually all methods to evaluate liver fat content, whether tissue- or radiology-based, assess fat content on a fractional basis – the amount of fat per unit area or volume” (Page 2).
However, as further taught by Tang et al, “[m]easuring liver fat content on a fractional basis may be problematic… as liver fat may be distributed heterogeneously, and sampling variability may occur when fractional fat content is quantified only in select portions of the liver” and, “[m]oreover, measuring fractional liver fat content may provide an incomplete picture of total liver fat burden, which relates not only to the fractional fat content but also to liver volume” since “[l]iver volumes vary across the population, and individuals with similar fractional fat content but dissimilar liver volumes will have different total liver fat burdens” (Page 2).
As such, Tang et al teaches a “combination of liver segmentation and MRI-based fat estimation may be used to monitor fraction fat content (as estimated by PDFF), liver volume, and total liver fat burden (as assessed by TLFI) as quantitative imaging biomarkers in clinical trials” (Page 10). As taught by Tang et al, “[m]easurement of these biomarkers may provide a more complete picture of liver fat content and its longitudinal change than traditional measurements based solely on fractional fat content” (Page 10).
Accordingly, based further on Tang et al, it would have been prima facie obvious to measure the liver volume of the subject to be treated according to the method of Belanoff et al. It would have been obvious to do so in order to overcome the problems associated with measuring liver fat content on a fractional basis and “to provide a more complete picture of liver fat content and its longitudinal change than traditional measurements based solely on fractional fat content” with a reasonable expectation of success.
And, as to (c): while Belanoff et al do not specifically teach administration of miricorilant thrice-weekly administration for a period of at least twelve weeks, Belanoff et al do teach that “[t]he state of the art allows the clinician to determine the dosage regimen for each individual patient” (Paragraph 0135), further discussing tailoring administration “depending on the dosage and frequency as required and tolerated by the patient” (Paragraph 0136).
And, as stated by MPEP 2144.05, “[g]enerally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical” (see also In re Aller (220 F.2d 454 (CCPA): “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation…” Indeed, as further discussed by the court, “[s]uch experimentation is no more than the application of the expected skill of the [ordinarily skilled artisan] and failure to perform such experiments would, in our opinion, show a want of the expected skill”; see also In re Peterson, 315 F.3d at 1325 (Fed. Cir. 2005): “[t]he normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages” and “[o]nly if the ‘results of optimizing a variable’ are ‘unexpectedly good’ can a patent be obtained for the claimed critical range” (quoting In re Antonie (559 F.2d 618 (CCPA 1977))).
In the instant case, the dosing regimen and duration of administration of an active ingredient in the treatment of any condition is clearly a result-effective variable as evidenced by Goodman & Gilman’s The Pharmacological Basis of Therapeutics, discussing the “Design and Optimization of Dosage Regimens” (Page 18, Column 2 to Page 21, Column 2) and identifying a variety of “considerations [which] apply after multiple dosing associated with long-term therapy, and [which] determine the amount and frequency of drug administration to achieve an optimal therapeutic effect” (Page 18, Column 2).
Accordingly, in practicing the method of Belanoff et al, it would have been customary for an artisan of ordinary skill in the art to determine the frequency of miricorilant administration and duration of therapy. It would have been obvious to do so “to achieve an optimal therapeutic effect”.
In view of all of the foregoing, it would have been prima facie obvious to carry out the instantly claimed method for the treatment of a fatty liver disorder, in particular NAFLD and even more specifically NASH, with a reasonable expectation of success.
And, in doing so, it is necessarily the case that the prima facie obvious administration of miricorilant – in the same amount and according to the same regimen to the same patient population having a baseline liver fat content of greater than about 5% of liver tissue as measured by MRI-PDFF to treat the same condition therein as instantly claimed – would necessarily reduce the amount of the patient’s liver fat, as measured by MRI-PDFF, as compared to the patient’s baseline liver fat content as measured by MRI-PDFF.
Indeed, Belanoff et al specifically demonstrate a reduction in liver fat accumulation by about 60% and a reduction of liver fat by about 50% following administration of miricorilant (Paragraphs 0171-0177, Example 3; see also Figure 4) and it is asserted, absent evidence to the contrary, that thrice-weekly administration for a period of at least twelve weeks would similarly reduce said amount of the patient’s liver fat, as measured by MRI-PDFF, as compared to the patient’s baseline liver fat content as measured by MRI-PDFF. While the fact that a certain result or characteristic may occur or be present in the prior art is not sufficient to establish the inherency of that result or characteristic (In re Rijckaert, 9 F.3d 1531 (Fed. Cir. 1993); see also In re Robertson, 169 F.3d 743 (Fed. Cir. 1999), “[i]nherency may not be established by probabilities or possibilities”), it is well settled that “inherency may supply a missing claim limitation in an obviousness analysis” so long as “the limitation at issue necessarily must be present or the natural result of the combination of elements explicitly disclosed by the prior art” (PAR Pharm., Inc. v. TWI Pharm., Inc. 773 F.3d 1186 (Fed. Cir. 2014)). “If… the disclosure is sufficient to show that the natural result flowing from the operation as taught would result in the performance of the questioned function, it seems to be well settled that the disclosure should be regarded as sufficient” (quoting In re Oelrich, 666 F.2d 578 (C.C.P.A. 1981). Thus, as stated by the court in PAR Pharm., Inc. v. TWI Pharm., Inc., “inherency... is present… when the limitation at issue is the ‘natural result’ of the combination of prior art elements” (Id.). And, as stated by the court in In re Dillon (919 F.2d 688 (Fed. Cir. 1990)), “it is not necessary in order to establish a prima facie case of obviousness… that there be a suggestion in or expectation from the prior art that the claimed [invention] will have the same or similar utility as one newly discovered by applicant”.
While the court in PAR Pharm., Inc. v. TWI Pharm., Inc. further indicates that “the concept of inherency must be limited when applied to obviousness” and “[a] party must… meet a high standard in order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis”, it must also be remembered that the U.S. Patent Office is not equipped with analytical instruments to test prior art compositions for the infinite number of ways that a subsequent Applicant may present previously unmeasured characteristics. As such, a prior art disclosure of a product or method “appearing to be substantially identical” to that instantly claimed, and rationale or evidence “tending to show inherency”, shifts the burden to the Applicant to prove otherwise (MPEP 2112 (IV)-(V)). As stated in In re Best, Bolton, and Shaw (562 F2d 1252 (CCPA 1977)), “[w]here… the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product” (see also In re Fitzgerald 619 F2d 67 (CCPA 1980): the burden is shifted to the applicants to “prove that subject matter shown to be in the prior art does not possess characteristic relied on”).
This is especially true in cases where the newly discovered, inherent limitation is claimed functionally rather than structurally. For example, in In re Kubin (561 F.3d 1351 (Fed. Cir. 2009)), discussing claims drawn to an isolated nucleic acid molecule encoding a polypeptide “wherein the polypeptide binds CD48”, the court stated that there is “no obligation to predicate [an] obviousness finding on factual findings regarding a prior art teaching of [the polypeptide’s] binding to the CD48 protein” – the limitation is “not an additional requirement imposed by the claims on the [polypeptide], but rather a property necessarily present in” the polypeptide. As stated by the court in Santarus, Inc. v. Par Pharm., Inc., 694 F.3d 1344 (Fed. Cir. 2012), “[t]o hold otherwise would allow any formulation – no matter how obvious – to become patentable merely by testing and claiming an inherent property” (discussing claims drawn to methods of administering a active agent “wherein upon oral administration… an initial serum concentration of the [active agent] greater than about 0.1 µg / ml is obtained at any time within about 30 minutes after administration” and further noting that “[t]he initial blood serum concentration resulting from administering [the active agent] is an inherent property of the formulation, and an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations”).
In the instant case, the claimed and prior art methods are substantially identical. As such, absent evidence to the contrary, it is asserted, absent evidence to the contrary, that the prima facie obvious method of treating NASH taught by Belanoff et al comprising thrice-weekly administration or miricorilant for a period of at least twelve weeks to a patient in need thereof would necessarily reduce said amount of the patient’s liver fat, as measured by MRI-PDFF, by compared to the patient’s baseline liver fat content as measured by MRI-PDFF.
As such, claims 1, 3-4, 7 and 10 are rejected as prima facie obvious.
Claim 2 is drawn to the method of claim 1, wherein said method of treatment is effective to reduce the volume of the patient’s liver as compared to said baseline liver volume.
For the same reasons as discussed above, it is asserted, absent evidence to the contrary, that the prima facie obvious method of treating NASH based primarily on Belanoff et al would necessarily reduce the volume of the patient’s liver as compared to said baseline liver volume.
As such, claim 2 is also rejected as prima facie obvious.
Claim 6 is drawn to the method of claim 1 wherein the patient suffers from liver fibrosis.
As taught by Belanoff et al, “NASH… is characterized by… fibrosis” (Paragraph 0083) and “NASH can be diagnosed using histopathological methods on liver samples to assess… fibrosis” (Paragraph 0089).
As such, claim 6 is also rejected as prima facie obvious.
As amended, claim 11 is drawn to a method of treating a fatty liver disorder (more specifically, NAFLD (claim 13), even more specifically NASH (claim 14)) in a patient suffering therefrom – said patient suffering from a baseline amount of liver fat content greater than about 5% of liver tissue as measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) and having (i) a baseline level of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) and (ii) a baseline liver volume – the method comprising:
measuring a baseline liver fat content of a patient by MRI-PDFF;
identifying a patient having a baseline liver fat content greater than about 5% of liver tissue;
determining a baseline level of alanine aminotransferase (ALT) and/or of aspartate aminotransferase (AST) as well as a baseline liver volume in said patient identified as having a baseline liver fat content greater than about 5% of liver tissue;
administering (orally (claim 17)) to said identified patient twice-weekly doses, for at least twelve weeks (more specifically, in doses of about 75 mg, about 100 mg, or about 150 mg (claim 20)) of (E)-6-4-(4-phenylcyclohexyl)-5-(3-trifluoromethylbenzyl)-1H-pyrimidine-2,4-dione (aka miricorilant) having the following structure:
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effective to:
reduce said amount of the patient’s liver fat, as measured by MRI-PDFF, as compared to the patient’s baseline liver fat content as measured by MRI-PDFF;
treat said fatty liver disorder; and
(as further recited by claim 12) reduce the volume of the patient’s liver as compared to said baseline liver volume.
As such, the method of claims 11-14, 17 and 20 is identical to the method of claims 1-4, 6-7 and 10 except that the method of claims 11-14, 17 and 20 comprises twice-weekly doses for at least twelve weeks, as opposed to thrice-weekly doses for at least twelve weeks.
Yet, for the same reasons as discussed above, it would have been customary for an artisan of ordinary skill in the art to determine the frequency of miricorilant administration and duration of therapy. It would have been obvious to do so “to achieve an optimal therapeutic effect”.
As such, claims 11-14, 17 and 20 are also rejected as prima facie obvious.;
As amended, claim 16 is drawn to the method of claim 11 wherein the patient suffers from a baseline level of liver fibrosis and wherein said administering twice-weekly doses, for at least twelve weeks, of miricorilant is effective to reduce the level of liver fibrosis in said patient in comparison to said baseline level of liver fibrosis, and treat said liver fibrosis in said patient.
As discussed above, Belanoff et al teach that “NASH… is characterized by… fibrosis” (Paragraph 0083) and “NASH can be diagnosed using histopathological methods on liver samples to assess… fibrosis” (Paragraph 0089). And, for the same reasons as discussed above, it is asserted, absent evidence to the contrary, that twice-weekly administration of miricorilant for at least twelve weeks would reduce the level of liver fibrosis in said patient in comparison to said baseline level of liver fibrosis, and treat said liver fibrosis in said patient.
As such, claim 16 is also rejected as prima facie obvious.
Claims 21-22 are drawn to the methods of claims 1 and 11, respectively, wherein said miricorilant administration ceases at least twelve weeks after beginning said miricorilant administration, and said levels of ALT and/or AST in the patient remain or return to near said baseline levels of ALT and/or AST following cessation of said miricorilant administration.
As discussed above, Belanoff et al teach that “[t]he state of the art allows the clinician to determine the dosage regimen for each individual patient” (Paragraph 0135). Additionally, Belanoff et al teach administering miricorilant daily for 6 weeks to mice and administering miricorilant daily for 3 weeks to mice, after which treatment ceases (Paragraphs 0171-0177, Example 3; see also Figure 4). And for the same reasons discussed above, it is asserted, absent evidence to the contrary, that the levels of ALT and/or AST in the patient would necessarilyl remain or return to near said baseline levels of ALT and/or AST following cessation of said miricorilant administration in the method taught by Belanoff et al.
As such, claims 21-22 are also rejected as prima facie obvious.
Conclusion
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611