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 .
Response to Amendments
No amendment to the claims has been presented.
Response to Arguments
The examiner’s response set forth below is similar to his previous response as Applicant’s arguments are similar to those set forth in Applicant’s arguments of February 11, 2025.
Applicant argues that Takizawa does not disclose or teach treating NAFLD or reducing fat deposition in the liver. Further, Leighton suggests nothing about NAFLD being associated with increased visceral fat. Applicant argues that the claimed effects are not predictable in view of the prior art. Applicant argues that “merely overlapping of patient population or targets” does not provide a reasonable expectation of success.
The examiner notes that the combination of prior art establishes much more than merely overlapping subject populations.
Takizawa teaches the claimed agent to be a promoter of production of FGF21, which will reduce visceral fat and treat obesity. The nexus between reducing visceral fat and treating obesity and treating NAFLD and NASH is set forth by Leighton and Coskun.
Leighton teaches adipose tissue has a primary role in the pathogenesis of non-alcoholic fatty acid liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), namely the central (or upper body) obesity phenotype associated with increased visceral fat. The nexus between the claimed subject population and visceral fat is expounded upon below:
Adipose tissue has a primary role in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), namely the central (or upper body) obesity phenotype associated with increased visceral fat. Studies have shown that the amount of intra-hepatocellular lipids increases by approximately 20% for any 1% increase in total or subcutaneous adipose tissue, but doubles for any 1% increase in intra-abdominal adipose tissue. Therefore, even modest increases in visceral fat (in the absence of increased body mass index (BMI)) may cause steatosis (Bugianesi E., et al., Diabetologia (2005) 48:634-642).
Even further, Coskun teaches FGF21 is a metabolic regulator that increases energy expenditure, fat utilization, lipid excretion, and reduced hepatosteatosis, among other things. The data suggest that FGF21 exhibits therapeutic characteristics to treat obesity and fatty liver disease as well as mitigate the pathogenesis of NAFLD and NASH.
Applicant argues that none of the references have performed treatment with the claimed, specific compound.
The examiner notes that the prior art is enabled. Actual treatment is not required to render obvious or enable prior art. The nexus linking the effect of the claimed compound as a known FGF21 promoter to treatment of claimed conditions is well-established and described by the prior art such that a reasonable expectation of success is established that the claimed agent can treat the claimed conditions as a promoter of production of FGF21, which will reduce visceral fat, treat obesity, and treat fatty liver disease at claimed dosages. Moreover, Coskun explicitly teaches FGF21 will treat fatty liver disease. The references are applied as a whole for all that they teach.
As such, no claim is allowed.
Claim of Priority
The examiner notes that Applicant’s foreign priority documents have been received. However, while not presently relevant, foreign priority has not been perfected because an English language translation of the foreign priority document has not been received by the Office.
Status of the Claims
Claims 5-16 are pending. Claim 8 is withdrawn. Claims 5-7 and 9-16 are examined.
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.
Claims 5-7, 9, and 11-16 are rejected under 35 U.S.C. 103 as being unpatentable over Takizawa et al. (U.S. 2012/0165377) in view of Leighton (U.S. 8,765,694), in view of Coskun et al., “Fibroblast Growth Factor 21 Corrects Obesity in Mice,” Endocrinology December 2008, 149(12):6018-6027, in view of Boettcher et al. (2012/0129766).
Takizawa et al. teach a method of reducing visceral fat with administration of an effective amount of the claimed compound or a salt thereof (claims 1-12 and 27). The present invention may employ a solvate of the compound which includes a hydrate. More particularly, Takizawa teaches the claimed compound to act as a promoter of production of FGF21, which will reduce visceral fat and treat obesity. See prior art claim 1, e.g. Takizawa et al. are silent on the treatment of nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis. Takizawa teaches an alcohol solvate and ethanol solvate as an example. See par. 75. Takizawa teaches using compound A (i.e., the claimed compound) in an amount of 1 mg/kg and 3 mg/kg, e.g. This equates to 70 mg in a 70 kg human and 210 mg in a 70 kg subject. Each of these amounts fall within the broad range that is claimed and the optimization (even if necessary) of a known result-effective variable with a known mechanism of action would be obvious absent evidence of a criticality. See M.P.E.P. § 2144.05.
Leighton teaches that adipose tissue has a primary role in the pathogenesis of non-alcoholic fatty acid liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), namely the central (or upper body) obesity phenotype associated with increased visceral fat. Even modest increased in visceral fat may cause steatosis (column 2, lines 54-64).
Coskun teaches FGF21 is a metabolic regulator that increased energy expenditure, fat utilization, lipid excretion, and reduced hepatosteatosis, among other things. The data suggest that FGF21 exhibits therapeutic characteristics to treat obesity and fatty liver disease. See abstract. Systemic administration of FGF21 with a range of doses/delivery routes led to profound improvement in steatohepatitis. Coskun explains the following on page 6018.
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Moreover, Boettcher teaches a new polypeptide FGF21 that has improved pharmaceutical properties and it treat FGF21-associated disorders including obesity, metabolic disorders, and NASH. See par. 1. FGF21 is a potent metabolic regulator and taught to treat a patient by administering a FGF21 polypeptide or protein variant, wherein the subject has a metabolic disorder, NASH, among others. See prior art claims 15 and 16.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to administer the claimed compound to treat nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis. One would have been motivated to do so because Takizawa teaches a claimed agent to promote FGF21 and reduce visceral fat and obesity. Coskun teaches that FGF21 will treat obesity and fatty liver disease and was shown to reduce hepatosteatosis when administered systemically and through various routes of administration. Moreover, Boettcher teaches a more stable FGF21 polypeptide and teaches administering an FGF21 or a variant thereof to treat obesity, a metabolic disorder or NASH, among other conditions. As such, there is a reasonable and predictable expectation of treating a fatty liver disease by administering an agent that promotes FGF21 because FGF21 is taught to treat metabolic disorders, including fatty liver diseases, as well as steatohepatitis and NASH.
Claim 10 is rejected under 35 U.S.C. 103(a) as being unpatentable over Takizawa et al. (U.S. 2012/0165377) in view of Leighton (U.S. 8,765,694), in view of Coskun et al., “Fibroblast Growth Factor 21 Corrects Obesity in Mice,” Endocrinology 149(12):6018-6027, in view of Boettcher et al. (2012/0129766), and further in view of Remington’s Pharmaceutical Sciences (Sixteenth Edition; 1980, p.420-425) and Berge et al. ("Pharmaceutical Salts", Journal of Pharmaceutical Sciences, 66(1); 1977:1-19).
The combination of Takizawa et al. (U.S. 2012/0165377) in view of Leighton (U.S. 8,765,694), in view of Coskun et al., “Fibroblast Growth Factor 21 Corrects Obesity in Mice,” Endocrinology 149(12):6018-6027, in view of Boettcher et al. (2012/0129766) is set forth supra. The combination differs by not reciting the salt forms recited in claim 10.
Remington’s Pharmaceutical Sciences (p.420-425) teaches that drugs are formulated into salts to modify the duration of action of a drug; to modify the transportation and distribution of the drug in the body; to reduce toxicity; and to overcome difficulties encountered in pharmaceutical formulation procedures or in the dosage form itself (col.2, p.424, para.1).
Berge et al. teaches a variety of salt forms approved for use by the Food and Drug Administration (FDA) (see Table I, p.2), such as, inter alia, the benzoate salt, citrate salt, hydrochloride salt, malate salt, mesylate salt, nitrate salt, phosphate salt, sulfate salt, tartrate salt, etc.
One of ordinary skill in the art at the time of the present invention would have found it prima facie obvious to employ a salt formulation of the claimed compound because, as evidenced by Remington’s, pharmaceutical salt formulations are known to modify the duration of action of a drug, modify the transportation and distribution of the drug in the body, reduce toxicity, and to overcome difficulties encountered in pharmaceutical formulation procedures or in the dosage form itself. Thus, it would have been prima facie obvious to the skilled artisan motivated by any one or more of these factors to formulate a salt form of the claimed compound into a pharmaceutically acceptable salt to enhance the pharmacokinetic parameters of the drug or to reduce the toxicity with the reasonable expectation that the therapeutic benefit of the agent in salt form would have been the same or substantially similar to that of the parent amphetamine compound itself. Furthermore, one of ordinary skill in the art at the time of the invention would have found it prima facie obvious to employ, e.g., the benzoate salt, citrate salt, hydrochloride salt, malate salt, mesylate salt, nitrate salt, phosphate salt, sulfate salt, or tartrate salt, etc. of such a compound because Berge et al. teaches that these salts are known in the art to be one or more of a finite number of pharmaceutically acceptable salts usable for formulating pharmaceutical compositions at the time of the invention. As a result, one of ordinary skill in the art at the time of the invention would have found it prima facie obvious to employ any of these known pharmaceutically acceptable salts to elicit the advantages disclosed by Remington’s with a reasonable expectation of success because (1) a person with ordinary skill in the art has good reason to pursue known options within his or her technical grasp and (2) Berge et al. teaches the equivalency of such salt forms for pharmaceutical use and (3) Remington’s teaches clear benefits to using pharmaceutical agents in salt form.
As such, no claim is allowed.
Conclusion
THIS ACTION IS MADE FINAL. 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 extension fee 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 JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 571-272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JARED BARSKY/Primary Examiner, Art Unit 1628