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 .
Continued Examination Under 37 CFR 1.114 and
Application Status
2. 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 7, 2026 has been reviewed by the examiner and entered of record in the file.
3. Claim 1 is amended.
4. Claims 1, 3 and 7-9 are under examination and are the subject of this office action.
Previous Claim Rejections - 35 USC § 103
5. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
6. Claims 1, 3, and 9 remain rejected under 35 U.S.C. 103 as being unpatentable over Zeiler et al., Bioorg. Med. Chem. (2012), in view of Niphakis and Cravatt, Annual Review of Biochemistry (2014), and further in view of Tucci et al., Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy (2010).
Claim 1, as amended, is drawn to a method of treating obesity, comprising administering to an individual in need thereof a therapeutically effective amount of an inhibitor of ClpP, wherein the inhibitor of ClpP is (3RS,4RS)-3-(non-8-en-1-yl)-4-(2-(pyridine-3-yl)ethyl)oxetan-2-one, (A2-32-01), wherein the amount is effective for decreasing fat tissue in the individual, preventing weight gain in the individual, increasing insulin sensitivity and/or increasing glucose tolerance of the individual.
Claim 9 is drawn to claim 1, further comprising a step of measuring insulin sensitivity of the individual.
7. Zeiler et al. disclose the ClpP inhibitory activity of b-lactones, in particular, the b-lactone Compound 2 (wherein “X” =N), which is the same as Applicant’s instantly claimed compound: ((3RS,4RS)-3-(non-8-en-1-yl)-4-(2-(pyridine-3-yl)ethyl)oxetan-2-one):
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(see Figure 2A and Figure 5). Zeiler et al. teach that “[t]he lactone 2 was found to fully inhibit ClpP peptidase activity,” (page 584, left column, first full paragraph). Zeiler et al. is silent to the treatment of obesity.
8. However, Niphakis discusses a library of b-lactones having ClpP inhibitory activity: “Click chemistry was used to identify the targets of a diverse library of clickable β-lactones, leading to the discovery of selective caseinolytic protein protease (ClpP) inhibitors,” (see page 361, Figure 8 summary). Niphakis teaches that the b-lactone THL (aka Orlistat or Xenical®) is known for the treatment of obesity (page 360, right column, last paragraph).
9. And, Tucci et al. teach that the b-lactone THL has been evaluated in many clinical studies for the treatment of obesity, followed by a measurement of insulin resistance, i.e., the administration of THL at therapeutically effective doses of 373 mg and 750 mg/day increased fat elimination and a dose of 120 mg taken three times/day achieved significant weight loss and resulted in “significantly decreased glycemia, glycated hemoglobin, insulin resistance and cardiovascular disease risk factors,” [emphasis added] (page 133, right column, lines 15-17, 21-22 and 27-29). And, by decreasing insulin resistance, one is necessarily increasing insulin sensitivity.
10. As such, one skilled in the art would have have reasonably expected that the mechanism of inhibiting ClpP, demonstrated by THL as being effective for treating obesity, would be present in Applicant’s instantly recited Compound 2. Thus, one of skill in the art would have been motivated to substitute the b-lactone Compound 2 (aka A2-32-01) for THL in the treatment of obesity, with a reasonable expectation of success. And, as noted by the court in In re Font, 675 F.2d 297 (CCPA 1982), an express suggestion to substitute one equivalent component (i.e., a similar b-lactone) for another is not necessary to render such substitution obvious. In the instant case, (1) the prior art element of Niphakis and Tucci performs the function specified in the claim with only insubstantial differences (i.e., b-lactone having ClpP inhibitory activity for treating obesity); (2) the claimed component (i.e., the b-lactone (3RS,4RS)-3-(non-8-en-1-yl)-4-(2-(pyridine-3-yl)ethyl)oxetan-2-one) and its function (ClpP inhibitory activity) was known in the art; (3) a person of ordinary skill in the art would have recognized the interchangeability of the elements and could have substituted one known element for another; and (4) the results of the substitution would have been predictable, i.e., a reasonable expectation of success in the treatment of obesity in an individual in need thereof. Thus one of skill in the art before the effective filing date of the claimed invention would have been motivated to treat an individual with obesity by administering a therapeutically effective amount of the compound (3RS,4RS)-3-(non-8-en-1-yl)-4-(2-(pyridine-3-yl)ethyl)oxetan-2-one), with a reasonable expectation of success.
As such, claims 1 and 9 are prima facie obvious.
Claim 3 is drawn to claim 1, wherein the inhibitor of ClpP is administered such that reduction of ClpP expression is liver-specific, and the amount administered is effective for increasing insulin sensitivity of the individual.
11. Claim 3 is drafted in terms of the intended outcome of the administration of the ClpP inhibitor (3RS,4RS)-3-(non-8-en-1-yl)-4-(2-(pyridine-3-yl)ethyl)oxetan-2-one: “...wherein the inhibitor of ClpP is administered such that a reduction of ClpP expression is substantially liver-specific.” However, a claimed composition maybe obvious because it was suggested by, or structurally similar to, a prior art composition even though a particular benefit of the claimed composition asserted by patentee is not expressly disclosed in the prior art. It is the differences in fact in their respective properties which are determinative of nonobviousness. If the prior art composition does in fact possess a particular benefit, even though the benefit is not recognized in the prior art, Applicant's recognition of the benefit is not in itself sufficient to distinguish the claimed composition from the prior art, In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1991). In this case, the reduction of ClpP expression in the liver is considered a latent property of the known ClpP inhibitor (3RS,4RS)-3-(non-8-en-1-yl)-4-(2-(pyridine-3-yl)ethyl)oxetan-2-one disclosed by Zeiler et al. and the alleged unexpected result does not confer patentability.
As such, claim 3 is prima facie obvious.
12. Claims 7 and 8 remain rejected under 35 U.S.C. 103 as being unpatentable over Zeiler et al., Bioorg. Med. Chem. (2012), in view of Niphakis and Cravatt, Annual Review of Biochemistry (2014), and Tucci et al., Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy (2010), as applied to claims 1, 3 and 9, above, and further in view of Cole et al., Cancer Cell (2015, cited on Applicant’s IDS of August 2, 2022).
Claim 1 is addressed in detail, above.
Claim 7 is drawn to claim 1, wherein the ClpP inhibitor is delivered directly to the individual’s liver, and the amount administered is effective for increasing insulin sensitivity of the individual. Claim 8 is drawn to claim 1, wherein the administration comprises local injection.
13. Zeiler et al. in view of Niphakis and Tucci et al. suggest a method of treating obesity comprising administering the b-lactone small molecule ClpP inhibitor (3RS,4RS)-3-(non-8-en-1-yl)-4-(2-(pyridine-3-yl)ethyl)oxetan-2-one to an individual in need thereof, but do not teach administration via local injection.
14. Yet, Cole et al. teach the administration of (3RS,4RS)-3-(non-8-en-1-yl)-4-(2-(pyridine-3-yl)ethyl)oxetan-2-one (aka Compound A2-32-01) via intraperitoneal injection, (page 873, Figure 7 summary at top of page). Intraperitoneal injection is a local injection. And, optimization of parameters such as route of administration is a routine practice that would be obvious for a person of ordinary skill in the art to employ. Nothing unobvious is seen in one of skill in the art optimizing the location of local injection, as method of administration is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize given the guidance of the prior art. Thus it would have been obvious to one of skill in the art before the effective filing date of the claimed invention to administer compound A2-32-01 via local injection
As such, claims 7 and 8 are prima facie obvious.
Response to Arguments
15. Applicant traverses the previous obviousness rejection of claims 1, 3, and 9, over Zeiler, in view of Niphakis and Cravatt, and of claims 7 and 8 further in view of Tucci, and argues the following:
Applicant argues that orlistat and A2-32-01 are beta-lactones, yet the compounds differ in their C4 side chains, stereochemistry, molecular weight, and utility. Applicant argues that orlistat is a gut-restricted covalent inhibitor of pancreatic/gastric lipases for obesity, while Zeiler discloses A2-32-01 narrowly as an anti-virulence agent against S. aureus via ClpP dysregulation.
Applicant alleges that given their structural and functional differences, one of skill in the art would have no motivation to substitute the structurally dissimilar A2-32-01 for orlistat in obesity therapy.
16. Applicant's arguments have been fully considered but they are not persuasive. In response to Applicant’s argument that orlistat (THL) and A2-32-01 are structurally dissimilar; even if two compounds do not share a large portion of their structures in common, both compounds are known to inhibit ClpP, i.e., the mechanism of action of inhibiting ClpP is the same, and therefore one skilled in the art would expect that said mechanism would be effective in the treatment of obesity. And, Bhaskaran et al. (EMBO 2018) teach that ClpP knockout (ClpP -/-) mice have reduced adiposity and improved insulin sensitivity, which protects them from diet-induced obesity, glucose intolerance, and insulin resistance (see abstract).
Thus, Zeiler is relied upon for teaching the beta-lactone compound A2-32-01, which is the same compound that is instantly recited by Applicant. Tucci is relied upon for teaching the administration of a therapeutically effective amount of the beta-lactone orlistat (aka THL) for the treatment of obesity, “the administration of THL at therapeutically effective doses of 373 mg and 750 mg/day increased fat elimination,” (page 133, right column). Thus, it would have been obvious to one skilled in the art before the effective filing date of the claimed invention to substitute one beta-lactone for another, i.e., A2-32-01 for orlistat, with the expectation that the shared mechanism would still be effective for treating obesity in an individual in need thereof.
17. Applicant is additionally reminded that the patient population is still not defined, i.e., the claim does not recite administration for treating obesity in a subject “in need thereof.” In claim 1, the preamble recites a method of “treating obesity,” however, the patient population is not defined as the claim does not recites treating a disease/ disorder/condition in a subject in need thereof, rather, the claim is drawn to “treating obesity comprising administering to an individual in need thereof.” That is, the preamble recites treating obesity, not a method of treating obesity in an individual in need thereof. It is recommended that the claim be drafted as: “A method of treating obesity in an in an individual in need thereof...[language omitted]”.
Conclusion
18. In conclusion, claims 1, 3, and 7-9 are pending in the application. Claims 1, 3 and 7-9 are rejected. No claim is presently allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached on Monday-Friday 8:30AM-5PM EST.
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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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/JANET L COPPINS/Examiner, Art Unit 1628
/AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
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