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 Amendment and
Status of the Claims
2. Applicant’s amendment and response, submitted September 29, 2025, has been reviewed by the examiner and entered of record in the file. Claims 1 and 3 are amended, and claims 2 and 4-6 are canceled.
3. Claims 1, 3 and 7-9 are under examination and are the subject of this office action.
Information Disclosure Statement
4. Applicant’s Information Disclosure Statement (IDS), submitted October 10, 2025, is in compliance with the provisions of 37 CFR 1.97, and have been considered by the examiner. Please refer to the signed copy of Applicant’s PTO-1449 forms, attached herewith.
Previous Claim Rejections - 35 USC § 112(b)
5. Claims 1 and 3 were previously rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
7. Claim 1 was previously rejected for the recitations of “decreasing an amount” and “preventing or reducing weight gain of the individual.” In view of Applicant’s amendatory changes to clarify that the amount is effective for decreasing fat tissue in the individual, or preventing weight gain of the individual, the previous indefiniteness rejection is overcome and is withdrawn.
8. Claim 3 was previously rejected for reciting the limitation “wherein the ClpP is administered such that reduction of ClpP expression is substantially liver-specific.” In view of Applicant’s amendment to clarify that the reduction of ClpP expression is liver-specific, the previous indefiniteness rejection is overcome and is withdrawn.
Previous Claim Rejections - 35 USC § 112(a)
9. Claims 1, 3 and 7-9 were previously rejected under 35 U.S.C. 112(a) as lacking enablement for treating all types of liver disease and diabetes comprising the administration of any/all of the other compound species encompassed by “an inhibitor of ClpP.”
10. In view of Applicant’s amendment to limit the genus of ClpP inhibitors to be administered to the species A2-32-01 and limit the disorder to be treated to obesity, the previous enablement rejection is overcome and is withdrawn.
Previous Claim Rejections - 35 USC § 103
11. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
12. 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 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.
13. 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.
14. 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).
15. 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.
16. As such, one skilled in the art would have been motivated to substitute the b-lactone Compound 2 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.
17. 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.
18. Claims 7 and 8 are 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.
19. 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.
20. 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
21. Applicant traverses the previous obviousness rejection of claims 1, 3, and 9, over Zeiler, in view of Niphakis and Cravatt and further in view of Tucci, and argues the following points:
(i) Applicant argues that Zeiler is limited to bacterial ClpP and never suggests a mammalian therapeutic use. Applicant alleges that Zeiler investigates five b-lactones solely as anti-virulence agents against Staphylococcus aureus, and provides no teaching or suggestion that mammalian ClpP exists, let alone that its inhibition could treat obesity. Applicant contends that Zeiler is focused exclusively on anti-infective chemistry.
22. Applicant's arguments have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, 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).
While Zeiler does not teach the inherent property of the instantly claimed compound to treat an individual with obesity, this result flows from the administration step itself. MPEP § 2112 (II) states "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. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003)." Furthermore, Integra Life Sciences I Ltd. v. Merck KGaA, 50 USPQ2d 1846 (DC SCalif, 1999) makes clear that a reference teaching a process may anticipate claims drawn to a method comprising the same process steps, despite the recitation of a different intended use in the preamble or the later discovery of a particular property of one of the starting materials or end products.
23. Applicant is additionally reminded that a preamble is generally not accorded any patentable weight where it merely recites the purpose of a process or the intended use of a structure, and where the body of the claim does not depend on the preamble for completeness but, instead, the process steps or structural limitations are able to stand alone. See In re Hirao, 535 F.2d 67, 190 USPQ 15 (CCPA 1976) and Kropa v. Robie, 187 F.2d 150, 152, 88 USPQ 478, 481 (CCPA 1951).
24. In the instant case, the patient population is not defined, the claim does not recite administration to a subject “in need thereof,” and the active step (i.e., administration of a therapeutically effective amount of the compound A2-32-01 to an individual is suggested by Zeiler in view of Tucci.
See also Hoffer v. Microsoft Corp., 405 F.3d 1326 (Fed. Cir. 2005), noting that a “whereby clause in a method claim is not given weight when it simply expresses the intended result of a process step positively recited” (quoting Minton v. Nat ’l Ass ’n of Securities Dealers, Inc., 336 F.3d 1373 (Fed. Cir. 2003)). Although the Hoffer court was discussing the weight of a whereby clause, the reasoning applies equally to the weight of a preamble. In the instant case, as discussed above, the wherein clauses in the last 3 lines of the claim (i.e., decreasing fat tissue in the individual, preventing weight gain of the individual, increasing insulin sensitivity of the individual, and/or increasing glucose tolerance of the individual) simply expresses the intended result of a process step positively recited, (i.e., administering a therapeutically effective amount of A2-32-01).
See also In re King, 801 F.2d 1324 (Fed. Cir. 1986), noting that “[u]nder principles of inherency, if a structure in the prior art necessarily functions in accordance with the limitations of a process or method claim of an application, the claim is anticipated. This is not to say that the discovery of a new use for an old structure based on unknown properties of the structure might not be patentable to the discoverer as a process... [but] if a previously patented device, in its normal and usual operation will perform the function which an appellant claims in a subsequent application for a process patent, then such application for process patent will be considered to have been anticipated by the former patented device.”
25. As such, 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 compounds similar in structure will have similar properties, for administration to an individual in a therapeutically effective amount that is effective for decreasing fat tissue in the individual.
(ii) Applicant argues that Niphakis does not remedy the deficiencies of Zeiler, because Niphakis does not disclose or suggest treating obesity with ClpP inhibition. Applicant alleges that the only obesity-related content is a single sentence noting that the serine-hydrolase inhibitor orlistat (tetrahydrolipstatin) is an FDA-approved pancreatic lipase inhibitor for weight loss (p. 360, right column), and Niphakis fails to mention ClpP, b-lactones or mitochondrial processes.
26. Applicant's arguments have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, Niphakis is relied upon for teaching that a library of beta-lactones demonstrated ClpP inhibitory activity (see Figure 8a, page 361), wherein the antiobesity drug orlistat is a known beta-lactone.
27. In response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the feature upon which applicant relies (i.e., treating obesity with ClpP inhibition) is not recited in the rejected claim(s). In claim 1, the preamble recites a method of “treating an individual with obesity,” however, the patient population is not defined as the claim does not recite administration to a subject “in need thereof.” That is, the preamble recites treating an individual who happens to have obesity, not a method of treating a disease or disorder in an individual in need thereof: i.e., “a method of treating obesity in an in an individual in need thereof.” And, while the claim recites administering a therapeutically effective amount of an inhibitor of ClpP, wherein the inhibitor is the compound A2-32-01, this compound is previously known and its administration to an individual is suggested in view of Zeiler and Tucci. The fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
(iii) Applicant argues that Tucci reviews digestive-enzyme inhibitors (a-amylase, lipase, a-glucosidase) for obesity management, by surveying compounds that block intestinal nutrient absorption. Applicant contends that Tucci is silent regarding ClpP, mitochondria, or systemic insulin sensitivity.
28. Applicant's arguments have been fully considered but they are not persuasive. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In this case, Tucci is relied upon for teaching the administration of orlistat/THL at therapeutically effective doses of 373 mg and 750 mg/day increased fat elimination (i.e., decreased fat tissue in the individual) and a therapeutically effective dose of 120 mg taken three times/day achieved significant weight loss and resulted in decreased insulin resistance (page 133, right column, lines 15-17, 21-22 and 27-29). By decreasing insulin resistance, one is necessarily increasing insulin sensitivity.
(iv) Applicant argues that the teaching of Cole is limited to the administration of A2-32-01 in tumor-bearing mice to inhibit bacterial-like ClpP in cancer cells. Applicant alleges that Cole does not teach (i) obesity therapy, (ii) liver-directed delivery, or (iii) improvement of metabolic endpoints. Applicant contends that targeting the liver is not a mere routine optimization, and that they discovered that the liver “is uniquely responsible for the systemic insulin-sensitizing effect of ClpP inhibition (see, for example, instant specification at Example 7 and Figure 6),” (Applicant’s Remarks, page 5, third paragraph).
29. Applicant's arguments have been fully considered but they are not persuasive. In this case, Cole is relied upon for teaching the IP administration of the compound A2-32-01, which involves injecting a substance into the peritoneal cavity, i.e., a local injection. And, Al Shoyaib et al. (Pharm Res 2020) evidence that IP drug administration results in the drug being absorbed into the mesenteric blood supply, which is then carried directly to the liver via the portal vein, where it undergoes significant hepatic first-pass metabolism: “[e]ven though IP administration of pharmacological agents results in faster and more complete absorption compared to oral, intramuscular and SC routes, this route as any other, has certain limitations. One limitation is the first pass metabolism, similar to what is observed with orally administered drugs, because substances absorbed from the peritoneal cavity end up in portal vein and pass through the liver,” (Page 13, last paragraph). As such, one of skill in the art would reasonably expect that a compound administered via IP injection would be carried directly to the liver via first pass metabolism.
Conclusion
30. 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.
31. 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 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.
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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/JANET L COPPINS/Examiner, Art Unit 1628
/JARED BARSKY/Primary Examiner, Art Unit 1628
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