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 .
Election/Restrictions
Applicant’s election of Group (I) in the reply filed on 11/06/2025 is acknowledged and maintaind..
Applicant’s election of compound 16024
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and cachexia as the elected species in the reply filed on 11/06/2025 is acknowledged and maintained.
Priority
This application is a National Stage Application, filed under 35 U.S.C. 371, of International Application No. PCT/US2021/054804, filed October 13, 2021, which claims the benefit of priority to U.S. Provisional Patent Application Number 63/092,684, filed October 16, 2020; filed October 16, 2020.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on May 19, 2026. Claims 1, 3, 7, 9, 10, 12-14, and 16-23 are pending. Claims 1, 3, 7, 9, 10, 12-14, 16, and 22 are withdrawn. Claims 2, 4-6, 8, 11, and 15. Claims 17-21, and 23 are examined in accordance to the elected species.
Action summary
Claims 17-21 rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, are withdrawn in light of the claim amendment, narrowing the scope of the claim.
Claims 17-21 rejected under 35 U.S.C. 103 as being unpatentable over Jin et al (Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 2, 15 January 2017, Pages 347-353) in view of Morley et al (The American Journal of Clinical Nutrition, Volume 83, Issue 4, April 2006, Pages 735-743) and Clark et al (WO2005/087769 A1), are withdrawn in light of Applicant’s amendment to claim 17, which changes the disease state and therapeutic endpoint, thereby necessitating further search and consideration.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 17-21 and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Jin et al (Bioorganic & Medicinal Chemistry Letters, Volume 27, Issue 2, 15 January 2017, Pages 347-353) in view of Morley et al (The American Journal of Clinical Nutrition, Volume 83, Issue 4, April 2006, Pages 735-743), Clark et al (WO2005/087769 A1), and Braun et al. (Front Physiol. 2015 Feb 3;6:12, pages 1-12).
Jin teaches a synthesis of novel steroidal agonists, partial agonists, and antagonists for the glucocorticoid receptor. (See Title.) Moreover, Jin teaches compound 14h
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. Compound 14h with excellent antagonist action is the same as the elected compound. Jin also teaches after stimulation with various compounds, the Fkbp5 mRNA levels in these muscle fibers generally reflected the GR activity profiles observed in the luciferase reporter assays where substitution of the beta-directed hydroxyl with small alkyl groups led to a 40-fold increase in Fkbp5 mRNA levels (compare 8b to 14a–c), indicating a potent, full GR agonist-like effect. In contrast, substitution of this hydroxyl with bulkier alkyl groups did not have a striking effect on Fkbp5 expression (compare 8b to 14a-h), consistent with a GR antagonist profile. Compound 14e is noted to have a substantial decreased Fkbp5 mRNA levels in mouse C2C12 myotubes (See Tables 1-4, third paragraph of the left column bridging second paragraph of the right column of page 352.) The lack of effect of Fkbp5 expression with compound 14e suggests that compound 14e would not affect muscle fibers or wasting. Additionally, Jin teaches these novel steroidal based GR agonist 8f and 10d, partial agonists 8b, 8e, 10e, 10f, 14a, 14b, 14c and 16, and antagonists 8a, 8c, 8d, 8g, 10g, 14d, 14e, 14f, 14g and 14h were successfully synthesized. Glucocorticoids with dissociated phenotypes in vitro have shown reduced anti-inflammatory/transactivation ratio in vivo and in humans. This may reflect the variety of glucocorticoid target tissues that contribute to both inflammatory cytokine secretion and metabolic parameters such as glucose disposal, suggesting anti-inflammatory effect of these compounds. (See third paragraph of the left column of page 353.)
Jin does not expressly teach administration of compound 14e (i.e. elected compound 16024) for treating muscle atrophy or weakness associated cachexia or muscle dystrophy.
Morley teaches the major cause of cachexia appears to be cytokine excess. Other potential mediators include testosterone and insulin-like growth factor I deficiency, excess myostatin, and excess glucocorticoids. (See Abstract.) Moreover, Morley teaches. excessive elaboration of proinflammatory cytokines such as interleukin (IL) 1, IL-2, interferon ϒ, and tumor necrosis factor α (TNF-α) is probably the most common cause of cachexia observed in acutely ill patients. Cytokines activate nuclear transcription factor κB (NF-κB), which results in decreased muscle protein synthesis. (See first paragraph of the right column of page 735.)
Clark teaches a method of treating a disorder or condition through antagonizing a glucocorticoid receptor, the method comprising administering to a subject in need of such treatment, an effective amount of the compound of the formula (I). (See claim 30.) Moreover, Clark teaches GR modulators may also affect a wide variety of disease states, such as cachexia. (See paragraph [0066].)
Braun teaches that glucocorticoid signaling is common mediator of skeletal muscle wasting and cachexia. Moreover, Braun teaches glucocorticoids promote muscle atrophy through increased protein degradation and suppression of protein synthesis and that anti-glucocorticoid therapy and glucocorticoid antagonists represent promising therapeutic approaches for attenuating muscle wasting and restoring anabolic pathways. (See Abstract.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to administer the compound 14e or 16024 in a pharmaceutical composition to as subject suffering from muscle atrophy or weakness associated with cachexia. One would have been motivated to do so, because Jin teaches potent GR antagonists having anti-inflammatory activity and favorable muscle-cell activity, Morley teaches that cachexia is characterized excessive glucocorticoid signaling and inflammation leading to decreased muscle protein synthesis, Clark teaches that GR modulators may affect cachexia, and Braun teaches that glucocorticoid antagonism represents a promising therapeutic approach for preventing muscle and restoring anabolic processes. Therefore, one of ordinary skill in the art would have been motivated to employ compound 14e or 16024 taught by Jin to ameliorate or prevent muscle wasting and weakness associated with cachexia.
One of ordinary skill in the art would have had a reasonable expectation of success because Jin teaches potent GR antagonists exhibiting anti-inflammatory properties and favorable activity in C2C12 myotubes, Morley teaches excess glucocorticoids and inflammatory cytokines contribute to muscle wasting and reduced protein synthesis, Clark teaches the therapeutic utility of GR modulation in cachexia, and Braun teaches that inhibition of glucocorticoid signaling preserves muscle mass and restores anabolic pathways. Accordingly, one would have reasonably expected administration of compound 16024 or 14e to ameliorate or prevent muscle atrophy or weakness associated with cachexia.
With respect to claim 18, Braun teaches that glucocorticoids suppress anabolic pathways and that anti-glucocorticoid therapies preserve muscle mass and restore anabolic processes. Therefore, one of ordinary skill in the art would have reasonably expected compound 16024 or 14e, which is potent glucocorticoid receptor antagonist taught by Jin to exhibit anabolic properties in skeletal muscle.
With respect to claim 23, the limitation that treating muscle atrophy or weakness comprises ameliorating or preventing muscle atrophy or weakness does not patentably distinguish over the treatment recited in claim 17. Moreover, Braun teaches that anti-glucocorticoid therapies are useful for preventing muscle wasting, thereby suggesting prophylactic as well as therapeutic administration.
Acknowledgement is made of the receipt and entry of Applicant’s arguments/remarks filed on May 19, 2026.
Applicant argues that Clark does not teach or suggest use of glucocorticoid receptor agonist or antagonist to treat cachexia and that, at best the references merely suggest that glucocorticoid receptor antagonists may not cause cachexia. Applicant further argues that failure to cause cachexia would not have been suggested treatment of cachexia.
In response to applicant's arguments against the references individually, one cannot show non-obviousness 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 the instant case, the rejection is based upon the combined teachings of Jin, Morley, Clark, and Braun. The rejection does not rely merely on the absence of cachexia-inducing effects. Rather, Jin teaches potent glucocorticoid receptor antagonists possessing anti-inflammatory properties and favorable muscle-cell activity. Morley teaches cachexia involves excessive glucocorticoid signaling and inflammatory cytokines that decrease muscle protein synthesis, Clark teaches that glucocorticoid receptor modulators may affect cachexia. Braun further teaches that glucocorticoid signaling mediates skeletal muscle wasting and that anti-glucocorticoid therapy represents a promising approach for preserving muscle mass and restoring anabolic pathways. Therefore, one of ordinary skill in the art would have reasonably expected administration of compound 14e or 16024 to ameliorate or prevent muscle atrophy or weakness associated with cachexia.
Applicant further argues that none of Jin, Morley, and Clark teaches or suggests glucocorticoid receptor agonists, partial agonists, or antagonist having anabolic activity and that it was not known prior to Applicant’s disclosure that compound 16024 possessed anabolic activity.
In response, Applicant’s argument is not persuasive. Braun expressly teaches that glucocorticoids suppress anabolic pathways and that anti-glucocorticoid therapies preserve muscle mass and restore anabolic processes. Therefore, one of ordinary skill in the art would have reasonably expected potent glucocorticoid receptor antagonists such as compound 16024 or 14e taught by Jin to exhibit anabolic effects in skeletal muscle. Accordingly, the combined teachings of Jin, Morley, Clark, and Braun render the claimed subject matter obvious.
Conclusion
Claims 17-21 and 23 are not 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 JEAN P CORNET whose telephone number is (571)270-7669. The examiner can normally be reached Monday-Thursday from 7.00am-5.30pm.
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, Amy L Clark can be reached at 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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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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