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 .
Applicant’s remarks filed 10/22/2025 are acknowledged and entered into the record. Applicants amended claim 17 and canceled claim 32 in the remarks of 10/22/2025.
The instant application is subject to Continued Examination Under 37 CFR 1.114.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. The present application is drawn from PCT/US2019/066908, filed 12/17/2019; and claims benefit under 35 U.S.C. 119(e) to U.S. Provisional application 62/781226, filed 12/18/2018.
Status of Claims
Claims 17, 21 and 29-30 are pending and are being examined on the merits.
Claim Rejections- Maintained, Amended
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.
The rejection has been amended to account for amendments to claim 17. Specifically, the limitations of canceled claim 32 have been moved into amended claim 17. Therefore, the rejection over claim 17 has been amended to include the rationale previously recited for claim 32, in the office action of 4/22/2025.
Claims 17, 21 and 29-30 remain rejected under 35 U.S.C. 103 as being unpatentable over Latres et al., (C27 from IDS; Nature Communications, 2017, 8) and Gromada et al., (B6 from IDS; WO 2018089532; published 5/17/2018). It is noted that WO2018089532 qualifies as prior art under 35 USC 102(a)(1) and 102(a)(2).
Instant specifications identify the GDF8 antibody of claim 17 as REGN1033 (pg. 17, para. 0055) and the Activin A antibody of claim 17 as REGN2477 (pg. 20, para. 0065). Latres et al. teaches the combined inhibition of GDF8 and Activin A for increasing muscle mass (abstract). Specifically, Latres teaches the administration of the fully human monoclonal antibody REGN2477, that inhibits Activin A, in combination with the anti-GDF8 monoclonal antibody REGN1033 (pg. 2, col. 1, para. 3). Latres teaches that subcutaneous administration of REGN1033 in combination with REGN2477 in SCID mice increased muscle mass in a dose-dependent manner (Fig. 1c, d); and that the combination treatment had synergistic effects in increasing muscle mass over the effects of either antibody alone (pg. 2, col. 2, para. 2- pg. 3; Fig. 1). Latres shows that the combinatorial effects on increased muscle mass occur through increases in muscle fiber size (Fig. 1f), and resulted in increased muscle force (pg. 4, Fig. 2a, d). Latres further demonstrates the synergistic combinatorial effects of REGN1033 and REGN2477 increases muscle mass in C57BL/6 mice (Fig. 1l). Thus, Latres teaches the combination of REGN1033 and REGN2477 as a treatment to increase muscle mass. However, Latres does not teach the composition of REGN1033 and REGN2477 in combination with a LEPR antagonist to increase food intake, body weight and adiposity.
Gromada et al. teaches the use of antibodies that bind to, and inhibit, the leptin receptor (LEPR); and methods of using the antibodies in the treatment of various conditions (abstract). Gromada teaches one such antibody is H4H18457P2, which comprises an antigen binding domain comprising a VH region comprising SEQ ID NO: 42 and a VL region comprising SEQ ID NO: 10 (pg. 30, table 1). SEQ ID NO: 42 is 100% identical to instant SEQ ID NO: 1 of the VH domain of the anti-LEPR antibody of instant claim 17; and SEQ ID NO: 10 is 100% identical to instant SEQ ID NO: 2 of the VL domain of the anti-LEPR antibody of instant claim 17. Thus, H4H18457P2 is identified as the anti-LEPR antibody of instant claim 17 (instant specs. pg. 12, para. 0038). Gromada teaches that subcutaneous injection of 30 mg/kg H4H18457P2 significantly increased food intake (Fig. 1), body weight (Fig. 2), and fat mass (Fig. 3) of mice compared to control treatment groups (pg. 49, example 8, paras. 0137-0138). Gromada summarizes, “in conclusion, treatment with LEPR antagonist antibody, but not an isotype control antibody, increased food intake, body weight and adiposity in mice.” Gromada further teaches antibody H4H18457P2 comprised in a pharmaceutical composition (pg. 54, claim 11) and for use in a method to treat diseases or conditions associated with or caused by leptin signaling including anorexia, psychiatric eating disorders and cachexia (pg. 54, claims 12-13); and that the method may further comprise a second therapeutic agent for treating the loss of muscle mass, muscle function and/or muscle strength either with or without cachexia (pg. 55, claim 17).
It would have been obvious to one of skill in the art to modify the therapeutic combination taught by Latres et al for increasing muscle mass with the addition of a LEPR antagonist. One would have been motivated to do so given the suggestion by Gromada et al that a LEPR antagonist can be combined with agents that treat the loss of muscle mass with or without cachexia as a method for increasing food intake and body weight. There would have been a reasonable expectation for success given the knowledge that the anti-LEPR antibody, H4H18457P2, increases food intake, body weight and fat mass in a method for treating cachexia, as taught by Gromada et al. Thus, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Regarding claim 17, the combination of the anti-GDF8/Anti-Activin A/anti-LEPR antibody composition is made obvious as described above. Latres teaches that subcutaneous administration of REGN1033 in combination with REGN2477 in SCID mice increased muscle mass in a dose-dependent manner (Fig. 1c, d). Gromada et al. teaches the modified composition for use in a method for increasing food intake and body weight in a subject in need thereof (claim 17). Gromada teaches that subcutaneous injection of 30 mg/kg H4H18457P2 significantly increased food intake (Fig. 1), body weight (Fig. 2), and fat mass (Fig. 3). Thus, the modified combination therapy of Latres and Gromada increases both lean mass and fat mass in subjects. Further, Latres teaches the combination of GDF8/Activin A antagonists significantly increased lean mass in monkeys (pg. 7, Figure 5a); and reported “no changes in body fat mass were observed for any of the dosing groups,” (pg. 7, col. 1, para. 1). As the LEPR antagonist causes increases in fat mass, and the GDF8/Activin A antagonist combination causes increases in lean mass and no increase in fat mass, it stands to reason that the triple combination would result in a decreased proportion of fat mass to lean mass in the patient, as these are the additive effects of each of the compounds when used in the combination treatment. Therefore makes obvious the method of claim 17.
Regarding claim 21, the modified composition of Latres and Gromada is described above. Gromada teaches the use of the composition for treatment of subjects with cachexia (pg. 54-55, claims 11-12 and 17).
Regarding claims 29-30, the modified composition of Latres and Gromada teach an anti-LEPR antibody, H4H18457P2, which has 100% amino acid sequence identity with the HCDRs 1-3 of SEQ ID NOs 6-8, the LCDRs 1-3 of SEQ ID NOs 3-5 and the VH of SEQ ID NO: 1 and VL of SEQ ID NO: 2; and an anti-GDF8 antibody, REGN1033, which comprises 100% amino acid sequence identity with HCDRs 1-3 of SEQ ID NOs 14-16, the LCDRs 1-3 of SEQ ID NOs 11-13 and the VH of SEQ ID NO: 9 and VL of SEQ ID NO: 10; and an anti-activin A antibody, REGN2477, which comprises 100% amino acid sequence identity with HCDRs 1-3 of SEQ ID NOs 22-24, the LCDRs 1-3 of SEQ ID NOs 19-21 and the VH of SEQ ID NO: 17 and VL of SEQ ID NO: 18.
Response to Arguments
Applicant's arguments filed 10/22/2025 have been fully considered but they are not persuasive. Applicants amended independent claim 17 to include the limitation of “increasing lean mass and decreasing the proportion of fat mass to lean mass, in a subject in need thereof”. Applicants contend that the triple combination of GDF8/Activin A/LEPR antagonists resulted in unexpected and surprising results in the increases of lean and fat mass, particularly with respect to the proportions of lean vs fat mass increases, and disagree with the examiner in that the combination was expectedly additive (remarks, pgs. 5, last paragraph – pg. 6, para. 3). Further, applicants highlight that the combination treatment decreased the amount of fat mass gained from administration of only the fat-mass increasing LEPR antagonist, suggesting that the ability of the GDF8/Activin A antagonists to reduce the total fat mass gained from the LEPR antagonist compared to when the LEPR antagonist is administered alone is unexpected (remarks, pg. 7, paras. 1-2; figure). Applicants also contend that a property is not inherent unless it is present in every embodiment, and a skilled artisan could not have predicted the results of increasing lean mass and decreasing the proportion of fat mass to lean mass; and therefore it is not an inherent property of the combination of GDF8/Activin A/LEPR antagonists to do so (remarks, pg. 7, para. 3).
In response the examiner wants to address the question of proportionality, according to amended claim 17. Claim 17 recites wherein the triple combination of GDF8/Activin A/LEPR antagonists decreases the proportion of fat mass to lean mass, in a subject in need thereof. When speaking comparatively about changing proportions, it is important to consider what the change is being compared to. The examiner interprets claim 17 to be referencing the changes in lean mass/fat mass gained, in the subject, in response to treatment, in accordance to Table 2C of the specifications (pg. 41). If a subject is given the (primarily) fat mass-increasing LEPR antagonist of Gromada, then their body mass increases by primarily fat mass. If the subject is given the lean mass-increasing combination of GDF8/Activin A antagonists, whereby the combination (primarily) only increases lean mass (see above; also see Latres pg. 7, col. 1, para. 1), then their increase in body mass is primarily a lean mass increase. The GDF8/Activin A antagonist combination disproportionally increases lean mass over fat mass, as taught by Latres. Therefore, when a combination of GDF8/Activin A/LEPR antagonists are administered, it is expected that the fat mass to lean mass proportion will be decreased; by way of adding the lean mass increasing GDF8/Activin A treatment to the fat mass LEPR treatment. That is, any increase in lean mass will decrease the fat mass-to-lean mass ratio compared to a treatment that primarily increases fat mass, like the LEPR antagonist of Gromada. Here, the lean mass increasing compounds are the GDF8 and Activin A antagonists, which are being given in combination. Latres teaches that the combination of GDF8 and Activin A antagonists leads to a strong and synergistic increase in muscle mass in mice and monkeys; and that the data provide support for the combination inhibition for the treatment of muscle atrophy in patients (Latres, pg. 2, col. 1, para. 2). Therefore, as 2 lean mass increasing drugs, which work synergistically to increase lean mass, are being combined with 1 fat mass increasing drug, it is expected that lean mass will be increased more than fat mass in total. Indeed, Table 2C (specs. pg. 41) shows that the group effects of the GDF8/Activin A/LEPR antagonist triple combination resulted in a 3.99g increase in lean mass and a 3.4g increase in fat mass. Therefore, the skilled artisan would fully expect that combining GDF8/Activin A/LEPR antagonists would result in a decrease in the proportion of fat mass-to-lean mass gains in the subject. Such a result would be due to using 2 disproportionally lean mass increasing drugs with a single disproportionally fat mass increasing drug, whereby the 2 lean mass effector drugs also work synergistically to disproportionally increase lean mass compared to either one alone. Each of the compounds are working according to their intended use, as described in Latres and Gromada, and the additive effect of combining the treatments would be expected to result in an increase in lean mass, and a decrease in the proportion of fat mass to lean mass gained.
Regarding applicant’s remarks about the data of Table 8D being unexpected or surprising. The examiner believes the applicant is suggesting that the GDF8/Activin A antagonists reduced the fat mass-elevating effects of the LEPR antagonists, and that this effect was unexpected, and not purely additive. Examiner points to MPEP section 716.02 regarding allegation of unexpected results. “The court held that unexpected results for a claimed range as compared with the range disclosed in the prior art had been shown by a demonstration of a marked improvement over the results achieved under other ratios, as to be classified as a different in kind, rather than one of degree. A difference in degree is not as persuasive as a different in kind—i.e., if the range produces ‘a new property dissimilar to the known property,’ rather than producing a predictable result but to an unexpected extent.” As described above, combining agents which primarily increase lean mass with an agent that primarily increases fat mass would be expected to decrease the proportion of fat mass to lean mass gains. Applicants highlight that the GDF8/Activin A antagonists seemed to reduce the increases in fat mass induced by the LEPR antagonists, compared to the LEPR antagonist administered alone. However, the LEPR antagonists still induced an increase in fat mass, and the GDF8/Activin A antagonists, by way of increasing lean mass, still decreased the proportion of fat mass to lean mass gains compared to the LEPR antagonist administered alone. Therefore, the effects cited by applicants (Table 8D) are not “a new property dissimilar to the known property”, but rather, “a predictable result but to an unexpected extent.” The results would be generally expected by the skilled artisan, based on the properties of each of the GDF8/Activin A/LEPR antagonists, as they were individually taught in the art; though perhaps the reduction in the proportion of fat mass gains expected to be imparted by the LEPR antagonist, in a GDF8/Activin A/LEPR antagonist triple combination, were, in the case of Table 8D, to an unexpected extent. Further, a skilled artisan’s expected results, based on the known properties of the antagonists, can be adjusted by changing the relative dosages of each agent administered in the combination through routine optimization of the dosage administration protocol. That is, if a skilled artisan, intending to balance lean mass and fat mass increases in a subject via administering a GDF8/Activin A/LEPR antagonist triple combination, wanted to decrease the proportion of fat mass to lean mass gains, they could simply adjust the dosages of the 3 antagonists to achieve such a result. The data of Table 8D does not demonstrate a new property that would prevent the artisan from optimizing the protocol to achieve an expected decrease in the proportion of fat mass to lean mass gains resulting from the triple combination, and which would meet the limitations of amended claim 17 in a predictable manner. Applicant’s arguments are not found to be persuasive, and the rejections are maintained.
Claim Rejections- Maintained
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
See the office action of 6/21/2024 for the particular reasons why the claims are anticipated by, or obvious over, the conflicting patents/applications. The rejected claims are amended to reflect the amended claims of 3/11/2025.
Claims 17, 21, 29-30 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 8, 11 and 14 of U.S. Patent No. 10550192 ('192; to Gromada et al.; published 2/4/2020) in view of Gromada et al., (B6 from IDS; WO 2018089532; published 5/17/2018) and Latres et al., (C27 from IDS; Nature Communications, 2017, 8).
Claims 17, 21, 29-30 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3, 6, 10-19, 22 and 24 of U.S. Patent No. 11535675 ('675; to Gromada et al.; published 12/27/2022) in view of Gromada et al., (B6 from IDS; WO 2018089532; published 5/17/2018) and Latres et al., (C27 from IDS; Nature Communications, 2017, 8).
Claims 17, 21, 29-30 and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 4, 7, 10 and 13 of co-pending Application No. 18/056411 in view of Gromada et al., (B6 from IDS; WO 2018089532; published 5/17/2018) and Latres et al., (C27 from IDS; Nature Communications, 2017, 8). This is a provisional nonstatutory double patenting rejection.
Claims 17, 21, 29-30 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 12-23, 25-29, 31, 33-36, 38, 40 and 41 of U.S. Patent No. 9718881 ('881; from IDS; to Gromada et al.; published 8/1/2017) in view of Gromada et al., (from IDS; WO 2018089532; published 5/17/2018).
At least claim 17 is rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of the following issued U.S. Patents:
Patent Number
GDF8 antibody SEQ ID NOs
Activin A antibody SEQ ID NOs
Pertinent claims
11248044
360 and 368
553 and 537
1-27
10934349
360 and 368
1-29
10526403
217 and 221
15-31
8871209
9 and 13
1-11
10400036
9 and 13
1-18
8840894
360 and 368
1-5
9260515
360 and 368
1-6
9890212
360 and 368
5, 8-14
Response to Arguments
Applicant's arguments filed 10/22/2025 have been fully considered but they are not persuasive. Applicants disagree with the nonstatuatory double patenting rejections for the same reasons they disagree with the prior art rejections above (remarks, pg. 9). Examiner has responded to the applicant’s remarks, and maintained the prior art rejections above; therefore the examiner also maintains the nonstatuatory double patenting rejections.
Conclusion
No claims are allowed.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JAMES R. MELCHIOR whose telephone number is (703)756-4761. The examiner can normally be reached M-F 8:00-5:00 CST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Daniel E. Kolker can be reached at (571) 272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JAMES RYLAND MELCHIOR/Examiner, Art Unit 1644
/DANIEL E KOLKER/Supervisory Patent Examiner, Art Unit 1644