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
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/28/25 has been entered.
Election/Restrictions and Claim Status
Applicants’ amendments and arguments filed 8/28/25 are acknowledged. Any objection or rejection from the 3/28/25 office action that is not addressed below is withdrawn based on the amendments.
Previously, Group 1 and the species of setmelanotide and T112M mutation were elected.
Claims 11-20 are drawn to a non-elected group. Applicants elected the T112M mutation which is a genetic mutation reading on claim 1 but not claim 7.
Claims 11-20 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 7/22/24.
Claim 7 is withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 7/22/24.
Claims 2-6, 8, 10 and 21 have been canceled.
Claims 1 and 9 are being examined.
Priority
The priority information is provided in the filing receipt dated 4/24/24.
Claim Rejections - 35 USC § 112
The rejection below is a new rejection necessitated by amendment.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 and 9 are 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.
Claim 1 as amended recites ‘determining that the subject has an MC4R deficiency comprising impaired NFAT signaling, without impaired Galphas signaling’. Thus, to determine appropriate subjects the determination of impaired NFAT signaling and the determination of no impairment of Galphas signaling is necessary. With respect to guidance in the specification, the specification recognizes that Galphas signaling can be determined by measuring cAMP accumulation (page 26 lines 20) and that measurement of PLC can be employed to monitor NFAT signaling (page 26 lines 31-32). With respect to determination of what qualifies as being impaired or not impaired there is not adequate guidance. MPEP 2173.05(b) IV recognizes that claim scope cannot depend solely on the unrestrained, subjective option of a particular individual purported to be practicing the invention.
Figure 13A reports cAMP accumulation and shows wild type at an approximate value of 35 nM, and T112M with an approximate value of 25 nM and V166I with an approximate value of 17 nM. As shown, there appears to be an approximate 50% decrease when comparing wild type (~35 nM) to V166I (~17nM). Figure 13 caption reports that ‘all variants perform essentially as MC4R-WT’ (pages 34-35 connecting paragraph of the specification).
Figure 13B reports PLC activation and shows wild type at an approximate value of 140000 rlu and T112M with an approximate value of 70000 rlu and N274S with an approximate value of 100000 rlu. As shown, there appears to be an approximate 50% decrease when comparing wild type (~140000 rlu) to N274S (~70000 rlu). Figure 13 caption reports that ‘essentially nearly all variants show a loss of function’ (pages 34-35 connecting paragraph of the specification).
As such, it is not clear what changes rise to the level of ‘impairment’. Figure 13A appears to show all mutants having less cAMP accumulation and mutant V166I have an approximate 50% decrease. It is unclear if a 50% decrease in cAMP is to be considered ‘without impairment’ or ‘with impairment’. Figure 13B appears to also show examples with an approximate 50% decrease in rlu and it is unclear if such decrease is to be considered ‘without impairment’ or ‘with impairment’.
Applicants arguments of 8/25/25 (page 9) point to page 4 lines 18-27 which refer to ‘do not display any alteration of Galphas signaling, but a significantly reduced NFAT signaling’. Applicants also argue (page 9) that figure 13A shows that ‘the mutations perform essentially the same as MC4R-WT’. Applicants also argue (page 9) that figure 15A shows WT-similar cAMP levels. However, these arguments do not lead to any clearer determination of what is considered ‘without impairment’ or ‘with impairment’.
To determine appropriate subjects as claimed, the determination of impaired NFAT signaling and the determination of no impairment of Galphas signaling is necessary. However, the defining feature of such determination is unclear making the appropriate subjects and claim scope unclear. Dependent claim 9 does not clarify the claim scope.
Claim 1 as amended recites ‘human MC4R gene selected from…T112M…’. T112M is not a gene. As such, claim 1 appears to provide contradictory or unclear information. If the intent is to refer to positions of a human MC4R protein, language as in claim 6 of the 12/23/24 claim set should be considered. Dependent claim 9 does not clarify the claim scope.
Although unclear, the claims have been given the broadest reasonable interpretation consistent with the specification. The claims have been interpreted as including no new matter.
Response to Arguments - 112
Applicant's arguments filed 8/28/25 have been fully considered but they are not persuasive with respect to the rejections set forth above.
Although applicants argue that the claims have been amended, the amended claims are addressed above.
Claim Rejections - 35 USC § 103
Claims were previously rejected under 103 based on the references cited below. Since the claims have been amended, the rejection is updated to correspond to the instant claims.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1 and 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Collet et al. (NPL cite 2 of IDS 8/20/20; ‘Collet’) in view of Collet et al. supplement (Supplement to Collet et al. ‘Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency’ Molecular Metabolism v6(10) 2017 pages 1-8; ‘ColletSupplement’) in view of Collet et al. spreadsheet supplement (Supplement to Collet et al. ‘Evaluation of a melanocortin-4 receptor (MC4R) agonist (Setmelanotide) in MC4R deficiency’ Molecular Metabolism v6(10) 2017 pages 1-12; ‘ColletSpreadsheet’) in view of Yang et al. (‘Biased signaling at neural melanocortin receptors in regulation of energy homeostasis’ BBA- Molecular Basis of Disease, v1863 April 2017 pages 2486-2495) in view of Negulescu et al. (US 2006/0008855; ‘Negulescu’).
Collet teach that setmelanotide binds to human MC4R and has been shown to reduce food intake and body weight in various organisms (page 1322 2nd complete paragraph). Collet teach that setmelanotide is also known as RM-493 (page 1322 2nd complete paragraph). Collet teach administration of setmelanotide in a human clinical trial (methods section of abstract). Collet teach that obese individuals were administered setmelanotide (section 3.4 and Table 1). Collet teach subjects with early onset obesity (section 2.1). Collet teach setmelanotide can lead to weight loss in obese people with MC4R deficiency (first paragraph of section 4). Collet teach mutations in MC4R in subjects with severe obesity and hypothesize that setmelanotide might lead to weight loss by rescuing signaling or by increasing signaling (page 1322 3rd complete paragraph). Collet teach that patients including those with complete loss of function showed profound weight loss response and suggest certain patients might benefit more readily from setmelanotide treatment (page 1327 last complete paragraph). Collet teach the MC4R sequence and recites mutations including T112, V166, I170 and A175 among others (Figure 1). ColletSpreadsheet (see appendix A of Collet) teach that the specific mutations include T112M (page 5), V166I (pages 6-7), I170V (page 7), and A175T (page 7). Collet teach that setmelanotide subjects experienced significant weight loss without any adverse effects on cardiovascular parameters (page 1322 3rd complete paragraph). Collet teach that the cardiovascular profile of setmelanotide might be due to coupling through different signaling pathways (pages 1327-1328 connecting paragraph). Collet teach that MC4R is known to be a Galphas coupled GPCR and teach that the ability of agonists to induce cyclic AMP was assessed (section 3.2 on page 1324) and specifically teach the use of a CREB reporter assay (section 2.4 page 1323). Collet teach that there is evidence of biased signaling for MC4R (pages 1327-1328 connecting paragraph).
Collet does not specifically administer to a subject with the elected T112M mutation including a testing step as in claim 1.
Yang teach that the global prevalence of obesity highlights the importance of understanding the regulation of energy homeostasis and that MC4R plays a crucial role in energy homeostasis (abstract). Yang teach that a biased ligand activates MC4R selectively and induces Gq signaling resulting in less cardiovascular side effects (figure 2) and shows signaling still occurs via Galphas (figure 2). Yang teach that biased ligands that trigger Galphaq signaling would be better drugs for targeting MC4R (pages 2491-2492 connecting paragraph). Yang teach that RM-493 has been demonstrated to reduce food intake and lead to persistent weight loss without alteration of cardiovascular functions (page 2492 first complete paragraph). Yang teach that although the exact mechanism is unknown, a potential explanation is that RM-493 is a MC4R biased agonist which selectively couples MC4R to the particular signaling pathways (page 2492 first complete paragraph).
Negulescu teach methods of identifying ligands and compounds that modulate signal transduction (abstract). Negulescu teach screening for Gq type activation where modulation of activity initiates signaling via PLC which is detected using NFAT (figure 2 and section 0024).
It would have been obvious to one of ordinary skill in the art before the effective filing date to modify the teachings of Collett because Collet teach mutations in MC4R in subjects with severe obesity and hypothesize that setmelanotide might lead to weight loss by rescuing signaling or by increasing signaling (page 1322 3rd complete paragraph). Collet teach that patients including those with complete loss of function showed profound weight loss response and suggest certain patients might benefit more readily from setmelanotide treatment (page 1327 last complete paragraph). Collet teach the MC4R sequence and recites complete loss of function mutations including T112 (Figure 1). ColletSpreadsheet teach that the specific mutation is T112M (page 5). Thus one would have been motivated to administer to a subject with the T112M mutation. Further, Collet teach subjects with early onset obesity (section 2.1) so one would have been motivated to administer to such subjects. Collet teach that MC4R is known to be a Galphas coupled GPCR and teach that the ability of agonists to induce cyclic AMP was assessed (section 3.2 on page 1324) and specifically teach the use of a CREB reporter assay (section 2.4 page 1323) so one would have been motivated to monitor cAMP. One would have had a reasonable expectation of success since Collet teach setmelanotide can lead to weight loss in obese people with MC4R deficiency (first paragraph of section 4). Collet teach that patients including those with complete loss of function showed profound weight loss response (page 1327 last complete paragraph).
Further, Collet teach that the cardiovascular profile of setmelanotide might be due to coupling through different signaling pathways and recites Galphaq (pages 1327-1328 connecting paragraph) and teach that there is evidence of biased signaling for MC4R (pages 1327-1328 connecting paragraph). Yang teach that biased ligand activates MC4R selectively and induces Gq signaling resulting in less cardiovascular side effects while still using Galphas (figure 2). Yang teach that biased ligands that trigger Galphaq signaling would be better drugs for targeting MC4R (pages 2491-2492 connecting paragraph). Yang teach that RM-493 (i.e. setmelanotide see page 1322 2nd complete paragraph of Collet) has been demonstrated to reduce food intake and lead to persistent weight loss without alteration of cardiovascular functions (page 2492 first complete paragraph). Yang teach that although the exact mechanism is unknown, a potential explanation is that RM-493 is a MC4R biased agonist which selectively couples MC4R to the particular signaling pathways (page 2492 first complete paragraph). Since Yang expressly states that biased ligands that trigger Galphaq signaling would be better drugs for targeting MC4R (pages 2491-2492 connecting paragraph) one would have been motivated to identify such ligands using the known assays taught by Negulescu. One would have had a reasonable expectation of success since Negulescu teach methods for identifying ligands that modulate signal transduction (abstract).
In relation to the administering of claim 1, Collet teach administration of setmelanotide in a human clinical trial (methods section of abstract) and teach that obese individuals were administered setmelanotide (section 3.4 and Table 1).
In relation to the MC4R agonist of claim 1, Collet teach administration of setmelanotide in a human clinical trial (methods section of abstract) and teach that obese individuals were administered setmelanotide (section 3.4 and Table 1). Since the elected agent was administered, such agent is interpreted as having the functionality recited in claim 1.
In relation to the subject of claim 1, Collet teach setmelanotide can lead to weight loss in obese people with MC4R deficiency (first paragraph of section 4). Collet teach the MC4R sequence and recites complete loss of function mutations including T112 (Figure 1). ColletSpreadsheet (see appendix A of Collet) teach that the specific mutation is T112M (page 5). The elected species of T112M has been interpreted as having the recited function. Further, Yang expressly states that biased ligands that trigger Galphaq signaling would be better drugs for targeting MC4R (pages 2491-2492 connecting paragraph) and Negulescu teach NFAT as downstream of that signaling (figure 2).
In relation to testing of claim 1, the determination related to impaired or not impaired is unclear (see 112 rejection above). Collet teach that MC4R is known to be a Galphas coupled GPCR and teach that the ability of agonists to induce cyclic AMP was assessed (section 3.2 on page 1324) and specifically teach the use of a CREB reporter assay (section 2.4 page 1323).
Yang expressly states that biased ligands that trigger Galphaq signaling would be better drugs for targeting MC4R (pages 2491-2492 connecting paragraph) and Negulescu teach methods of assaying NFAT signaling of receptors (figure 2). Since Yang expressly states that biased ligands that trigger Galphaq signaling would be better drugs for targeting MC4R (pages 2491-2492 connecting paragraph) one would have been motivated to identify such ligands using the known assays taught by Negulescu. Further, Collet teach loss of function (LOF) mutations in MC4R in subjects with severe obesity and hypothesize that setmelanotide might lead to weight loss by rescuing signaling or by increasing signaling (page 1322 3rd complete paragraph). Although unclear, since the prior art suggest known methods of testing the claim limitations have been interpreted as being met.
In relation to claim 9, Collet teach setmelanotide can lead to weight loss in obese people with MC4R deficiency (first paragraph of section 4) and teach subjects with early onset obesity (section 2.1).
Response to Arguments - 103
Applicant's arguments filed 8/28/25 have been fully considered but they are not persuasive with respect to the rejection set forth above.
Although applicants argue that the claims have been amended, the amended claims are addressed above.
Although applicants argue about impairment, as discussed in the 112 rejection above the claim language is unclear. Figure 13A reports cAMP accumulation and shows wild type at an approximate value of 35 nM, and T112M with an approximate value of 25 nM and V166I with an approximate value of 17 nM. As shown, there appears to be an approximate 50% decrease when comparing wild type (~35 nM) to V166I (~17nM). Figure 13 caption reports that ‘all variants perform essentially as MC4R-WT’ (pages 34-35 connecting paragraph of the specification). Figure 13B reports PLC activation and shows wild type at an approximate value of 140000 rlu and T112M with an approximate value of 70000 rlu and N274S with an approximate value of 100000 rlu. As shown, there appears to be an approximate 50% decrease when comparing wild type (~140000 rlu) to N274S (~70000 rlu). Figure 13 caption reports that ‘essentially nearly all variants show a loss of function’ (pages 34-35 connecting paragraph of the specification). Stated another way, it appears that applicants argue that an approximate 50% decrease is not an impairment (see Figure 13A and caption) while an approximate 50% decrease is an impairment (see Figure 13B and caption).
Although applicants argue about the teachings of references individually, the instant rejection is a multiple reference 103 rejection and as such any single reference does not necessarily anticipate the claims. 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).
Although applicants argue about the teachings of the specification in relation to impairments, as discussed in the 112 rejection above the claim language is unclear. Applicants arguments of 8/25/25 (page 9) point to page 4 lines 18-27 which refer to ‘do not display any alteration of Galphas signaling, but a significantly reduced NFAT signaling’. Applicants also argue (page 9) that figure 13A shows that ‘the mutations perform essentially the same as MC4R-WT’. Applicants also argue (page 9) that Figure 15A shows WT-similar cAMP levels. However, these arguments do not lead to any clearer determination of what is considered ‘without impairment’ or ‘with impairment’.
Although applicants argue about a lack of motivation, Collet teach (LOF) mutations in MC4R in subjects with severe obesity and hypothesize that setmelanotide might lead to weight loss by rescuing signaling or by increasing signaling (page 1322 3rd complete paragraph). Collet teach that patients including those with loss of function showed profound weight loss response and suggest certain patients might benefit more readily from setmelanotide treatment (page 1327 last complete paragraph). Thus, one would have been motivated based on the known beneficial properties of setmelanotide.
Conclusion
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RONALD T. NIEBAUER
Primary Examiner
Art Unit 1658
/RONALD T NIEBAUER/Examiner, Art Unit 1658