DETAILED ACTION
Notice of 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 with traverse of a single method in the reply filed on 8/03/2026 is acknowledged. As argued by Applicant, “in view of the amendment to claim 1... Buezo no longer reads on amended claim 1... the common biomarker-based selection of the patient population remains a special technical feature... and the species therefore remain linked by a single general inventive concept” (Applicant Arguments, Page 7).
The argument is not found persuasive. The amended claims do not present a contribution over Fava et al (Annals of Clinical Psychiatry 33:18-26, published 2/01/2021) in view of Al-Hakeim et al (Acta Neuropsychiatrica 32:99-108, 2020) as discussed in the basis of the rejection below.
Applicant further traverses each of the required elections to provide a single method of treating MDD.
The arguments are not found persuasive. As drafted, the claims embrace countless methods of treating MDD comprising administering aticaprant, including treating a patient not have been previously treated for depression and expressing elevated levels of CRP and TNF-alpha, CRP and sIL6R, CRP and TNF-alpha and sIL6R, dynorphin, CRP and TNF-alpha and dynorphin, CRP and sIL6R and dynorphin, CRP and TNF-alpha and sIL6R and dynorphin, a patient previously treated for depression and having an inadequate response to said treatment and expressing elevated levels of CRP and TNF-alpha, CRP and sIL6R, CRP and TNF-alpha and sIL6R, dynorphin, CRP and TNF-alpha and dynorphin, CRP and sIL6R and dynorphin, CRP and TNF-alpha and sIL6R and dynorphin, and thousands of additional methods.
As such, the requirement is still deemed proper and is therefore made FINAL.
The elected species read upon claims 1, 9-14, 16 and 22-27. Claims 2-8, 15 and 17-21 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
Claim Objections
Claims 27 is objected to for the following reason:
Claims 26-27 are drawn to the method of claim 25, which is in turn drawn to the method of claim 1, wherein claims 26-27 each recite “[t]he method of claim 25, wherein the first reference dynorphin is about pg/ml and the second reference dynorphin level is about 8 pg/ml”.
Claim 27 is objected to as being a substantial duplicate of claim 26.
Claims 26-27 are additionally objected to as reciting “pg/ml” wherein the “l” in “ml” is lowercase, whereas claims 20-24 recite “pg/mL” wherein the “L” in “mL” is uppercase. Applicant should amend claims 26-27 to be consistent with the remainder of the claims.
Claim Rejections - 35 USC § 112
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.
Claims 26-27 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claims 26-27 are drawn to the method of claim 25, which is in turn drawn to the method of claim 1, wherein claims 26-27 each recite “[t]he method of claim 25, wherein the first reference dynorphin is about pg/ml and the second reference dynorphin level is about 8 pg/ml”.
Claims 26-27 are indefinite because the claims, which recite that the first reference dynorphin “is about pg/ml” do not define a first reference dynorphin level. Furthermore, there is insufficient antecedent basis in claims 25 and claim 1 the recitation of a second reference dynorphin level in claims 26-27.
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.
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.
Claims 1, 10-14 and 22-24 are rejected under 35 U.S.C. 103(a) as being unpatentable over Fava et al (Annals of Clinical Psychiatry 33:18-26, published 2/01/2021) in view of Al-Hakeim et al (Acta Neuropsychiatrica 32:99-108, 2020).
Claim 1 is drawn to a method of treating major depressive disorder (MDD) in a human patient, comprising:
(a) obtaining a biological sample from the human patient;
(b) identifying a patient as a biomarker signature positive patient when a level of dynorphin in the biological sample is determined to be greater than a first reference dynorphin level (more specifically, wherein the first reference dynorphin level is about 11.4 pg/mL (claim 24) or about 20 pg/mL (claim 22)); and
(c) administering (more specifically, orally administering (claim 13) once daily (claim 14)) to a human patient identified as a biomarker signature positive patient according to step (b) a therapeutically effective amount (more specifically, about 10 mg (claims 10-11)) of aticaprant.
The method, as thus summarized, reads on claims 1, 10-11, 13-14, 16, 22 and 24-25.
As taught by Fava et al, “[k]appa receptors and [their] endogenous ligand dynorphin are localized in brain areas mediating reward and mood” and, as further taught by Fava et al, “the kappa-opioid receptor system, has been implicated as a contributing factor for MDD... with the dysphoric component of stress being encoded by activation of the dynorphin kappa opioid system” (Page 19, Column 1). Recognizing that “[n]umerous kappa antagonists have shown antidepressant-like effects in animal models of depression” (Page 19, Column 1) and in an effort to further assess whether “[k]appa-opioid antagonism may possess antidepressant properties”, Fava et al teach oral administration (Page 19, Column 2) of “10 mg/d of CERC-501”, i.e., aticaprant, “a kappa-selective opioid receptor antagonist” (Title), “in a proof-of-concept pilot trial among [human] patients with major depressive disorder with inadequate response to antidepressants” (Abstract). As taught by Fava et al, the “results suggest that CERC-501 may have antidepressant effects”, although “[a]dditional studies are necessary to further explore these effects of CERC-501” (Abstract).
As such, Fava et al teach a method of treating major depressive disorder (MDD) in a human patient, comprising administering to said patient in need thereof a therapeutically effective amount of the kappa-selective opioid receptor antagonist aticaprant. Additionally, Fava et al motivate additional studies into the treatment of MDD in a human patient, comprising administering to said patient in need thereof a therapeutically effective amount of aticaprant.
However, Fava et al do not teach the treatment of MDD in a patient identified as a biomarker signature positive patient as recited by the instant claims.
Yet, as further taught by Al-Hakeim et al – noting that “dynorphin bind[s] predominantly to KORs” (Page 5) to promote “dynorphin-mediated KOR activation” (Page 13) – “serum dynorphin and KOR were significantly increased in MDD as compared with controls and... increases in those opioid peptides and their receptors are interrelated, suggesting that dynorphin/KOR signaling is significantly increased in MDD” (Page 12, Discussion). However, Al-Hakeim et al also teach that “KOR and the index dynorphin/KOR signaling are both significantly decreased in MDD subjects with comorbid nicotine dependence” and “[s]moking is highly prevalent among people with MDD” (Page 16). In particular, Al-Hakeim et al report dynorphin levels of 17.04 + 2.55 pg/ml in healthy controls, 18.83 + 1.86 pg/ml in MDD patients, and 17.50 + 1.79 pg/ml in MDD patients with nicotine dependence (Page 33, Table 1).
Considering that “dynorphin bind[s] predominantly to KORs” to promote “dynorphin-mediated KOR activation” and, furthermore, that “serum dynorphin and KOR [are] significantly increased in MDD... suggesting that dynorphin/KOR signaling is significantly increased in MDD” (as taught by Al-Hakeim et al) – and further recognizing that “the kappa-opioid receptor system has been implicated as a contributing factor for MDD” (as taught by Fava et al) – a person of ordinary skill in the art would have reasonably concluded that the kappa-selective opioid receptor antagonist aticaprant exerts its antidepressant effects in the treatment of MDD (as taught by Fava et al) via blockade of dynorphin binding to KORs and inhibition of dynorphin-mediated KOR activation. At the same time, a person of ordinary skill in the art would have reasonably predicted that blockade of dynorphin binding to KORs and inhibition of dynorphin-mediated KOR activation would not exert antidepressant effects in the treatment of MDD in patients wherein dynorphin and KOR levels are not elevated relative to healthy controls, such as MDD subjects with comorbid nicotine dependence, a well-established cohort of patients suffering from MDD (as taught by Al-Hakeim et al).
In view of all of the foregoing, it would have been prima facie obvious to limit the method of Fava et al (for the treatment of MDD comprising orally administering 10 mg of the kappa-selective opioid receptor antagonist aticaprant) specifically to the treatment of MDD in a patient identified as a biomarker signature positive patient based on having a level of dynorphin in a biological sample obtained from said patient that is greater than a first reference dynorphin level and, in particular, wherein the first reference dynorphin level is about 17.04 + 2.55 pg/ml to about 17.50 + 1.79 pg/ml (i.e., about 20 pg/mL), in further view of Al-Hakeim et al. It would have been prima facie obvious to do so in order to limit the method of Fava et al to those patients suffering from MDD that are likely to respond to treatment with the kappa-selective opioid receptor antagonist aticaprant, while excluding those patients suffering from MDD that are not likely to respond to treatment with the kappa-selective opioid receptor antagonist aticaprant, with a reasonable expectation of success.
As such, claims 1, 10-11, 13-14, 16, 22 and 24-25 are rejected as prima facie obvious.
Claim 12 is drawn to the method of claim 1, wherein the effective amount of aticaprant is about 5 mg.
As stated by MPEP 2144.05, “[g]enerally, differences in concentration... will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical” (see also In re Aller (220 F.2d 454 (CCPA): “where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation…” Indeed, as further discussed by the court, “[s]uch experimentation is no more than the application of the expected skill of the [ordinarily skilled artisan] and failure to perform such experiments would, in our opinion, show a want of the expected skill”; see also In re Peterson, 315 F.3d at 1325 (Fed. Cir. 2005): “[t]he normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages” and “[o]nly if the ‘results of optimizing a variable’ are ‘unexpectedly good’ can a patent be obtained for the claimed critical range” (quoting In re Antonie (559 F.2d 618 (CCPA 1977))).
In the instant case, the amount of active ingredient administered for the treatment of a condition is clearly a result-effective variable. In fact, as indicated by the court in Ariosa Diagnostics, Inc. v. Sequenom, Inc., 809 F.3d 1282, 1293 (Fed. Cir. 2015), every ordinary artisan in medicine performs “merely routine optimization of drug dosage to maximize therapeutic effect.” Accordingly, it would have been customary for an artisan of ordinary skill in the art to determine the optimal concentration of aticaprant to administer in order to best achieve the desired results.
As such, claim 12 is also rejected as prima facie obvious.
Claim 23 is drawn to the method of claim 1, wherein the first reference dynorphin level is about 30 pg/mL.
For the same reasons as discussed above regarding claims 22 and 24, it would have been prima facie obvious to limit the method of Fava et al (for the treatment of MDD comprising orally administering 10 mg of the kappa-selective opioid receptor antagonist aticaprant) specifically to the treatment of MDD in a patient identified as a biomarker signature positive patient based on having a level of dynorphin in a biological sample obtained from said patient that is greater than a first reference dynorphin level and, in particular, wherein the first reference dynorphin level is about 30 pg/ml.
It would have been prima facie obvious to do so in order to limit the method of Fava et al to those patients suffering from MDD that are likely to respond to treatment with the kappa-selective opioid receptor antagonist aticaprant, while excluding those patients suffering from MDD that are less likely to respond to treatment with the kappa-selective opioid receptor antagonist aticaprant, with a reasonable expectation of success. It is evident that a patient suffering from MDD having a dynorphin level of greater than 30 pg/mL would entail a patient having significantly elevated dynorphin levels and, thus, a patient highly likely to respond to treatment with the kappa-selective opioid receptor antagonist aticaprant.
As such, claim 23 is also rejected as prima facie obvious.
Claim 9 is rejected under 35 U.S.C. 103(a) as being unpatentable over Fava et al (Annals of Clinical Psychiatry 33:18-26, published 2/01/2021) in view of Al-Hakeim et al (Acta Neuropsychiatrica 32:99-108, 2020) as applied to claims 1, 10-14 and 22-24 above, as further evidenced by Cayman Chemical (“Aticaprant Product Information”, available online at https://www.caymanchem.com/product/35464/aticaprant, accessed 10/08/2026).
Claim 9 is drawn to the method of claim 1, wherein the aticaprant is S-aticaprant.
The findings of the prior art have been set forth above.
As evidenced by Cayman Chemical, the formal name of CERC-501 (i.e., aticaprant) is 4-[4-[[(2S)-2-(3,5-dimethylphenyl)-1-pyrrolidinyl]methyl]phenoxy]-3-fluoro-benzamide.
Accordingly, it is evident that the administration of CERC-501 (i.e., aticaprant) as taught by Fava et al in view of Al-Hakeim et al entails administration of aticaprant wherein the aticaprant is S-aticaprant.
As such, claim 9 is also rejected as prima facie obvious.
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 §§ 706.02(l)(1) - 706.02(l)(3) 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 USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The 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/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1, 9-14, 16 and 22-27 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims of EACH of U.S. Patent Nos. 11,998,524, 11,998,525, 12,150,929, 12,161,622, 12,171,743, 12,419,859.
Although the claims at issue are not identical, they are not patentably distinct from each other. Each of the above Patents are drawn to a method for treating MDD in a patient in need thereof, comprising orally administering about 2 mg to about 35 mg of aticaprant once daily to said patient.
It would have been obvious to
However, none of the Patents teach the treatment of MDD in a patient identified as a biomarker signature positive patient as recited by the instant claims.
For the same reasons as discussed above, it would have been prima facie obvious to limit the methods of the above Patents (for the treatment of MDD comprising orally administering about 2 mg to about 35 mg of the kappa-selective opioid receptor antagonist aticaprant once daily to a patient in need thereof) specifically to the treatment of MDD in a patient identified as a biomarker signature positive patient based on having a level of dynorphin in a biological sample obtained from said patient that is greater than a first reference dynorphin level, in further view of Al-Hakeim et al. It would have been prima facie obvious to do so in order to limit the methods of the above Patents to those patients suffering from MDD that are likely to respond to treatment with the kappa-selective opioid receptor antagonist aticaprant, while excluding those patients suffering from MDD that are not likely to respond to treatment with the kappa-selective opioid receptor antagonist aticaprant, with a reasonable expectation of success.
Conclusion
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611
