DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 12/05/2025 has been entered.
AIA Status of the Claims
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 Arguments
In Applicant’s response filed 3/17/2025, Applicant elected a single species of Formula (I), which is Compound 68 having the following structure:
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, which reads on claims 1-6, 13-16 and 18.
In the Action mailed on 5/02/2025, the elected species (i.e., instant Compound 68) was rejected under 35 U.S.C. 103(a) as being unpatentable over Kirpotina et al (Molecular Pharmacology 77:159-170, 2010; of record) in view of Williams et al (Foye’s Principles of Medicinal Chemistry, 5th Edition, Pages 59-63, 2002; of record) and the following two compounds were additionally rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kirpotina et al (Molecular Pharmacology 77:159-170, 2010; of record):
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; and
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.
In the Action mailed on 9/05/2025, the rejections of claims under 35 U.S.C. 102(a)(1) were WITHDRAWN, while the rejection under 35 U.S.C. 103(a) was MAINTAINED.
In Applicant’s instant response filed 12/05/2025, Applicant traverses the rejection of Compound 68 under 35 U.S.C. 103(a) as being unpatentable over Kirpotina et al (Molecular Pharmacology 77:159-170, 2010; of record) in view of Williams et al (Foye’s Principles of Medicinal Chemistry, 5th Edition, Pages 59-63, 2002; of record).
Applicant first argues that “Kirpotina does not teach or suggest any compound where R3 is chlorine” (Applicant Arguments, Page 8).
This is not disputed. Indeed, as discussed in the basis of the rejection, Kirpotina et al teach the following compound species:
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(Page 165, Table 3, Compound AG-9/49), which differs from Applicant’s elected compound species in comprising a bromine atom at the position identified in Formula (I) as R3 as opposed to a chlorine atom.
Applicant is, however, reminded that 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 (CCPA 1981); In re Merck & Co., 800 F.2d 1091 (Fed. Cir. 1986). In the instant case, it would have been prima facie obvious to a person of ordinary skill in the art at the time the invention was made to replace the bromine atom in Compound AG-9/49 taught by Kirpotina et al with a chlorine atom to arrive at Applicant’s instantly elected Compound 68 with a reasonable expectation of success, based further on Williams et al.
Yet, as further argued by Applicant, “the present application teaches the preference for chlorine at the R3 position with its presence being observed in all claimed compounds as well as most representative CB1 allosteric modulators in scheme 1” (Applicant Arguments, Page 8). In particular, pointing to “the specification as filed, pg 27, lines 10-3”, Applicant argues that “changes to this portion of the molecule... resulted in lowered potency” (Applicant Arguments, Page 8). As such, Applicant argues that “[o]ne of skill in the art would recognize this part of the core scaffold of the molecule to which changes would have an unpredictable effect producing different biological properties”, further pointing to MPEP § 2144.09(V), which states that “[t]he presumption of obviousness based on a reference disclosing structurally similar compounds may be overcome where there is evidence showing there is no reasonable expectation of similar properties in the structurally similar compound” (Applicant Arguments, Page 9).
The argument is not found persuasive. As discussed in the basis of the rejection, Williams et al teach that the replacement of a bromine atom with a chlorine atom is a known isosteric or bioisosteric replacement that can be carried out “without losing the desired biological activity” of the parent compound, with a reasonable expectation of success. That is, the prior art teaches that there is a reasonable expectation of similar properties in the structurally similar compounds. Applicant has not provided any evidence to suggest that the prima facie obvious compound, Compound 68, based on said modification of Compound AG-9/49 (taught by Kirpotina et al) exhibits different biological properties from Compound AG-9/49.
Applicant, however, argues that “[t]he changes at the indicated R3 position are not simple bioisosteric replacements” (Applicant Arguments, Page 9).
However, Applicant provides no support for this argument. As such, the argument is not found persuasive. It is maintained that, as taught by Williams et al, -Cl and -Br are classic monovalent bioisosteres that can replace each other, with a reasonable expectation of success (Page 61, Table 2.9).
Lastly, Applicant argues that, “looking at the compounds found in Table 5 pg 106... it can be seen that changes in other positions such as varying the halogen groups at the R6 position between Cl and F result in a 10-fold change in [35S]GTPγS binding IC50. Therefore, the rejection fails to adequately recognize the changes suggested between the claimed compounds and the cited art lack a reasonable expectation of similar properties” (Applicant Arguments, Page 10).
At the outset, the rejection is based on modifying Compound AG-9/49 (taught by Kirpotina et al) at the position identified in Formula (I) as R3 and not R6. Nevertheless, regarding the “10-fold change in [35S]GTPγS binding IC50” following modification at R6, as argued by Applicant, it is significant that Compounds 47 and 71 – which differ only in that R6 is 4-Cl or 4-Br, respectively (i.e., the exact modification that forms the basis of the instant rejection of claims) – exhibit no change in [35S]GTPγS binding IC50, confirming the teaching in Williams et al that one of ordinary skill in the art would reasonably expect structurally similar compounds differing only in the replacement of one halogen atom for another halogen atom to exhibit similar properties. Moreover, these two compounds (i.e. Compounds 47 and 71), as well as Compound 63 (wherein R6 is 4-F), all also exhibit a similar IC50 in the hCB1R Calcium assay (i.e., 164 + 15, 108 + 19 and 151 + 20, respectively). The fact that Compound 63 (wherein R6 is 4-F) exhibits a “10-fold change in [35S]GTPγS binding IC50” compared to Compounds 47 and 71 is considered to be unexpected.
For all the foregoing reasons, Applicant’s arguments are not found persuasive. The rejection of Compound 68 is MAINTAINED.
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 1-6, 13-16 and 18 are MAINTAINED rejected under 35 U.S.C. 103(a) as being unpatentable over Kirpotina et al (Molecular Pharmacology 77:159-170, 2010; of record) in view of Williams et al (Foye’s Principles of Medicinal Chemistry, 5th Edition, Pages 59-63, 2002; of record).
Claim 1 is drawn to a compound of Formula (I) which embraces Applicant’s elected compound species:
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wherein X1 is C; R1, R2, R4 and R5 are each H; R3 is chlorine; L1 is alkylene; and R6 is halide substituted aryl (i.e., chloride substituted phenyl), which reads on claims 1-6 and 13-16.
Kirpotina et al teach the following compound species
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(Page 165, Table 3, Compound AG-9/49), which differs from Applicant’s elected compound species in comprising a bromine atom at the position identified in Formula (I) as R3 as opposed to a chlorine atom.
Yet, as taught by Williams et al “[w]hen a lead compound is first discovered for a particular disease state, it often lacks the required potency and pharmacokinetic properties suitable for making it a viable clinical candidate… The medicinal chemist therefore must modify the compound to reduce or eliminate these undesirable features without losing the desired biological activity. Replacement or modification of functional groups with other groups having similar properties is known as isosteric or bioisosteric replacement” (Page 59). Although it is clear that “the use of bioisosteric replacement (classical or nonclassical) in drug development is highly dependent upon the biological system being investigated” and that “[n]o hard and fast rules exist to determine what bioisosteric replacement is going to work with a given molecule” it is also clear that “some generalizations have been possible” (Page 60). Notably, one such generalization is that -Cl and –Br (which are classic monovalent bi isosteres) can replace each other (Page 61, Table 2.9).
Accordingly, it would have been prima facie obvious to a person of ordinary skill in the art at the time the invention was made to replace the bromine atom in Compound AG-9/49 taught by Kirpotina et al with a chlorine atom. The person of ordinary skill in the art at the time the invention was made would have been motivated to make the bioisosteric modifications to synthesize similar compounds that retain biological activity, but have improved physiochemical properties and better pharmacokinetic behavior.
As such, claims 1-6 and 13-16 are rejected as prima facie obvious.
Claim 18 is drawn to a pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
As taught by Kirpotina et al, “[t]he compounds were diluted in DMSO at a concentration of 2 mg/ml and stored” (Page 160, Column 2, Materials).
It would have been obvious to similarly dilute the prima facie obvious compound in DMSO and, since DMSO entails a pharmaceutically acceptable carrier, claim 18 is also rejected as prima facie obvious.
Conclusion
All claims are drawn to the same invention claimed in the application prior to the entry of the submission under 37 C.F.R. 1.114 and could have been finally rejected on the grounds and art of record in the next Office Action if they had been entered in the application prior to entry under 37 C.F.R. 1.114. Accordingly, THIS ACTION IS MADE FINAL even though it is a first action after the filing of a Request for Continued Examination and the submission under 37 C.F.R. 1.114. See MPEP 706.07(b). Applicant is reminded of the extension of time policy as set forth in 37 C.F.R. 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 extension fee pursuant to 37 C.F.R. 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 CRAIG D RICCI whose telephone number is (571) 270-5864. The examiner can normally be reached on Monday through Thursday, and every other Friday, 7:30 am - 5:00 pm ET.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bethany Barham can be reached on (571) 272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/CRAIG D RICCI/Primary Examiner, Art Unit 1611
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