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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 04/30/2026 has been entered.
Election/Restrictions
Applicant’s election of Group (I) in the reply filed on 12/08/2024 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Applicant’s election of
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species in the reply filed on 12/08/2024 is acknowledged and maintained. This compound reads on the following substituents of the compound of formula (I)
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Expansion of Election of Species Requirement
A reasonable and comprehensive search conducted by the Examiner determined that the prior art at the time of the present invention was such that it did not anticipate or render obvious the elected species
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. In light of this discovery, the search is expanded to the subject matter of the subgenus of the elected species, i.e., the compound of the formula (I)
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and
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where:
Het is an unsubstituted aryl;
R1 and R2 are each a hydrogen atom;
n is 1;
R3 is hydrogen;
R4 is and hydrogen atom; and
R5 is –(C(O)R6 where R6 is an unsubstituted aryl.
Claims Status
Claims 1-3, 5, 9, 12, 14-21, 27-31 are pending. Claims 4, 6-8, 10-11, 13, 22-26, and 32-33 are canceled. Claims 15, 17, 30-31 are withdrawn. Claims 1-3, 5, 9, 12, 14, 16, 18-21, and 27-29 are examined in accordance to the expanded compound species.
Priority
This application is the US national phase under 35 U.S.C. § 371 of International Application No. PCT/US2020/014636, filed January 22, 2020, which claims priority to U.S. Provisional Application No. 62/795,549, filed January 22, 2019 and U.S. Provisional Application No. 62/871,951, filed July 9, 2019.
Action Summary
The objection to claims 1, 9, and 21 are withdrawn in light of the claim amendment.
The objection to Claim 3 is withdrawn in view of the newly formulated rejection set forth below.
Claims 1, 2, 4, 5, 9, 12, 14, 16, 18, 19, 21, and 28-29 rejected under 35 U.S.C. 102(a)(1) as being anticipated by Leibeschuetz et al (WO1999011657A1), are withdrawn in light of the claim amendment.
Claims 1, 2, 4, 5, 9, 12, 14, 16, 18-21, and 27-29 rejected under 35 U.S.C. 103 as being unpatentable over Leibeschuetz et al (WO1999011657A1) as applied to claims 1, 2, 4, 5, 9, 12, 14, 16, 18, 19, 21, and 28-29 set forth in the above rejection, are also withdrawn in light of the claim amendment.
New 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 1, 2, 5, 9, 12, 14, 16, 18-21, and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Zymalkowski et al (STN ACCESSION NUMBER: 1966:404153) as applied to claims 1, 2, 9, 12, 14, 16, 18-21, and 27 set forth in the above rejection in view of Holtman et al (US8,710,069 B2) and Balboni et al. (Eur. J. Med. Chem. 35 (2000) 979–988).
Zymalkowski teaches nornicotine derivatives comprising
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and
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. (See Abstract.) These compounds read on the claimed compound of the formula (I)
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where:
Het is an unsubstituted aryl;
R1 and R2 are each a hydrogen atom;
n is 0;
R3 is hydrogen;
R4 is and hydrogen atom; and
R5 is –(C(O)R6 where R6 is an unsubstituted aryl. With respect to the limitation of “wherein Rg, Rh and Ri are independently selected from alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cyano, hydroxy, amino, acylamino,preferably, methyl, ethyl, methoxy, ethoxy, chloro, fluoro, trifluoromethyl, trifluoromethoxy, hydroxy, acetylamino, butanoylamino, and pentanoylamino” of claims 14 and 19, which both depend from claim 1; the fact that Rg, Rh and Ri are optional substituents of aryl or heteroaryl or R6, then claim 2 is interpret to encompass compounds in which Rg, Rh and Ri are absent.
Zymalkowski does not expressly teach piperidine, but instead expressly teaches pyrrolidine. Moreover,Zymalkowski does not expressly teach pyridine is pyridyl-3yl as recited in claims 27- 28 and a pharmaceutically acceptable carrier in claim 29. Moreover,
Holtman teaches a pharmaceutical composition comprising an analgesically effective amount of a nornicotine compound and at least one pharmaceutically acceptable excipient. (See claims 21.) Moreover, Holtman teaches nornicotine
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, the primary metabolite of nicotine, binds to nicotinic receptors which are located in the brain, spinal cord and periphery (autonomic ganglia and Smooth muscle). It has recently been appreciated that nicotinic receptor binding can also modulate pain signals to the brain suggesting their potential use in the treatment of pain (acute, chronic, cancer-elated). (See column 1, lines 38-44.) Please note that nornicotine has the same core structure as the claimed compound of formula (I).
Balboni is directed to structure-activity for a series of thirty 2-(3-pyridylaminomethyl) azetidine, pyrrolidine and piperidine analogues as nicotinic acetylcholine receptor (nAChR) ligands and expressly investigates the effect of azacycle ring size on biding affinity and compares the pyrrolidine compound with the corresponding expanded piperidine derivatives. (See Abstract.) Balboni reports that ring-expanded derivatives 26 and 33 have affinities of 97 and 623 nM, respectively, compared with the parent pyrrolidinyl analogues 12 at 305 nM. It further reports that the 6-chloro piperidine derivatives 28 retains the binding property of its corresponding pyrrolidine analogue 26.
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. (See Table 1.)
It would have been prima facie obvious to one of ordinary skill in the art at the time the invention was filed to modify the pyrrolidine ring of Zymalkowski compound by expanding the five-membered pyrrolidine ring to the corresponding six-membered piperidine ring, as taught by Balboni, in order to obtain an additional ring-size homolog within the within the known class of 3-pyridyl-containing azacyclic compounds. Although Zymalkowski does not expressly describe a pharmaceutical utility of nicotinic activity for the disclosed nornicotine derivatives, Holtman teaches nornicotine and structurally related nornicotine compounds possess pharmacological activity, including activity associated with nicotinic acetylcholine receptors, and teaches their use as analgesic agents. Thus, Holtman would have provided one of ordinary skill in the art with reason to recognize the structurally related nornicotine compounds of Zymalskowski as useful lead compounds for obtaining additional pharmacologically active nicotinic compounds. Balboni provides an express reason for making this modification because Balboni specifically investigates azabicyclic ring size as a structural variation and prepares and evaluates both pyrrolidine and corresponding ring-expanded piperidine analogues.
One would have had a reasonable expectation of successfully obtaining the proposed piperidine analog because Holtman establishes pharmacological activity for structurally related nornicotine compound, while Balboni demonstrates that both pyrrolidine and ring-expanded piperidine members of structurally related 3-pyridiyl azacyclic compounds could be prepared and retained nicotinic receptor-binding activity. Thus, the prior art provided both a reason to make the proposed ring-size modification and a reasonable expectation that the resulting piperidine analog would retain useful nicotinic activity. The claims do not require any particular degree of nicotinic receptor affinity or improvement in activity.
With respect to claims 27-28, Zymalkowski further teaches 1-(N-glycyl-3-phenylalanyl)-2-(3-pyridyl)-(RN 6474-88-0), having an R3-bearing carbon corresponding to that recited in claims, wherein R3 is benzyl (an aralkyl) and the carbon bearing R3 is expressly shown as having the (S) absolute configuration. Thus, Zymalkowski expressly teaches the stereochemical confifuation recited in claim 27.
With respect to the alternative (R) configuration recited in claim 28, the (R) stereoisomer differs from the corresponding (S) taught by Zymalkowski only in the spatial configuration about the same stereogenic carbon while retaining the same atom connectivity and substituents. The (R) and (S) stereoisomers therefore possess a high degree of structural similarity. In the absence of evidence demonstrating that the claimed (R) stereoisomer possesses an unexpected property relative to the corresponding (S) stereoisomer, the structural similarity of the stereoisomers supports a prima facie case of obviousness. One of ordinary skill in the art would have had a reason to prepare the alternative member of the structurally related stereoisomeric pair and would have reasonably expected to possess properties generally associated with the same chemical structure.
Accordingly, the (S) and (R) configurations recited in claims 27 and 28, respectively, do not render the claimed compounds nonobvious over the combined teachings of Zymalkowski and Balboni.
With respect to claim 29, Zymalkowski and Balboni, as discussed above, collectively render obvious the compound of claim 1. However, Zymalkowski, Holtman, and Balboni do not expressly teach a pharmaceutical composition comprising the compound and a pharmaceutical acceptable excipient. Holtman further taches pharmaceutical compositions comprising a nornicotine compound and at least one pharmaceutically acceptable excipient. (See claim 21; column 1, lines 38-44.))
It would have been obvious to one of ordinary skill in the art before the effective filing dated of the claimed invention to formulate the compound suggested by Zymalkowski, Holtman, and Balboni with a pharmaceutically acceptable excipient, as expressly taught by Holtman, in order to provide the compound in a form suitable for pharmaceutical administration. One of ordinary skill in the art would have had a reasonable expectation of success because Holtman expressly teaches pharmaceutical compositions of structurally related nornicotine compounds comprising pharmaceutically acceptable excipients, and the use of such conventional pharmaceutically acceptable excipients would have been reasonably expected to provide a pharmaceutically administrable composition. Therefore, the combined teachings of Zymalkowski and Balboni, and Holtman render obvious the subject matter of claim 20.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Zymalkowski et al (STN ACCESSION NUMBER: 1966:404153) as applied to claims 1, 2, 5, 9, 12, 14, 16, 18-21, and 27-29 set forth in the above rejection in view of Holtman et al (US8,710,069 B2) and Balboni et al. (Eur. J. Med. Chem. 35 (2000) 979–988) in further view of Olesen et al. (Bioorganic & Medicinal Chemsitry 6 (1998) 1623-1629.)
The teachings of Zymalkowski, Holtman, and Balboni have been discussed above.
However, Zymalkowski, Holtman, and Balboni collectively do not teach the 1,2,5,6-dihydropyridine scaffold.
Olesen teaches 3-(5-alkylamino-4-isoxazolyl)1,2,5,6-tetrahydropyridines as a class of central nicotinic acetylcholine receptor ligands. (See Abstract.) Olesen explains that the tetrahydropyridine azacyclic unit had been used to produce ligands having affinity for central nicotinic receptors and further teaches that the tetrahydropyridine azacycle can be sued as a cationic head for preparing ligands having high affinity and selectivity for nicotinic acetylcholine receptors. (See p. 1623, introduction section right column.) Consistent therewith, Olesen prepared a series of 1,2,5,6-tetrahydropyridines compounds 4a-4h and demonstrated that several of these compounds exhibited high affinity for central nicotinic receptors. (See pp. 1624 and 1625, Scheme 1, and Table 1.) Olesen further reports that compounds 4a-4f exhibited affinity with compound 4c exhibiting anIC50 of 4.6 nM at the α4β2 receptor subtype, and concludes that the tetrahydropyridine azacycle constitutes a cationic heat capable of providing compounds selective for central nicotinic receptors. (See pp. 1625-1626.)
It would have been prima facie obvious to further modify the six-membered saturated azacyclic ring of the compound of Zymalkowski in view of Holtman and Balboni by introducing the corresponding degree of unsaturation to provide the 1,2,5,6-tetrahydropyridines azacyclic ring of Formula (IB), as taught by Olesen. One of ordinary skill in the art would have been motivated to make such modification because Olesen expressly teaches 1,2,5,6-tetrahydropyridines azacyclic unit as a useful cationic head for preparing nicotinic acetylcholilne receptor ligands having high affinity and selectivity and demonstrates that compounds containing this azacyclic unit exhibit nicotinic receptor-binding activity. Thus, in view of Holtman’s teaching that structurally related nornicotinie compounds possess pharmacological/nicotinic activity, Balboni’s teaches that modification of azacyclic ring is a recognized structure-activity variable in nicotinic receptor ligands, and Olesen’s teaching that unsaturated six-membered tetrahydropyridine azacycle is useful for providing nicotinic receptor ligands, one of ordinary skill in the art would have reason to employ the tetrahydropyridine azacycle taught by Olesen as an alternative six-membered azacycle moiety in the structurally related compound suggested by the combined teachings of Zymalkowski, Hotlman, and Baboni.
One of ordinary skill in the art would also have had a reasonable expectation of success in obtaining a compound retaining nicotinic receptor activity because Olesen does not merely suggest the tetrahydropyridine ring theoretically, but actually prepares compounds containing 1,2,5,6-tetrahydropyridines azacycle ad demonstrated nicotinic receptor binding activity for such compound. In particular. Olesen reports high affinity for several of compounds 4a-4f and expressly concludes that the tetrahydropyridine azacycle provides a cationic head useful in nicotinic receptor ligands. (See pp. 1624-1626; Tabes 1-2, Discussion and Conclusion Sections.) Accordingly, the combined teachings of Zymalkowski, Holtman, Balboni, and Olesen render compound of claim 3 prima facie obvious.
Response to Arguments
Acknowledgement is made of the receipt and entry of Applicant’s argument, filed on April 30, 2026.
As the outset, the rejection of claims 1, 2, 4, 5, 9, 12, 14, 16, 18, 19, 21, and 28-29 under 35 U.S.C. 102, are withdrawn in view of the amendment to claim 1, requiring n to be 1 or 2. Further, the previously present rejection under 35 U.S.C. 102 has been withdrawn and replaced by the new rejections set forth above Accordingly, Applicant’s argument directed specifically to the factual findings and rationale of the withdrawn rejections are moot. Nevertheless, to the extent Applicant’s argument concern the propriety of relying upon the structurally related compounds of Zymalkowski in an obviousness analysis, the arguments have been considered and not persuasive against the presently applied rejection.
Applicant argues that one of ordinary skill in the art seeking new or improved NF-Ϗβ inhibitors would not have looked to Zymalkowski or Holtman because those references do not concern NF-Ϗβ inhibition, but instead, concern nornicotine compounds and nicotinic receptor activity.
In response, this argument is not persuasive. The presently examined claimed compounds do not require that the claimed compounds inhibit NF-Ϗβ, much less require any particular degree of NF-Ϗβ inhibition. The patentability of the claimed compounds therefore does not turn upon whether the prior art would have motivated one of ordinary skill specifically to develop an NF-Ϗβ inhibitor. Rather, the relevant inquiry is whether the prior art as a whole would have provided a motivation to make the claimed compounds, with a reasonable expectation of obtaining the properties reasonably expected from the proposed structural modification. A prior art compound need not be modified for the same purpose ultimately identified by Applicant where the claimed structure itself would have been obvious for reason supplied by the prior art. See MEPE 2141; In re Dillon, 919 F.2f 688, 693, 16 USPQ 1897, 1902 (Fed Cir. 1990) (en banc).
Applicant further contends that selection of a Zymalkowski compound would constitute a random or hindsight-drive selection because Zymalkowski does not disclose NF-Ϗβ inhibition.
In response, this argument is likewise not persuasive under the presently formulated rejection. Zymalkowski is not relied upon merely because one of its compounds can be retrospectively modified to resemble Applicant’s compound. Rather, Zymalkowski expressly teaches nornicotine derivatives having a highly similar 3-pyridyl-substiuted nitrogen heterocyclic framework and the same relevant acylamino side-chain arrangement relied upon in the rejection. Thus, Zymalkowski provides a structurally specific starting point, rather than an arbitrary compound selected from the universe of known chemical structures.
Moreover, the present rejection does not rely upon Zymalkowski in isolation to establish why one of ordinary skill would have investigated modification of that structure. Holtman supplies the pharmacological context absent from Zymalkowski by teaching that nornicotine and structurally related nornicotine compounds were recognized as pharmacologically active compounds associated with nicotinic acetylcholine receptors. Balboni further provides an express structure-activity rationale for modifying the azacycle portion of such pyridiyl-containing nicotinic ligands. Specifically, Balboni expressly investigates azetidine, pyrrolidine, and piperidine analogues and expressly evaluates the effect of azacyclic ring size on nicotinic receptor-binding affinity. Thus, the proposed pyrrolidine-to-piperidine modification is not a modification selected with knowledge of Applicant’s disclosure, but instead is a structural variable expressly investigated in the prior art for closely related nicotinic ligands.
Applicant further argues that neither Zymalkowski nor Holtman provides guidance concerning which modification would produce new or improved NF-Ϗβ inhibitors and therefore asserts that numerous choices would have been necessary to reach the claimed compounds.
In response, this argument is not persuasive. This argument addresses a requirement not imposed by the claims or by §103. Because the compound claims do not require NF-Ϗβ inhibitory activity, the prior art need not have taught which structural changes would optimize NF-Ϗβ inhibition. The pertinent question is whether structural modification actually required to reach the claimed compound was suggested by the prior art. Here, Balboni expressly identifies zazcyclic ring size as an SAR variable and actually prepares and evaluates corresponding pyrrolidine and piperidine compounds. Thus, the presently applied rejection supplies a specific reason for the particular ring expansion rather than relying upon an unguided selection from innumerable possible modifications.
Applicant’s reliance upon in re Payne does not compel a different result. Applicant correctly notes that Payne involved prior-art and claimed compounds having pesticidal activity. However, Payne does not establish that a claimed compound can be obvious based upon structural similarity only when the prior art discloses the identical ultimate utility asserted by Applicant. MPEP §2144.09 explains that close structural similarity, together with the facts bearing upon expected properties, may establish a prima facie case and further makes clear that a true homologous or isomeric relationship is not required. Moreover, Dillon expressly recognizes that establishment of a prima facie case does not invariably require both structurally similarity and an expectation from the prior art that the claimed compound will possess the same newly discovered utility relied upon by Applicant.
In the present case, however, the rejection is stronger than on based on structural resemblance alone. Zymalkowski provides the closely related starting structure; Holtman establishes that pharmacological utility for the structurally related nornicotine class; and Balboni expressly teaches that particular azacyclic-ring modification employed in the rejection and demonstrates that both pyrrolidine and piperidine 3-pyridyl analogues possess nicotinic receptor-binding activity. Accordingly, the evidence provides both a reason to make the claimed structurally modification and a reasonable expectation that the resulting closely related compound would retain useful biological activity. Obviousness does not require certainty or an expectation that the modified compound would exhibit quantitatively identical or superior activity; only a reasonable expectation of success is required. MPEP §2144.09.
Applicant’s hindsight argument is not persuasive. The proposed modification is derived from the teachings of the prior art itsef: Zymalkowski supplies the structurally close nornicotine derivative, Holtman supplies the recognized pharmacological significance of the nornicotine structural class, and Balboni expressly identifies ring-size modification within closely related 3-pyridiyl azacyclic nicotinic ligands as a subject of structure-activity investigation. The rejection therefore does not reconstruct Applicant’s compound using Applicant’s disclosure as a roadmap.
With respect to claims 27 and 28, the presently applied rejection is additionally supported by Zymalkowski’s disclosure of pyrrolidine, 1-(N-glycyl-3-phenylalanyl)-2-(3-pyridyl) -(CAS RN 6474-88-0), which expressly provides the corresponding stereogenic carbon bearing the R3-substituent and shows the (S) absolute configuration. Accordingly, the limitation of claim 27 is expressly taught at the corresponding stereocenter. Claim 28 recites the alternative (R) configuration at that same stereocenter. The (R) and (S) configurations retain identical atomic connectivity and differ only in spatial configuration at the stereogenic carbon and therefore are closely structurally related stereoisomers. Such stereochemical relationship is a relevant consideration in the obviousness inquiry, absent evidence establishing that the alternative stereoisomer would have been expected to possess materially different or unpredictable properties. See MPEP §2144.09.
Applicant has not identified persuasive objective evidence demonstrating that the presently claimed compounds, including the recited stereoisomers, exhibit unexpected properties attributable to the structurally differences over the applied prior art. Accordingly, the arguments do not overcome the prima facie case establishing by the combined teachings of Zimalkowski, Holtman, and Balboni.
Conclusion
Claims 1-3, 5, 9, 12, 14, 16, 18-21, and 27-29 are not 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.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
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