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 .
Application Status
The amendment filed on 12/19/2025 is acknowledged and has been entered. Claims 72-74, 77-93 are currently pending and under consideration
Rejections Maintained/Amended in view of Applicants amendment
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.
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) 72-74 and 77 is/are rejected under 35 U.S.C. 103 as being unpatentable over Walpole et al. (J. Med. Chem. 1993, 36, 2381-2389, IDS).
Walpole et a. teach the structural consequences of structural variation of the hydrophobic side chain (“C-region) of the capsaicin molecule on activity in in vitro bioassays which we have established are predictive of analgesic activity
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(page 2381, First column, Introduction). When discussing these analogs, Walpole et al. teaches that it is clear from the data shown in Table 1 that aromatic substituents can be accommodated in this putative binding site, although the mode of attachment of the B ring unit is critical, wherein this is exemplified in the subset of p-chlorophenyl-substituted compounds shown in Table III suggest that a constrained, linear, extended conformation of a two-carbon spacer unit is optimal (high potency of 6b
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wherein the double bond is in the E and X is Cl and 12
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) (page 2383, 1st column, 1st full paragraph). Moreover, Walpole teaches that conformationally flexible analogues (8b
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wherein X is Cl and the bioequivalent “reverse” amide 13
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) can be accommodated well by this model (page 2383, 1st column, 1st full paragraph). In addition to the 4-choloro derivative, the reference teaches other substitutions at the 4 position including, but not limited to,
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The prior art differs from the claimed invention
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, wherein X is Cl, NO2, CN, I, or Ph or where X is in the 2 and 4 position substituted with Cl in that the single bond of for example, compound 13 is a double bond or alternatively, compound 8b, for example, has a reverse amide.
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to modify the compounds taught by Walpole et al. to either substitute the single bond with a double bond of for example, compound 13 or substitute the conformation position of the amide. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Walpole teaches that a constrained, linear, extended conformation of a two-carbon spacer unit is optimal such as in compounds 8b and 12, and
-Walpole et al. teach that conformationally flexible analogues (8b
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wherein X is Cl and the bioequivalent “reverse” amide 13
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) can be accommodated well by this model conformational.
Accordingly, there would be a reasonable expectation that a compound having the structure
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, wherein X is Cl, NO2, CN, I, or Ph or where X is in the 2 and 4 position substituted with Cl is with analgesic activity.
In order to expedite prosecution, the Examiner would like to address Applicants arguments relating to the previous rejection which concentrated primarily on X being a Cl. In response, Applicants contend that the compound of claim 77 (YB10) provides an unexpectedly superior 26 fold decrease in EC50 (0.047mM) in the Ca2+ influx assay compared to the 1.24 mM EC50 obtained with compound 6 b of Walpole et al.
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Accordingly, Applicants assert that the compound of claim 77 possess unexpectedly superior activity which would overcome a prima facie case of obviousness.
These arguments have been carefully considered, but are not found persuasive.
First, a careful review of the specification, as originally filed, does not appear to provide any experimentation involving determining the Ca2+ influx of the compound of claim 77. As such, it is unclear whether the results are truly unexpected since the assay conditions can not be compared. Moreover, objective evidence which must be factually supported by an appropriate affidavit or declaration to be of probative value includes evidence of unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor. See, for example, In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984). Assuming arguendo that Applicants are correct in that the reverse amide (Compound YB-10 in claim 77) decreased Ca2+ influx compared to compound 6b of the reference the results do not appear to be unexpected. For example, a comparison of compound 8b (EC50 of 3.09) and 13 (EC50 of 0.66) of Walpole et al. appears to suggest that reversing the amide bond results in a significant decrease in Ca2+ influx (4 fold decrease) (see Table 1). As such, there is a reasonable expectation that such decrease would also apply to compound 6b and YB-10. The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992)
Claim(s) 83-87 and 90-93 is/are rejected under 35 U.S.C. 103 as being unpatentable over Walpole et al. (J. Med. Chem. 1993, 36, 2381-2389, IDS), as applied above to claims 72-74 and 77, in view of Campbell et al. (US5,962,532, 1999-10-05).
The teachings of Walpole et al. have been described above and incorporated herein. In particular, Walpole et al. suggests a structurally similar capsaicin compound to analogue 8b
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and the bioequivalent “reverse” amide 13
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having the structure
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wherein X is Cl, NO2, CN, I, or Ph or where X is in the 2 and 4 position substituted with Cl which would reasonably be expected to have analgesic activity in view of the teachings of Walpole et al..
The suggestion of Walpole et al. differs in that the reference does not teach a pharmaceutical composition comprising the capsaicin compound or a method of treating a disorder such as pain from arthritis or cancer pain.
Campbell et al. teach methods and compositions for treating pain at a specific site with an effective concentration of capsaicin or analogues thereof (abstract). With regards to the pain, the US Patent teaches that pain includes, but is not limited to, pain associated with arthritic conditions and pain from soft tissues (column 2, lines 28-36). With regards to the compositions, the US patent teaches that composition include capsaicin or analogues thereof in a concentration between about 0.01 and 10% by weight ( column 3, lines 47-52).
It would have been prima facie obvious to one of ordinary skill in the art, prior to the effective filing date of the instantly claimed invention, to substitute the capsaicin analogues in compositions used in the method of treating pain taught by Cambell et al. for the compound suggested by Walpole et al. One of ordinary skill in the art would have been motivated to make such a substitution, with a reasonable expectation of success, because:
-Walpole teachings would have suggested that the capsaicin compound having the structure
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wherein X is Cl, NO2, CN, I or Ph would reasonably have similar analgesic activity to compounds 8b and 13 of Walpole et al..
Regarding the claims drawn to the functional activities of activating TRP or blocking the activation of Src or activating TRPV1 in vitro or in vivo or inhibiting cancer growth or metastasis in vitro or in vivo, the claimed limitations appear to be either a property of the compound or directly related to the amount of the compound given. In the instant case, the US patent teaches that composition include capsaicin or analogues thereof in a concentration between about 0.01 and 10% by weight. Accordingly, it would be reasonable to include the compound suggested by Walpole et al. in the composition in the same amount. Applicants are reminded that the office does not have the facilities and resources to determine if the composition of the prior art would also have those same properties. Burden is on Applicants to determine whether the prior arts compositions will function as presently claimed. See MPEP 2112.01.
Conclusion
Claims 78- 82 and 88-89 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BRANDON J FETTEROLF whose telephone number is (571)272-2919. The examiner can normally be reached M-F 6AM-4PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S Lundgren can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/BRANDON J FETTEROLF/ Primary Examiner, Art Unit 1626