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 .
Applicants' arguments, filed 12/01/2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Election/Restrictions
Claims 14-15, 22-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/15/2025.
Claim Rejections - 35 USC § 103--Previous
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) 1-13, 18 and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Kapp et al., (WO 2017/046416, cited in IDS) in view of Baranyai et al., (Dalton Trans. 2015).
Kapp et al. teaches compounds “exhibiting highly active and selective to ανβ6 integrin, which are represented by the following formula (I): Cyclo-(Arg-X1 - Asp-X2-X3-X4-X5-X6-X7) wherein the variables groups X to X have the following meanings X1: Ser, Gly, Thr, X2: Leu, lie, Nle, Val, Phe, X3: Leu, Nle, Val, Phe, Lys, Tyr, Arg, X5: D-Pro, N-Me-D-lipophilic amino acids, X6: Pro, N-Me-amino acids, N-Me-Lys(Ac), and X7; Ala, Lew, He, Nle, Val, Phe, Tyr, Trp or wherein the sub-sequence -X5-X6- represents a β-turn mimetic differing from the meanings above, or pharmaceutical acceptable salts, esters, solvates, polymorphs or modified forms thereof represented by the following general formula (II): (X0)n1L(X8)n2 wherein X0 represents the compound of the general formula (I) as specified above (excluding one hydrogen atom to allow bonding to the linker), L represents a linker, X8 represents the effector moiety and wherein n1 and n2 are each independently selected from the range of 1 to 5, wherein n1 +n2 represents the number of valences of the linker and is preferably in the range of from 2 to 6, more preferably 3-5, with the proviso that each n1 and n2 is at least 1, as well as uses therefore in therapy imaging” (Abstract).
The reference teaches specific embodiments “FRGDLAYp (NMe)K” and “YRGDLAFp (NMe)K” (p. 33, Table 1, compounds 19 and 21 respectively). Accordingly, it would have been obvious to provide the claimed Cp structure, i.e., cyclo(YRGDLAYp(NMe)K with the effector moiety.
Concerning the effector moiety and linker L, the prior art teaches, “The linker may also be multivalent to allow for the bonding of two or more compounds of the present invention and/or two or more effector moieties X8. . . . The additional one or more valences of the linker may be used for bonding additional compounds of the invention and/or additional moieties” (p. 20 last paragraph to p. 21,1st paragraph). Accordingly, it would have been obvious to have a conjugate of E(Tyr2)1, E(Tyr2)2, ETyr2)3,E(Tyr2)4 as per claim 2.
The prior art appears to suggest Cp(Aa’)p, as per claim 3, insofar as it teaches formula (II): (X0)n1L(X8)n2 wherein X0 represents the compound of the general formula (I) as specified above (Abstract).
Concerning claim 4, the prior art teaches, “Effector moieties that can be used as labels for SPECT or PET imaging include radioisotopes and atomic groups containing one or more of such radioisotopes” (p. 23, 3rd paragraph).
Concerning claims 5 and 8, the prior art teaches, “Imaging with the MRI technique can be effected by using a suitable contrast agent as the effector moiety X8. Most preferred are Gd(III) chelate complexes” (p. 23, last paragraph).
In regard to claims 6-7, the prior art teaches, “Suitable radioisotopes include 11C . . . 64Cu . . .” (p. 23, 4th paragraph).
Suitable effector moieties include “therapeutic agents” such as “a drug for the treatment of cancer, a virus disease, or fibrosis” (p. 24, 4th paragraph), as per claim 9, 14, 15.
Concerning claims 10 and 21, the prior art teaches use of a “linker”, sufficing as the “spacer” in the instant claims, which “may consist of or contain linear, branched and/or cyclic structural elements typically consisting of atoms selected from C, H, N, O, S and P”, wherein the number of atoms in the linker “may be within the range of 2 and 250, preferably 4 to 100 and more preferably 7 to 60” (p. 22, 1st paragraph).
Concerning claims 11-13 (and the elected species effector group), the prior art teaches, “For instance, it is advantageous to use azide groups and alkyne groups for copper catalyzed [3+2] cycloadditions. This approach is described by M.L.Hovlid et al. in ‘Guiding plant virus particles to integrin-displaying cells’ in Nanoscale 2012, 4, 3698 and in ‘A shortcut to high-affinity Ga-68 and Cu-64 radiopharmaceuticals: one-pot click chemistry trimerization on the TRAP platform’ by Z. Baranyai et al. in Dalton Trans., 2015, 44, 11137. The synthetic approaches taken in these articles may be adapted to the use of the compound of the present invention” (p. 26, last paragraph).
That being said, Baranyai et al. teaches, “Due to its 3 carbonic acid groups being available for bioconjugation, the TRAP chelator (1,4,7-triazacyclononane-1,4,7-tris(methylene(2-carboxyethylphosphinic acid))) is chosen for the synthesis of trimeric bioconjugates for radiolabeling” (Abstract).
Baranyai et al. teaches the structure formulae of TRAP:
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(see p. 11138), which makes obvious the elected species, 68Ga-TRAP (effector moiety), as well as newly added claim 21, where the R groups have been substituted by cyclo(YRGDLAYp(NMe)K.
Concerning claim 18, Kapp et al. teaches, “The compounds of the present invention can be formulated with excipients to yield pharmaceutical compositions” (p. 28, 1st paragraph).
It would have been obvious to a person having ordinary skill in the art at the time of applicant’s filing to make the conjugate as claimed for the advantage of binding ανβ6 integrin for therapeutic, diagnostic, and biomolecular research (see Kapp et al. p. 1, 1st paragraph). Following the suggestion of Kapp to use synthetic approaches by Z. Baranyai et al., it would have also been obvious to use the elected 68Ga-TRAP as the effector moiety.
Response to Arguments
i. Applicant argues, “the Office entirely fails to offer any explanation of why a skilled person would select either compound as a lead compound for modification” (p. 15). Applicant further argues, “the selection of compounds 19 and 21 as a starting point by the Office can only be explained based on structural similarity with the claimed conjugates” (p. 16).
The Examiner disagrees.
Lead-modification analysis is a useful tool but is not necessary to establish a prima facie case of obviousness. Altana Pharma AG v. Teva Pharms. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009) (“to the extent Altana suggests the prior art must point to only a single lead compound for further development efforts, that restrictive view of the lead compound test would present a rigid test similar to the teaching-suggestion-motivation test that the Supreme Court explicitly rejected in KSR.”)
The prior art teaches formula (I): Cyclo-(Arg-X1 - Asp-X2-X3-X4-X5-X6-X7) wherein the variables groups X to X would have provided the claimed cyclo(YRGDLAYp(NMe)K as evidenced by the specific embodiments shown in the prior art, i.e., “FRGDLAYp (NMe)K” and “YRGDLAFp (NMe)K” (p. 33, Table 1, compounds 19 and 21 respectively). One would only need to replace FRGD of claim 19 with YRGD of claim 21 to arrive at the claimed compound.
In Wrigley, the Federal Circuit found a "strong case of obviousness based on the prior art references of record. [The claim] recites a combination of elements that were all known in the prior art, and all that was required to obtain that combination was to substitute one well-known agent for another." Win. Wrigley Jr. Co. v. CadburyAdams USA LLC, 683 F.3d 1356, 1364 (Fed. Cir. 2012). The same situation applies here, where all of the elements were known in a single prior art reference and represented alternatives taught and exemplified by Kapp et al.
ii. Applicant argues, “Kapp that teaches away from the present claims” insofar as “affinity towards ανβ6 integrins for compound 18 (an IC50 value of 0.26 nM) is numerically superior to those for compounds 19 and 21” (p. 17). Applicant further states, “compound 18 differs from compounds 19 and 21 at least in that the former includes two phenylalanine residues, while each of the later has one of these residues replaced with a tyrosine residue” and “Kapp might accordingly teach the skilled person that replacement of phenylalanine by tyrosine in the compounds disclosed therein is harmful”.
However, Kapp does not teach away from the claimed compound insofar as it does not criticize, discredit, or otherwise discourage the making of the claimed compound. The claimed compound is simply an obvious variant of the formula I of Kapp et al.
Furthermore, no evidence has been presented proving harm associated with the construction or use of the claimed compound. It is well settled, “Arguments presented by the applicant cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965) and In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984).
iii. Applicant argues that the instant specification provides evidence of unexpected results sufficient to overcome the art of record. Specifically, applicant states, “the Tyr2 conjugate of the present claims reduced unspecific uptake (i.e., exhibited superior target specificity) as compared to the conjugate of Kapp” as well as “more rapid clearance from the blood pool” and “improved tumor/organ ratios” (p. 18).
However, any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected. In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986) (differences in sedative and anticholinergic effects between prior art and claimed antidepressants were not unexpected). In In re Waymouth, 499 F.2d 1273, 1276, 182 USPQ 290, 293 (CCPA 1974), the court held that unexpected results for a claimed range as compared with the range disclosed in the prior art had been shown by a demonstration of "a marked improvement, over the results achieved under other ratios, as to be classified as a difference in kind, rather than one of degree." Compare In re Wagner, 371 F.2d 877, 884, 152 USPQ 552, 560 (CCPA 1967) (differences in properties cannot be disregarded on the ground they are differences in degree rather than in kind); Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) ("we generally consider a discussion of results in terms of ‘differences in degree’ as compared to ‘differences in kind’ . . . to have very little meaning in a relevant legal sense").
In this case, applicant results, showing marked improvement over results with other conjugates constitute a difference in degree from what is expected from the combination rather than a difference in kind, as required for a demonstration of unexpected results. Again, the compounds of Kapp et al. “can be used as drugs or as tools for molecular imaging and diagnosis (PET/SPEC/UV-Vis tracers), for coating of medicinal relevant surfaces or for biophysical investigations of the function of this integrin subtype” (p. 1, 6th paragraph). One would need to engage in nothing more than routine optimization from among the various embodiments of the prior art to arrive at the claimed compound.
Conclusion
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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Any inquiry concerning this communication or earlier communications from the examiner should be directed to WALTER E WEBB whose telephone number is (571)270-3287 and fax number is (571) 270-4287. The examiner can normally be reached from Mon-Fri 7-3:30.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana Kaup can be reached (571) 272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Walter E. Webb
/WALTER E WEBB/Primary Examiner, Art Unit 1612