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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 06/22/2026 has been entered.
Applicants' arguments, filed 06/22/2026, 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 Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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.
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 remain 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).
FRGD and YRGD were known amino acid sequences at the time of applicant’s filing. The prior art 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
The declaration of Johannes Notni, filed 06/22/2026 is acknowledged.
In the declaration, affiant postulates that the claimed compounds demonstrate unexpected technical effects, specifically “entirely unexpected quality of diagnostic imaging as compared to state of the art” (p. 12, ¶ [21]). Affiant states, “The overall quality, tumor uptake, and tumor-to-background (muscle) ratios are unprecedented for avβ6-integrin targeted PET probes” (p. 4, ¶ [6]); “Tumor uptake doses are much higher than observed for previously reported avβ6-integrin targeted radioligand therapy agents, and entirely unprecedented for this compound class” (p. 6, ¶ [8]); “68Ga-Trivehexin PET/CT imaging shows 80.0% sensitivity and 93.8% specificity whereas [18F]FDG-PET/CT imaging accomplishes only 72.0% sensitivity and 62.5% specificity”, which “allows for improved therapy decisions for patients, meaning they can get more appropriate treatment based on 68Ga-Trivehexin PET/CT imaging” (p. 7, ¶ [10]). Applicant’s arguments echo the sentiment of the declaration arguing against routine optimization (p. 13-20).
However, the concepts relied upon to make and use the claimed conjugate are taught in Kapp et al. The compounds of Kapp et al. are taught to be “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 claimed cyclopeptide sequence is a species of formula (I) of Kapp et al., i.e. Cyclo-(Arg-X1 - Asp-X2-X3-X4-X5-X6-X7) and the concept of using 68Ga-Trivehexin, which is Gallium-68, cyclic peptide, complexed with TRAP, would have been obvious insofar as Kapp et al. taught, “Hermann, H.-J Wester. ‘TRAP, a Powerful and Versatile Framework for Gallium-68 Radiopharmaceuticals” (p. 23, 3rd paragraph) and “’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.” (p. 26, last para.).
Note: TRAP acts as the central molecular core and chelator in Trivehexin.
Note: Hermann and Baranyai et al. were part of the teaching in Kapp et al. insofar as they were incorporated therein by reference (see Kapp et al. p. 35, last line through p. 36, first line).
Further, since Kapp et al. also teaches the same utility, i.e. bioimaging of human cells (see Figure 1; p. 33-34 6.4. Example 3: Bioimaging of cancer cells), it is unclear how applicant’s results are unexpected. The compounds are taught to be “useful in a variety of applications including use as therapeutic agent, diagnostic agent, targeting moiety and biomolecular research tool” (p. 1, 1st paragraph). Moreover, “The diagnostic agents of the present invention are particularly suitable for imaging methods such as fluorescence-based imaging, positron emission tomography (PET), single-photon emission computed tomography (SPECT), optical imaging or magnetic resonance imaging (MM), X-ray based CT imaging, scintigraphy, ultrasonography and thermography” (p. 30, sec. 5.7, 2nd paragraph).
The artisan would have reasonably expected compounds of formula (I) to differ in their utility as bioimaging and diagnostic tools. See Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 ("The 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.");
The issue is whether the properties differ to such an extent that the difference is truly 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 of imaging over results with other conjugates constitute a difference in degree from what is expected from the compound 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
All claims are identical to or patentably indistinct from, or have unity of invention with claims in the application prior to the entry of the submission under 37 CFR 1.114 (that is, restriction (including a lack of unity of invention) would not be proper) and all claims 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 CFR 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 CFR 1.114. See MPEP § 706.07(b). 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
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