DETAILED ACTION
This Office Action details final action on the merits of the above referenced application No. Claims 1-20 are pending in this application.
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 .
Status of Claims
Claims 1-4, 6, 10, 14-16, and 19 are amended.
Response to Amendment
The claim amendments filed on 25 Aug. 2026 have been entered.
Response to Arguments
In view of Applicants amendments, the rejection of claim 7 under 35 USC 112(b) as being indefinite is withdrawn.
In view of Applicants amendments, the rejection of claims 1-8, 12-14, 16, and 20 under 35 USC 102(a)(1) as being anticipated by Li et al. (Med. Chem. Commun.; published 2012) is withdrawn.
In view of Applicants amendments, the rejection of claims 1-8, 11-16, and 20 under 35 USC 103 as being unpatentable over Li et al. (Med. Chem. Commun.; published 2012) is withdrawn.
In view of Applicants amendments, the rejection of claims 1-16 and 18-20 under 35 USC 103 as being unpatentable over Li et al. (Med. Chem. Commun.; published 2012), in view of Blom et al. (J. Label Compd Radiopharm.; published 2009) and Perrin et al. (WO 2009/012596 A1; published 2009) is withdrawn.
In view of Applicants amendments, the rejection of claims 1-20 under 35 USC 103 as being unpatentable over Li et al. (Med. Chem. Commun.; published 2012), in view of Blom et al. (J. Label Compd Radiopharm.; published 2009) and Perrin et al. (WO 2009/012596 A1; published 2009), in further view of Jacobson et al. (Bioconjugate Chem.; published 2015) is withdrawn.
In view of the approved terminal disclaimer, the rejection of claims 1-20 on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of US patent No. 11,628,229 B2, in view of Li et al. (Med. Chem. Commun.; published 2012), Blom et al. (J. Label Compd Radiopharm.; published 2009) and Perrin et al. (WO 2009/012596 A1; published 2009) is withdrawn.
New Grounds of Rejection
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 2-20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
In this case, instant claims 2 and 3 has been amended so that the 18F perfluoroaryl compound is reacted with the perfluoroaryl target tracer compound comprising radiolabeling and so that 18F perfluoroaryl compound is an 18F salt and claim 9 depends to claims 2 and 3 and requires that the 18F salt is K18F, etc. The amendment to claims 2 and 3 are indefinite and do not make sense since K18F is not a perfluoroaryl compound and since the 18F-perfluoroaryl compound in claim 1 is the 18F labeled radiotracer wherein the biological activity of the biological moiety is preserved. The Examiner suggests amending claims 2 and 3 so that the 18F perfluoroaryl compound is the 18F compound in claim 1. Dependent claims 4-11 fall therewith.
In this case, instant claim 13 is dependent to claim 1 and requires that the providing the 18F compound comprises radiolabeling and reacting the 18F compound with the target tracer compound comprises conjugation; however, claim 1 as amended requires a perflouroaryl target tracer compound having a biological active moiety and reacting the 18F compound with the perfluoroaryl target tracer compound and so in this case the 18F compound cannot be a perfluroaryl compound formed by reaction of an 18F salt with a non-radioactive perfluoroaryl compound that reacts with a target tracer compound to form a 18F-labeled radiotracer. Dependent claims 14-20 fall therewith.
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) 1-9, 11-16, 18, and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (Med. Chem. Commun.; published 2012), in view of Blom et al. (J. Label. Compd Radiopharm.; published 2009) and Perrin et al. (WO 2009/012596 A1; published 2009).
Li et al. teach harvesting 18F-fluoride ions in water via direct 18F-19F isotopic exchange (see title). The discovery of general and reliable protocols for the rapid incorporation of a 18F-fluorine atoms into biomolecules would be highly beneficial especially if the protocols could be carried out directly in irradiated water. Li et al. teach the use of a fluoride binding agent that is appended to a biomolecule and treated with 18F-fluoride just prior to use (pg. 1305). Li et al. teach the synthesis of 2 and 3
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(scheme 1). Li et al. teach the direct isotope 18F-19F isotopic exchange reaction employed for the radiolabeling of 1-3 in aqueous solution
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(scheme 2). The reactions are performed in 100±10 µL of [18O]water solution containing 15±5 µL of MeCN used for solubilization of the phosphonium trifluoroborate. The reactions are performed at room temperature for 20 min (table 1). Li et al. teach 85% and 87% conversions at pH 3.0 and 1.5, respectively (table 1).
(Method comprising: a) providing a 18F compound (18F-fluoride ion); b) providing a target tracer compound having a biological moiety (1-3; biological moiety=phosphonium moiety); and c) reacting the 18F compound with the target tracer compound in a solvent (water) and at a temperature (room temperature) that is mild for the biological moiety, thereby forming the 18F-labeled radiotracer, wherein the biological moiety is preserved and wherein the solvent in which the 18F compound is reacted with comprises a second solvent that is predominantly water and comprises a trace amount of MeCN cosolvent.)
The carboxylate functionalized borane 3 behaves similar to 1 and is amenable to facile radiofluorination by isotope exchange (pg. 1307). Li et al. teach injecting [18/19F]1 and [18/19F]2 in female nude mice and whole body PET imaging (pg. 1307; Fig. 2). The 18F-19F isotopic exchange reaction can be used to radiolabel aryltrifluoroborates directly in the irradiated [18O] water. Because of short reaction times and limited isotopic dilution, this method affords radiolabeled compounds with reasonably good activities. The carboxylic acid functionalized derivative 3 should be amenable to simple bioconjugation protocols, opening new horizons for the radiolabeling of amine terminated biomolecules (pg. 1308).
Li et al. do not teach providing a perfluoroaryl compound having a biological moiety and reacting the 18F compound with the perfluoroaryl target tracer compound. Li et al. do not further teach that the providing the perfluoroaryl tracer compound having a biological moiety comprises conjugation and reacting the 18F perfluoroaryl compound with the perfluoroaryl target tracer compound comprises radiolabeling wherein the 18F perfluoroaryl compound is a 18F salt such as K18F or Na18F and wherein the providing the perfluoroaryl target tracer compound having the biological moiety comprises reacting the target tracer compound with a non-radioactive perfluoroaryl compound in a first solvent that is predominantly water at a temperature that is mild for the biological moiety thereby forming a perfluoroaryl target tracer compound wherein the perfluoroaryl target tracer compound is non-radioactive and wherein a biological activity of the biological moiety is preserved optionally wherein the temperature is at most 60 oC and optionally wherein the target tracer compound is an antibody or organic small molecule. Li et al. do not teach that providing the 18F compound comprises radiolabeling and reacting the 18F compound with the target tracer compound comprises conjugation, optionally reacting an 18F salt (Na18F) with a non-radioactive perfluoroaryl compound such that the perfluoroaryl compound is 18F-labeled thereby forming the 18F compound. Li et al. do not teach that the 18F labeled radiotracer is used as a companion diagnostic or companion therapeutic for treatment or diagnostic applications.
Perrin et al. teach substituted aryl-fluoroborates as imaging agents (see title). Perrin et al. teach that aryl moieties are selected so that their substituents contribute to an overall electron withdrawing effect, permit the resulting fluoroborate to resist defluorination (pg. 2). Perrin et al. teach that groups which facilitate addition of a biomolecule are well known in the art. These include thiol and amine reactive group and other groups which may be useful for joining a compound of the invention to functionalities on biomolecules. Exemplary linking groups for coordination to biomolecules included
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(pg. 32). Perrin et al. teach biomolecules include peptides, antibodies, etc (pg. 33). Perrin et al. teach 84, RT 9-089 and CH-01-059 (pg. 41). Perrin et al. teach the NHS activated molecule
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(pg. 44). Perrin et al. teach aqueous solvent (pgs. 46,53). Tracer molecules used in this invention may be conjugated to a ligand such as biomolecule that preferentially interacts with a tissue type. A precursor of aryl boronic acid may be pre-conjugated to a biomolecule of interest and subsequently fluorinated when needed in a one-step aqueous fluorination reaction (pg. 46). Reaction temperature may be increased above room temperature but below a temperature that may destabilize or denature the selected biomolecule (pg. 47). Perrin et al. teach [18F]-NaF (pg. 59).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify the method of Li et al. (method of preparing an 18F labeled radiotracer for use in PET, the method comprising: a) providing an 18F compound (18F-fluoride); b) providing a target tracer compound having a biological moiety (1-3); and c) reacting the 18F compound with the target tracer compound in an aqueous solvent having tracer MeCN as a cosolvent and at room temperature that is mild for the biological moiety, thereby forming the 18F-labeled radiotracer wherein the biological activity of the biological moiety is preserved) so that the target tracer compound is a perfluoroaryl target tracer compound and so that the 18F compound is an 18F salt such as Na18F and so that the biologically moiety is a peptide or antibody and so that the providing of the perfluoroaryl target tracer compound comprises conjugations such that the target tracer compound reacts with a non-radioactive perfluoroaryl compound in a first solvent that is predominantly water at a temperature that is mild for the biological moiety (<60oC) thereby forming a perfluoroaryl target tracer compound wherein the perfluoroaryl target tracer compound is non-radioactive and wherein the biological activity of the biological moiety is preserved and so that the aqueous solvent comprises at most 10% ACN co-solvent) as taught by Li et al. and Perrin et al. because the perfluoroaryl compound would have been expected to provide stabilization with electron withdrawing groups and because the 18F salt such as Na18F would have been expected to provide an equivalent 18F compound suitable for forming a 18F tracer compound and because the peptide and antibody biologically active moiety conjugated to the pefluoroaryl compound by reacting the target tracer compound with a non-radioactive perfluoroaryl compound in a first solvent that is predominantly water at about room temperature would have been expected to advantageously provide a targeted tracer compound capable of fluoride capture with 18F just prior to injection. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify the method of Li et al. so that the 18F-labeled radiotracer is used as a companion diagnostic for treatment or diagnostic application as taught by Li et al. and Perrin et al. because it would have been expected to advantageously enable in vivo PET diagnosis and/or determining the effectiveness of treatment.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Li et al. so that providing the 18F compound comprises radiolabeling optionally by reacting an 18F salt such as Na18F with a non-radioactive perfluoroaryl compound such that the perfluoroaryl compound is 18F-labeled and reacting the 18F compound with the target tracer compound comprises conjugation and optionally prior to reacting the 18F salt with the non-radioactive perfluoroaryl compound conjugating the non-radioactive perfluoroaryl compound to a linker with an active functional group or optionally so that the non-radioactive perfluoroaryl compound has a functional group that acts as a linker for direct or indirect conjugation to the target tracer compound as taught by Li et al. and Perrin et al. because the radiolabeling, conjugation, and active functional group would have been expected to advantageously enable two step 18F labeling of a biological active moiety where labeling is performed prior to conjugation.
Claim(s) 1-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (Med. Chem. Commun.; published 2012), in view of Perrin et al. (WO 2009/012596 A1; published 2009), in further view of Blom et al. (WO 2009/012596 A1; published 2009) and Jacobson et al. (Bioconjugate Chem.; published 2015).
Li et al. teach as discussed above.
Li et al. do not further teach a perfluoroaryl compound according to the formula
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or a method wherein the target tracer compound has a functional group that reacts with the 18F labeled compound via aromatic nucleophilic substitution.
Perrin et al. teach as discussed above.
Blom et al. teach 18F/19F exchange in fluorine containing compounds for potential use in 18F-labeling strategies (see title). Blom et al. teach that multi-fluorinated molecules containing an electron withdrawing group were successfully labeled at room temperature, whereas monofluorinaed as well as those containing electron-donating groups required heating for the exchange reaction to take place (see abstract). Blom et al. teach incorporation yields for reaction of hexafluorobenzne 8, 11, and 16 with NCA [18F]fluoride at room temperature (Fig. 1, table 3). Blom et al. teach [K/K222]+18F- (pg. 509).
Jacobson et al. teach novel method for radiolabeling and dimerizing thiolated peptides (see title). Jacobson et al. teach that the hexafluorobenzene reacts with thiols to produce a unique perfluorinated linkage. This reaction was modified to produce a dimeric 18F-RGD-tetrafluorobenzene RGD, an integrin ανβ3 receptor ligand (see abstract, Fig. 30).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Li et al. so that the perfluoroaryl compound is a compound of formula
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wherein FG=NHS ester; each X=V; Y=F; and Z=Cl, Br, or NO2 as taught by Blom et al. and Perrin et al. because that perfluoroaryl compound would have been expected to provide a fluorinated functional organic prosthetic group comprising electron withdrawing substituents that enable mild 18F exchange labeling of biomolecules under mild conditions. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Li et al. so that the target tracer compound have functional group that reacts with the 18F labeled compound via aromatic nucleophilic substitution as taught by Blom et al. and Jacobson et al. because it would have been expected to advantageously enable a 18F-labeled biological formed under mild conditions and from a biomolecule have a reactive thiol group.
Applicants’ Arguments
Applicants assert that Li does not have the feature of providing a perfluoroaryl target tracer compound having a biological moiety. Li’s work is exchange of 18/19F borate groups which is fundamentally different from the present invention in nature and chemistry. Li’s low pH condition would be detrimental to the biological activity of the biological moiety, therefore Li cannot achieve the critical function of the feature of in the presently claimed invention.
Applicants’ arguments filed 25 Aug. 2026 have been fully considered but they are not persuasive. Li’s work is not fundamentally different from the claims because Li’s work is directed to the use of a fluoride binding agent (fluoride captor) that is appended to a biomolecule and treated with 18F-flouride just prior to injection. While Li carries out direct 18F-19F isotopic exchange with aryl trifluoroboronates at room temperature, the instant claims as amended do not exclude the use of trifluoroboronates appended to a perfluoroaryl group. Perrin is directed to 18F labeling and Perrin teaches that [18F]trifluoroboronates are stabilized by perfluoroaryl groups. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Li’s work so that the aryl trifluoroboronate is a perfluoroaryl trifluoroboronate because the perfluoroaryl trifluoroboronate because the perfluoroaryl trifluoroboronate would have been expected to advantageously provide enhanced stability without a triphenylphosphine group. In addition, Bloom teaches perfluoroaryl groups as analogous fluoride captors that the can be appended to a biomolecule and treated with 18F-fluoride just prior to injection. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Li’s work so that the 18F-19F exchange reaction is carried out a perfluoroaryl target tracer compound rather than a trifluoroboronate because the perfluoroaryl target tracer compound would have been expected to enable room temperature labeling at near neutral pH. Regarding Applicants assertion that Li’s work requires acidic radiolabeling conditions, the claims are not limited to biological moieties sensitive to the pH 1.5 and 3.0 taught by Li such that the biological moiety would completely degrade.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN R DONOHUE whose telephone number is (571)270-7441. The examiner can normally be reached on Monday - Friday, 8:00 - 5:00 EST.
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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618
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