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 .
Response to Arguments
Applicant's arguments, filed June 12, 2026, have been fully considered but they are not deemed to be fully persuasive. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 103
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.
Claims 1-4 and 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (US 8,912,319, 2014; cited on IDS filed August 28, 2023) in view of Wüst and Kniess (Journal of Labelled Compounds and Radiopharmaceuticals, 2004).
This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed March 12, 2026 and those set forth herein.
Regarding new limitations of amended claims 1 and 11, “at about 75 °C to about 95 °C for about 40 minutes to about 80 minutes”, these limitations are derived from canceled claims 6 and 8, and the claims 6 and 8 were rejected over Li in view of Wüst as discussed in the Office Action mailed March 12, 2026.
Applicant argues that the cited art fails to teach or suggest the limitations of amended claims. Applicant argues that Wüst teaches disappointing low yield (16% or 10% after purification) using 1,4-dioxane, which would discourage a person having ordinary skill in the art (PHOSITA) from using it.
This argument is unpersuasive. As discussed in the Office Action mailed March 12, 2026, Li discloses that the conjugation step can be performed at 80-85 °C for 60 minutes (column 15, line 7; Tables 2 and 3). Further, the reaction temperature and time are clearly result effective parameters that a PHOSITA would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a PHOSITA to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the reaction temperature and time in order to best achieve the synthesis efficacy. Wüst discloses that the use of 1,4-dioxane as a solvent can improve the synthesis of the labelled compounds (page 459, lines 1-2). A reference does not need to teach optimal or maximum yields to provide motivation. A reference dos not teach away from a combination simply because its disclosed embodiments exhibit less-than-optimal yields, provided it does not declare the method completely unworkable or obsolete. The express disclosure that 1,4-dioxane is a viable, operational solvent that outperforms other standard solvents such as toluene provides a clear, reasonable motivation for a PHOSITA to select it as a candidate for solvent optimization. Further, the low yield might be good enough as Applicant mentioned in Remarks (page 2, ¶ 4). In the specialized domain of 18F radiochemistry, reactions are performed on an ultra-trace scale solely to generate sufficient radiotracer for clinical imaging. Because high chemical mass yields are not a prerequisite for successful radiotracer deployment, Wüst’s confirmation that 1,4-dioxane yielded an operational, isolated, and pure radiofluorinated product delivers a sufficient and robust motivation to adopt the solvent system.
Applicant argues that a person of ordinary skill in the art would not combined the mechanically distinct systems of references because Wüst involves transition-metal cross-coupling, whereas Li relies on strongly Lewis acidic Friedel-Crafts catalysts. Applicant argues that 1,4-dioxane is a polar Lewis base that would be expected to coordinate to strong Lewis acids, thereby attenuating or completely quenching their catalytic activity, similar to how DMF and DMSO suppress or eliminate desired product formation.
This argument is unpersuasive. Both Li and Wüst belong to the same technical field, the radiosynthesis of 18F-labeled nucleoside analogues. The proper test for obviousness is not whether the specific mechanisms of the two reactions are identical, but whether a PHOSITA, seeking to solve the problem of solvent optimization in radiosynthesis, would look to related art for alternative solvent environments. A PHOSITA optimizing a radiochemical reaction is not confined to a single catalytic mechanism when choosing a solvent, rather they routinely screen solvents known to be effective and stable in radiofluorination conditions within that shared technical field. Regarding 1,4-dioxane as a Lewis base, Applicant’s argument improperly generalizes all polar Lewis bases. Applicant’s comparison of 1,4-dioxane to DMF and DMSO relies on an overbroad chemical generalization. DMA and DMSO are highly polar, strongly coordinating, aprotic solvents that irreversibly poison hard Lewis acids. In contrast, 1,4-dioxane is a cyclic ether. Ether-based solvents are notoriously understood not to permanently poison the catalyst. Instead, they form reversible, transient, and weak coordination complexes with ether Lewis acid. Modulating catalyst activity using weakly coordinating ether solvents is a routine optimization technique in Friedel-Crafts chemistry to prevent over-reaction or decomposition. Therefore, the failure of DMF/DMSO would not create a teaching away or a reasonable expectation of failure for a structurally and electronically distinct solvent like 1,4-dioxane. Further, in Li’s Table 2, entry 5 explicitly shows that THF which is also a cyclic ether and a polar Lewis base yielded a highly functional 38.9% of the desired β-anomer (page 4 of Applicant’s Remarks). Because Li explicitly teaches that a cyclic ether such as THF successfully drives the reaction without destroying the catalyst, a PHOSITA would possess a clear, reasonable expectation of success that a structurally related cyclic ether like 1,4-dioxane would seamlessly function in a similar manner.
Applicant argues that present invention shows surprising and unexpected results. Applicant argues that the substitution of DCE for 1,4-dioxane produces significantly, unexpectedly, improved radiochemical yields like from 32-33% to 48%. Applicant argues that the present invention also demonstrates superior stereoselectivity for diverse substrates.
This argument is unpersuasive. Applicant’s assertions of unexpected results fail to satisfy the requisite legal criteria established under MPEP § 716.02. Objective evidence of unexpected results must be supported by appropriate evidentiary showing, direct comparative data, and must be commensurate in scope with the claims. Applicant has failed to meet this burden based on the following criteria.
First, the alleged results are predictable, not truly unexpected. To establish unexpected results, the foaming or enhancement must significantly exceed what a PHOSITA would have reasonably anticipated. An increase in radiochemical yield from 32-33% to 48% is a modest, incremental improvement, representing a predictable quantitative enhancement (a matter of degree). Such fluctuations in yield and minor enhancements in stereoselectivity are the expected and predictable flow of routine solvent screening. It is known that the solvents like 1,4-dioxane participate in the transient stabilization of the oxocarbenium ion intermediate. By weakly coordinating the oxocarbenium face, the ether solvent effectively shields one side of the molecule, creating steric hinderance that actively directs the nucleophilic attack of the silylated nucleobase to face the β-configuration. While Li’s uncoordinated system lost stereochemical control under high-thermal stress, a PHOSITA seeking to resolve this exact degradation would intentionally select a weakly coordinating ether solvent such as 1,4-dioxane suggested by Wüst to stabilize the reaction intermediate at higher temperatures. Thus the observed retention of β-selectivity is the natural, predictable outcome of ether-mediated stereochemical control. Because the prior art (Wüst) already pointed to 1,4-dioxae as a useful solvent in this specific domain of radiochemistry, the fact that it yielded a favorable optimization profile does not elevate a routine technical success to the level of a patentable, non-obvious breakthrough.
Second, Applicant fails to provide direct comparison with the closest prior art (Li and Wüst individually or in a baseline combination). The evidence of unexpected results must involve a direct, side-by-side comparison between the claimed invention and the closest prior art. Without a direct comparison showing that the actual performance of the claimed compound is significantly better that what would be predicted from a simple additive effect of Li and Wüst, the showing is insufficient to rebut the obviousness.
Third, the results are not commensurate in scope with the claims. To effectively rebut a rejection of obviousness, the disclosure or evidence of unexpected results must be commensurate in scope with the claims to which the evidence is applied. However, Applicant’s arguments rely on narrow, specific comparison about β-anomer yield and stereoselectivity when DCE was substitute for 1,4-dioxane. The limited experimental data does not establish that the entire claimed method would exhibit the same allegedly unexpected properties.
Further, arguments or conclusory statements in the remarks section of a response do not take the place of evidence in the record. Allegations of unexpected results must be explicitly set forth in the originally filed specification or presented in a formal, signed declaration/affidavit accompanied by actual data. Absent the submission of such proper objective evidence, Applicant’s remarks remain mere unsubstantiated allegations that cannot overcome the rejection.
Accordingly, because the combination of teachings of Li and Wüst would have been obvious to a PHOSITA, and because the Applicant has not provided sufficient objective evidence to demonstrate unexpected results, the rejection is maintained.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Li et al. (US 8,912,319, 2014; cited on IDS filed August 28, 2023) and Wüst and Kniess (Journal of Labelled Compounds and Radiopharmaceuticals, 2004) as applied to claims 1-4 and 10-13 above, and further in view of USP 30 (USP 30, Chemical Tests <467> Residual Solvents, 2007).
This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed March 12, 2026 and those set forth herein.
Applicant argues that USP 30 fails to cure the deficiencies of Li in view of Wüst. Applicant argues that USP 30 does not provide the motivation nor an expectation of success that substituting or introducing the Stille reaction solvent environment into Li’s Friedel-Crafts process would yield a successful outcome. Applicant argues that dependent claims are nonobvious if independent claims from which they depend are nonobvious.
This argument is unpersuasive. As discussed in the Office Action mailed March 12, 2026, USP 30 teaches the limits of residual amounts that read on the limit of residual amount of instant claim 9. As discussed above, the combination of teachings of Li and Wüst would have motivated to a PHOSITA to utilize 1,4-dioxane as a solvent to synthesize the 19F-labeled compound more efficiently with a reasonable expectation of success. Accordingly, the dependent claim 9 is maintained obvious because the independent claim 1, from which it depends, is obvious for the reasons discussed above.
Claims 1-4 and 10-13 are rejected under 35 U.S.C. 103 as being unpatentable over Chen and Conti (WO 2019 191642; cited on IDS filed August 28, 2023) in view of Wüst and Kniess (Journal of Labelled Compounds and Radiopharmaceuticals, 2004).
This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed March 12, 2026 and those set forth herein.
Regarding new limitations of amended claims 1 and 11, “at about 75 °C to about 95 °C for about 40 minutes to about 80 minutes”, these limitations are derived from canceled claims 6 and 8, and the claims 6 and 8 were rejected over Chen in view of Wüst as discussed in the Office Action mailed March 12, 2026.
Applicant argues that Wüst provides no motivation to replace Chen’s Friedel-Craft solvent system with Wüst’s Stille cross-coupling solvent system. Applicant argues that Wüst provides no reasonable expectation that substituting or introducing the Stille reaction solvent environment into Chen's Friedel-Crafts process would yield a successful or even observable reaction. Applicant argues that Applicant's surprising and unexpected results of significantly more β-anomer yields often exceeding 50% and favorable β/α ratios are not obvious in view of Chen.
This argument is unpersuasive. As discussed above, both Chen and Wüst operate within the same or closely analogous technical fields, organic synthesis and radiosynthesis. 1,4-dioxane is not a solvent exclusive or restricted to Stille reaction. Rather it is a versatile polar aprotic solvent widely utilized in various organic transformations. A POSITA seeking to optimize reaction yields, improve solubility, or modify reaction conditions for Chen’s Friedel-Crafts mechanism would naturally look to known organic solvents including 1,4-dioxane as Wüst teaches the use of 1,4-dioxane as a solvent can improve the synthesis of the labelled compounds. Routine substitution or optimization of a solvent system represents the exercise of ordinary creativity. As discussed above, Applicant has failed to establish unexpected results because an increase in yield or an improved isomeric ratio is reasonably viewed as the result of routine optimization of reaction conditions which is well within the capability of a POSITA. It represents a predictable quantitative enhancement (a matter of degree). Applicant has failed to provide objective comparative data demonstrating that the claimed methods yields a significant critical difference in results when compared directly to the closest prior art. Applicant has failed to provide sufficient experimental data in the originally filed specification or presented in a formal, signed declaration/affidavit to establish that the entire claimed method would exhibit the same allegedly unexpected properties.
Claim 9 is rejected under 35 U.S.C. 103 as being unpatentable over Chen and Conti (WO 2019 191642; cited on IDS filed August 28, 2023) and Wüst and Kniess (Journal of Labelled Compounds and Radiopharmaceuticals, 2004) as applied to claims 1-4 and 10-13 above, and further in view of USP 30 (USP 30, Chemical Tests <467> Residual Solvents, 2007).
This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed March 12, 2026 and those set forth herein.
Applicant argues that USP 30 fails to cure the deficiencies of Chen in view of Wüst. Applicant argues that USP 30 does not provide the motivation nor an expectation of success that substituting or introducing the Stille reaction solvent environment into Li’s Friedel-Crafts process would yield a successful outcome. Applicant argues that dependent claims are nonobvious if independent claims from which they depend are nonobvious.
This argument is unpersuasive. As discussed in the Office Action mailed March 12, 2026, USP 30 teaches the limits of residual amounts that read on the limit of residual amount of instant claim 9. As discussed above, the combination of teachings of Chen and Wüst would have motivated to a PHOSITA to utilize 1,4-dioxane as a solvent to synthesize the 19F-labeled compound more efficiently with a reasonable expectation of success. Accordingly, the dependent claim 9 is maintained obvious because the independent claim 1, from which it depends, is obvious for the reasons discussed above.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-4 and 9-13 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. US 8,912,319 (cited on IDS filed August 28, 2023) in view of Wüst and Kniess (Journal of Labelled Compounds and Radiopharmaceuticals, 2004), Chen and Conti (WO 2019 191642), and USP 30 (USP 30, Chemical Tests <467> Residual Solvents, 2007).
This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed March 12, 2026 and those set forth herein.
Regarding new limitations of amended claims 1 and 11, “at about 75 °C to about 95 °C for about 40 minutes to about 80 minutes”, these limitations are derived from canceled claims 6 and 8, and the claims 6 and 8 were rejected over the ‘319 in view of Chen as discussed in the Office Action mailed March 12, 2026.
Applicant argues that the cited art, either alone or in combination, fails to teach, suggest, or properly motivate with any reasonable expectation of success that substituting or introducing the Stille reaction solvent environment into Li's Friedel-Crafts process would yield a successful or even observable reaction. Applicant argues that the cited art gives no indication of the surprising and unexpected results achieved by the embodiments described in the instant application.
This argument is unpersuasive. As discussed above and in the Office Action mailed March 12, 2026, a PHOSITA would have been motivated to utilize 1,4-dioxane as a solvent for Friedel-Crafts synthesis method and would have reasonably expected success based on the teachings of Wüst. Accordingly, applying the teachings of Wüst to the method of the ‘319 to utilize 1,4-dioxane as a solvent to improve the synthesis of labeled compound constitutes no more than the predictable use of prior art elements according to their established functions, thereby rendering instant claims obvious. As discussed above, Applicant has failed to establish unexpected results because the data provided in the instant application shows only a limited, predictable improvement, and lacks a direct comparison with the closest prior art.
Conclusion
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 JONG HWAN BAEK whose telephone number is (571)272-0670. The examiner can normally be reached Mon - Thu, 9 am - 3 pm ET.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael G Hartley can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JONG HWAN BAEK/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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