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 27, 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.
Drawings
Applicants amended the drawings filed June 27, 2026, the issues identified in the March 23, 2026 Office have been fully resolved. Therefore, the drawings received on June 27, 2026 are acceptable.
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, 2, 6, 12, 13, 18, and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Brotin and Dutasta (Chemical Reviews, 2009) in view of Panagopoulos et al. (The Journal of Organic Chemistry, 2010).
This rejection is MAINTAINED for the reasons of record set forth in the Office Action mailed March 23, 2026 and those set forth herein.
Regarding new claim 18, Brotin discloses that the cryptophanes can be complexed with laser-polarized xenon such as 129Xe for NMR (Nuclear Magnetic Resonance) spectroscopy, magnetic resonance imaging (MRI), and other medical diagnostics applications (pages 114-120, 9. Xenon in the Cryptophane Cavity; pages 127-128, 11. Conclusion).
Regarding new claim 20, Brotin discloses the structure of cryptophane-C (page 89, Chart 1), which has OMe at Z1, Z2, and Z3 positions
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Applicant argues that the rejection requires impermissible hindsight reconstruction of Applicant's claimed aza-cryptophane compounds. Applicant argues that Brotin and Panagopoulos would not have provided a reason to perform the specific transformation required to arrive at CR1N.
This argument is unpersuasive. As discussed in the Office Action mailed March 23, 2026, Brotin teaches the structure of cryptophane-C which is substantially similar to that of CR1N of instant application, differing only in the presence of nitrogen functionalization. Brotin explicitly teaches that cryptophanes, including cryptophane-C are useful as 129Xe-based biosensors for NMR and MRI diagnostic applications. In biomedical sensing, modulating electronic charges, tuning host-guest interactions, and improving solubility are well-known, ongoing technical objectives. Panagopoulos explicitly teaches that replacing apical methylene carbon atoms with nitrogen atoms (aza-substitution) in cyclotriveratrylene (CTV)-based structures allows modulation of electronic charges, tuning of host-guest properties, and improved utility in diagnostic system. Therefore, applying Panagopoulos’s nitrogen substitution strategy to Brotin’s diagnostic cryptophane scaffolds to enhance biomedical utility represents a logical and predictable modification to a PHOSITA. The motivation to combine Brotin and Panagopoulos stems directly from the explicit problem-solving disclosures within the prior art itself, rather than impermissible hindsight.
Applicant argues that the cited references provide no reason to make particular sequence of selections because the number of possible combinations and modifications suggested by the references is substantial.
This argument is unpersuasive. Cryptophane-C, discloses in Chart 1 of Brotin is substantially similar in basic frame to the claimed CR1N compound. Combining known host scaffolds with established substitution strategies is obvious. The mere existence of multiple design options in the prior art does not confer patentability on a specific selection. The existence of a finite number of potential choices does not preclude obviousness. The fact that it would have been equally obvious to use other possible combinations and modification from the references does not make the claimed structure any less obvious. Selecting a specific option from a finite number of predictable choices discloses in the prior art is within the routine skill of a PHOSITA.
Applicant argues that the cited references would not have provided a reasonable expectation that the resulting modified cryptophane would be successfully synthesized, would maintain the required cryptophane cage structure, or would retain useful xenon-complexing properties.
This argument is unpersuasive. Panagopoulos provides a clear blueprint for nitrogen substitution in CTV units. Applying the teachings of Panagopoulos to the closely related cryptophane-C scaffold of Brotin constitutes no more than the predictable use of prior art elements according to their established functions. A PHOSITA would have expected success because Panagopoulos demonstrates that nitrogen substitution in CTV-based structures preserves the fundamental host framework while fine-tuning host-guest properties. There is no evidence suggesting that nitrogen replacement collapses the core cavity structure. Given Panagopoulos’s teaching that aza-substitution modulates the properties for diagnostic utility, a PHOSITA would reasonably expect the modified cryptophane to retain core cage geometry and xenon-complexing capabilities. Neither Brotin nor Panagopoulos teaches away from the modification, nor does the prior art suggest that aza-substitution would render the cryptophane inactive or structurally unstable. Further, Applicant fails to provide any comparable data or unexpected technical results demonstrating that the specific aza-substitution at the apical position disrupts the overall cryptophane structure or abolishes xenon binding. Absence persuasive evidence of technical failure or unexpected properties, a PHOSITA would have arrive at the claimed invention through routine experimentation with a high expect of success.
Applicant argues that CR1N has improved solubility compared with cryptophane-A. Applicant argues that the specification also shows that nanoemulsions loaded with cryptophane-A are less stable than nanoemulsions loaded with cryptophane of the invention. Applicant argues that Panagopoulos does not teach that replacing apical carbon atoms of a cryptophane scaffold with nitrogen atoms would improve solubility, loading, or nanoemulsion stability.
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. The primary reference in the rejection is cryptophane-C, not cryptophane-A. The applicant’s comparative data against cryptophane-A fails to demonstrate unexpected results over the closest prior art (cryptophane-C). To establish unexpected results, the foaming or enhancement must significantly exceed what a person having ordinary skill in the art would have reasonably anticipated based on the prior art. Applicant fails to provide direct comparison with the closest prior art (Brotin and Panagopoulos 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 than what would be predicted from a simple additive effect of Brotin and Panagopoulos, the showing is insufficient to rebut the obviousness. Furthermore, Panagopoulos explicitly teaches that nitrogen atom substitution improves physicochemical properties and diagnostic utility. Any resulting increase in solubility or formulation stability is a predictable quantitative enhancement (a matter of degree) consistent with the prior art teachings, rather than an unexpected technical effect. Applicant cannot rely on properties that naturally flow from a modification that is obvious to a PHOSITA. The limited experimental data such as solubility and nanoemulsion loading of a specific species compared with a specific compound does not establish that the entire claimed genus of claim1 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 Brotin and Panagopoulos to substitute one known element for another would have been obvious to a PHOSITA, and because the Applicant has not provided sufficient objective evidence to demonstrate unexpected results, the rejection of claim 1 is maintained.
Applicant argues that the claims 2, 6, 12, and 13 are in condition for allowance because they depend on claim 1 and none of the other references are submitted to cure the deficiencies of the cited art.
This argument is unpersuasive. As discussed above and in the office action mailed March 23, 2026, claims 1, 2, 6, 12, 13, 18, and 20 are rejected over Brotin in view of Panagopoulos. No other references are necessary to maintain this rejection.
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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/JONG HWAN BAEK/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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