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 .
Acknowledgement of Receipt
Applicant’s Response, filed 4/15/2026, in reply to the Office Action mailed 12/23/2025, is acknowledged and has been entered. Claims 65, 70 and 71 have been amended. Claims 70-84 are newly added. Claims 65-84 are pending, of which claims 74-79 are withdrawn from consideration at this time as being drawn to a non-elected invention. Claims 65-73 and 80-84 encompass the elected invention and are examined herein on the merits for patentability.
Response to Arguments
Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. New grounds for rejection are set forth herein, necessitated by claim amendment.
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.
Claim 84 is 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. The claim is directed to a composition comprising (i) at least one fluorocarbon; and (ii) at least one fluorous chelator; wherein the at least one fluorous chelator is at least partially soluble in the fluorocarbon, and wherein the at least one fluorous hydroxamic acid chelator is the structure shown. However, the claimed structure does not feature a hydroxamic acid moiety (i.e. a structure bearing a -C(=O)-N-(OH)- functional group), which may be the result of a typographical mistake, as such it is unclear in what way a hydroxamic acid is part of the claimed invention. Clarification is requested.
Claim Objections
Claims 80, 81 and 83 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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.
Claim(s) 65-73 and 82 are rejected under 35 U.S.C. 103 as being unpatentable over Tsien et al. (WO 17/147212) in view of Koshti et al. (Synthetic Commun., 2002, 32(24), p. 3779-3790).
Tsien teaches non-invasive imaging methods, comprising (a) administering to a subject a cellular labelling composition comprising a compound comprising fluorine-19 (19F), wherein said compound comprising fluorine-19 (19F) associates with one or more cells; and (b) detecting said association using an imaging modality, wherein said association can include cellular binding and/or cellular uptake. In some embodiments, the method is used for cytotherapy, e.g., cell-based therapy (paragraph 0011).
In some embodiments, the compound comprising fluorine-19 (19F) comprises a perfluorinated compound. In certain embodiments, the compound comprising fluorine- 19 (19F) comprises a metalated perfluorinated compound. In some embodiments, the perfluorinated compound binds and tightly retains metal ions in the fluorous phase. The metal ions can be selected from the group consisting of VO2+, Cr3, Mn2+, Mn3+, Fe3+... 44Sc3+, 52Mn2+, 61Cu²+, 64Cu²+, 66 Ga3+, 68Ga3+, etc. (paragraph 0013- 14). In some embodiments, the perfluorinated compound is formulated as a nanoemulsion. The nanoemulsion can further comprise a perfluorocarbon (paragraph 0015).
Novel metal complexes are provided. In certain embodiments, the metal complexes are represented by formula MLx, wherein M is an element with atomic number 12, 13, or from 23 to 31, or from 38 to 50, or from 56 to 83, L is a suitable ligand bearing a fluorinated substituent Rr, and X is an integer from 1 to 10, including general structures 1-4.
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Z represents O, S, Se, or NR³ X and Y, for each occurrence, independently represent (A)-H, (A)-F, (A)-OR, (A)-SR, (A)- NHR4, or (A)-NR4R5,, wherein A represents a spacer containing from 0 to 8 carbon or heteroatoms, in any combination, optionally substituted with groups R-R20, as a straight chain or branched chain, or containing one or more rings, R1-20 may for each occurrence include, hydrogen , hydroxamic acid, etc. (paragraph 0103).
In some embodiments, the perfluorocarbon compound of the compositions described herein includes or is derived from a linear perfluoropolyether (PFPE), (PFPE- OMe), (PFPEDEA), (PFOB), and PF2G (paragraph 0106).
The fluorinated diketone and/or the perfluorocarbon can be formulated as an aqueous nanoemulsion, such as an oil-in-water colloidal suspension or an oil-in-water colloidal emulsion. Such nanoemulsions can also be formulated to include additional fluorocarbons or fluorocarbon blends (e.g., a mixture of two or more different fluorocarbons). The nanoemulsions can be metalated with a transition metal ion or a lanthanide ion. In some embodiments, the composition ofthe present invention includes iron(III) tris-B-diketonate and perfluoroether (paragraph 0112).
In some embodiments, the nanoemulsion is prepared by microfluidization. An exemplary embodiment of method for preparing a useful emulsion is provided herein. The fluorocarbon oil blends were prepared from PFPE, PFPE-DEA (Exfluor), PFOB, and pAn-FDK agents. Proportions (Table 1) were prepared gravimetrically in a 15 or 50 mL conical Falcon tube. Per 1 gram of PFC blend, 0.5 mL aqueous solution of Pluronic F68 (i.e. surfactant) was added, and the mixture was vortexed at the highest speed.
Water (8.5 mL) was added, followed by brief vortexing and ultrasonication (paragraph 0129).
Pluronic F68-coated emulsions (such as exemplary emulsions 3-9 of Table 1) are easily metalated by a variety of d- and f-block metals in aqueous solution at optimal pH (paragraph 0130). See also paragraph 0145+ directed to emulsions.
Tsien does not specifically recite wherein the chelator contains a fluorinated hydroxamic acid has a structure corresponding to chelator 1, wherein R is an alkyl linker having 4 to 20 carbon atoms.
Koshti teaches that hydroxamic acids are well known to bind hard metal ions like Fe(III) or An(IV). As part of our ongoing program on the synthesis of hydroxamic acids, we have been interested in the synthesis of N-fluoroalkyl-hydroxamic acid ligands with the aim of developing chelating systems that have applications for the extraction of actinides into supercritical carbon dioxide. To our surprise, methodology to access N- fluoroalkylhydroxamates. has not been documented in the literature. Some reports on the synthesis of hydroxamic acids with fluorinated acyl groups have been reported. In this paper, we report the synthesis of three new reagents and their application to prepare a variety of N-fluoroalkylhydroxamic acids, a new class of extractants. See Table 1, showing synthesized N-fluoroalkylhydroxamic acids.
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It would have been obvious to one of ordinary skill in the art at the time of the invention to provide an emulsion containing a fluorinated compound and a metal ligand complex wherein the ligand bears a fluorinated substituent RF, including general structures 1-4 and including a hydroxamate bearing substituent in view of Tsien. One would have been motivated to do so because Tsien teaches that metalation of fluorinated nanoparticles or nanoemulsion can impart contrast in multiple imaging modalities. Introduction of high quantities of metals into the fluorous phase is feasible using metal-binding ligands that are soluble in the fluorous phase (page 113), and further teaches a hydroxamate to be one of a few suitable substituents for use in the fluorinated metal ligand complex (paragraph 0103). It is noted that the fluorinated emulsions contain a surfactant and fluorocarbon. It would have been further obvious to provide a radionuclide as the metal because Tsien teaches that doing so allows for positron emission tomography imaging (paragraph 0120). It would have been further obvious to one of provide a fluorinated hydroxamic acid corresponding to chelator 1 when the teaching of Tsien is taken in view of Koshti. The Supreme Court in KSR International Co. V. Teleflex Inc., 550 U.S. , 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143. In the instant case, the substituted components, fluoroalkyl hydroxamates, and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted one known fluorinated hydroxamic acid chelator for another, and the results of the substitution would have been predictable, that is binding metal, such as iron.
With regard to the limitation wherein the fluorinated hydroxamic acid has a structure corresponding to chelator 1, and wherein R is an alkyl linker having 4 to 20 carbon atoms, it is noted that Koshti’s chelator 9b comprises an alkyl linker having 3 carbon atoms. See MPEP 2144.09. Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
Response to arguments
Applicant argues that Tsien does not describe or suggest fluorous hydroxamic acid chelators, Koshti does not describe or suggest the chelator structures recited in amended claim 65, and that there would have been no motivation to combine Tsien and Koshti. Applicant asserts that in Tsien's system, the metal-binding functionality is provided by the ß-diketone moiety, not by any peripheral R-group substituent, and that the incidental mention of hydroxamic acid as one possible R-group among many does not teach or suggest the use of a compound whose metal chelation is based on hydroxamic acid groups, as recited in amended claim 6.
Applicant’s arguments have been fully considered but are not found to be persuasive. See MPEP 2145. One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). It is respectfully submitted that the rejection is based on the combined teachings of Tsien and Koshti, each of which address hydroxamic acid-containing chelating ligands for the purpose of chelation of a metal.
With respect to Chelator 1, Applicant argues that the closest compound in Koshti is compound 9b, a tetra-N- fluoroalkylhydroxamic acid prepared from 1,3-diaminopropane (Koshti, Table 1, page 3782). Compound 9b has a propylene (C3) backbone linking the two central nitrogen atoms. Applicant asserts that amended claim 65 recites that R in Chelator 1 is an alkyl linker having 4 to 20 carbon atoms, and a propylene (C3) linker is excluded from this definition.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is noted that Koshti’s chelator 9b comprises an alkyl linker having 3 carbon atoms. However, see MPEP 2144.09. Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril.). A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
Applicant argues that the references are directed to a different field of endeavor, and that in Koshti, fluorocarbon solubility is not addressed. A person of ordinary skill would not have had a reasonable expectation that Koshti's compounds, designed for methanol/supercritical CO₂ systems, would be soluble in Tsien's fluorocarbon liquids.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that the purpose of the chelators in Koshti is to bind metal ions, e.g. iron. Accordingly, it is considered that the metal binding ligands meeting the structural requirements taught by Tsien would be suitable for the purpose of binding metal ions. With regard to fluorocarbon solubility, it is noted that the fluorinated hydroxamic structures in Koshti meet the structure of the fluorinated metal binding ligand functional units in Tsien’s general structures 1-4, as such it is considered that suitable solubility would be achieved.
Applicant further argues that the claimed compositions produce results not predicted by the prior art, citing that octadentate coordination results in a stable complex that minimizes demetallation and non-specific radioisotope leakage when the chelator is encapsulated in a fluorocarbon nanoemulsion, and that neither Tsien nor Koshti teaches or predicts this.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that allegations of unexpected results should be commensurate in scope with the claimed invention, see MPEP 716.02, and that an affidavit or declaration under 37 CFR 1.132 must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness. In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). “A comparison of the claimed invention with the disclosure of each cited reference to determine the number of claim limitations in common with each reference, bearing in mind the relative importance of particular limitations, will usually yield the closest single prior art reference.” In re Merchant, 575 F.2d 865, 868, 197 USPQ 785, 787 (CCPA 1978) (emphasis in original). Where the comparison is not identical with the reference disclosure, deviations therefrom should be explained, In re Finley, 174 F.2d 130, 81 USPQ 383 (CCPA 1949), and if not explained should be noted and evaluated, and if significant, explanation should be required. In re Armstrong, 280 F.2d 132, 126 USPQ 281 (CCPA 1960) (deviations from example were inconsequential).
Conclusion
No claims are allowed at this time.
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.
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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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