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 .
Status of Application
Applicant’s amendments of claim(s) 1, 3, 9, and 12-14 in the reply filed on 04/21/2026
is acknowledged.
Applicant’s cancellation of claim(s) 2 in the reply filed on 04/21/2026 is
acknowledged.
Claims 1 and 3-14 are under examination.
Applicant's arguments, filed 04/21/2026, 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objections not reiterated from previous office actions are hereby withdrawn.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.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. 202211155484.8, filed on September 22, 2022.
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.
Claim(s) 1, 3, 5-8, 10-14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dehaen, G.; et al. (Dehaen, G. et al. A Heterobimetallic Ruthenium-Gadolinium Complex as a Potential Agent for Bimodal Imaging. Inorg. Chem, 2011, 50, 10005-10014) in view of Pope, S. J. A.
(Pope, S. J. A. Dual-emissive complexes: Visible and Near-infrared luminescence from bis-pyrenyl lanthanide(III) complexes. Polyhedron, 2007, 26, 4818-4824), Ko, C-N. et al. (Ko, C-N.; Wu, C.; Li, G.; Leung, C-H.; Liu, J-B.; Ma, D-L. A long-lived ferrocene-conjugated iridium(III) complex for sensitive turn-on luminescence detection of traces of DMSO in water and human serum. Analytica Chimica Acta, 2017, 984, 193-201), and Fu, W. C.; et al. (Fu, W. C.; Wu, Y.; So, C. M.; Wong, S. M.; Lei, A.; Kwong, F. Y. Catalytic Direct C2-Alkenylation of Oxazoles at Parts per Million Levels of Palladium/PhMezole-Phos Complex. Org. Lett. 2016, 18, 5300-5303).
Dehaen, G.; et al. (hereafter referred to as Dehaen) teaches a multimodality molecular imaging probe (title, abstract (lines 16-17), introduction (pg 10005, col 1, lines 1-3) with a structure containing a central diethylenetriaminepentaacetic acid (DTPA) and two terminal 1,10-phenanthroline derivatives (title; abstract (image); pg 10006, Figure 1; pg 10006, Scheme 1; pg 10007, Scheme 2) for the combination of an MRI contrast agent (pg 10005, col 1, lines 4-5, 8-10, and 13-17; and pg 10005, col 2, lines 4-8; pg 10011, conclusions, lines 19-22) and optical probe (pg 10005, introduction, col 2, lines 11-12) and methods for preparing the compound (pg 10006, Scheme 1; pg 10006, col 1, lines 20-25) and complexes with transition metals (pg 10006, col 1, line 25 – col 2, lines 1-6; pg 10007, Scheme 2).
As to claim 1, Dehaen teaches a multi-modality molecular imaging probe having a structure with (1) a DTPA center complexed to gadolinium (pg 10007, Scheme 2); (2) two 1,10-phenanthroline derivatives attached to the DTPA through a phenyl linker (pg 10006, Figure 1; pg 10006, Scheme 1; pg 10007, Scheme 2) obtained by a Suzuki cross-coupling reaction (pg 10006, col 2, lines 11-16); (3) a transition metal attached to the 1,10-phenanthroline derivative and bound to additional moieties (pg 10007, Scheme 2); and, (4) chloride counterions (pg 10007, Scheme 2).
Dehaen does not teach the compound without the phenyl linker between the DTPA and 1,10-phenanthroline derivative.
Dehaen does not teach iridium.
Dehaen does not teach all the moieties to attach to the iridium.
Pope, S. J. A. (hereafter referred to as Pope) also teaches a multi-responsive molecular imaging probe (title; abstract (lines 1-5); pg 4818, col 2, lines 1-5; pg 4820, col 2, Scheme 2) and teaches a method of linking the DTPA directly to the two terminal ring-structures (pg 4819, Scheme 1; pg 4823, col 1, lines 34-51; and pg 4823, col 2, lines 5-12). The works of Dehaen and Pope are drawn to compounds with gadolinium for use within similar fields, a person of ordinary skill in the art could have combined the elements of these references since each element merely performs the same function as it does separately. Therefore, it would be obvious at the time of filing to combine elements from Dehaen and Pope.
Regarding the linker between the DTPA and 1,10-phenanthroline derivative, Dehaen teaches combining the 1,10-phenanthroline with DTPA (title; abstract (image); pg 10006, Figure 1; pg 10006, Scheme 1; pg 10007, Scheme 2).
Dehaen does not teach the compound without the phenyl linker.
Pope teaches direct attachment of the DTPA to the aromatic ring complex using an amidation reaction between a primary amine on the aromatic ring complex with a dianhydride protected DTPA (pg 4819, Scheme 1; pg 4823, col 1, lines 34-51; and pg 4823, col 2, lines 5-12). Dehaen teaches attachment of the DTPA to 1,10-phenanthroline using a Suzuki cross-coupling reaction between a 1,10-phenanthroline and DTPA. The prior art contained a product which differed from the claimed product by the substitution of some components (step, element, etc.) with other components. The substituted components and their functions were known in the art. Therefore, a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable. See MPEP 2143(I)(B).
Regarding the use of iridium, Dehaen teaches the use of ruthenium complexes within the optical functional unit for luminescence (abstract (lines 14-16); pg 10005, introduction, col 2, lines 11-12; pg 10012, col 2, lines 20-34).
Dehaen does not teach iridium in luminescence type compounds.
Ko, C-N.; et al. (hereafter referred to as Ko) teaches a two-metal compound containing iridium(III)-based luminescent complex (title; abstract (lines 2-4); pg 197, Figure 3.(a); pg 197, Scheme 1) and a variety of moieties that can be used to adjust the iridium complex for desired effect (pg 195, Figure 1, structures 1a-1h; pg 196, Figure 2, structures 2a-2h) and methods of synthesis (pg 194, col 2, lines 21-42). Given that Dehaen, Pope, and Ko are drawn to transition metal compounds for luminescence, a person having ordinary skill in the art would be motivated to combine elements from Ko with Dehaen and Pope. The prior art included each element claimed although not necessarily in a single reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. A person having ordinary skill in the art could have combined the iridium elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately. Therefore, a person of ordinary skill in the art would have recognized that the results of the combination were predictable. See MPEP 2143(I)(A).
Regarding the moieties to attach to iridium, Dehaen teaches 1,10-phenanthroline-type moieties (pg 10006, Scheme 1).
Dehaen does not teach 2-phenylpyridine with or without alkyl and halogen substitutions on the phenyl ring.
Dehaen does not teach benzoquinoline.
Dehaen does not teach 2-phenylquinoline.
Dehaen does not teach 2-phenylbenzothiazole or 2-phenylbenzooxazole.
Ko teaches 2-phenylpyridine (pg 195, Fig 1(a), structure 1e) and with halogen substituents (pg 195, Fig 1(a), structure 1g) and with alkyl substituents (pg 195, Fig 1(a), structure 1d).
Ko teaches benzoquinoline (pg 195, Fig 1(a), structure 1c).
Ko teaches 2-phenylquinoline (pg 195, Fig 1(a), structure 1a).
Ko teaches 2-phenylbenzothiazole (pg 195, Fig 1(a), structure 1h).
The combined teachings of Dehaen, Pope and Ko included each of the above elements claimed although not necessarily in a single reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. A person of ordinary skill in the art could have combined the element as claimed by known methods, and that in combination, each element merely performs the same function as it does separately. Therefore, a person of ordinary skill in the art would have recognized that the result of the combination were predictable. See MPEP 2143(I)(A).
The combined teachings of Dehaen, Pope, and Ko do not teach 2-phenylbenzoxazole.
Fu, W. C.; et al. (hereafter referred to as Fu) teaches benzoxazole-derivative moieties that are useful for luminescent iridium complexes (abstract (image); pg 5301, Table 1; pg 5302, Scheme 2; pg 5302, Scheme 4; pg 5302, col 1, lines 10-16) and methods of synthesis of ligands (pg 5302, Scheme 3). Given that Fu is drawn to luminescent iridium complexes and Dehaen, Pope, and Ko are also drawn to luminescent compounds containing transition metals, a person having ordinary skill in the art would be motivated to combine elements from Fu with the teachings of Dehaen, Pope, and Ko. Particularly, Fu teaches benzoxazole moieties on iridium is useful for luminescence (pg 5301, Table 1; pg 5302, Scheme 2; pg 5302, Scheme 4; pg 5302, col 1, lines 10-16). Given that Fu contains luminescent iridium compounds with benzoxazoles and Ko contains luminescent iridium compounds with 2-phenyl-benzothiazole, a simple substitution of one known element (oxygen) for another (sulfur) in 2-phenyl-benzothiazole would obtain predictable results. The prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components. The substituted components and their functions were known in the art. Therefore, a person of ordinary skill in the art could have substituted one known element for another, and the result of the substitution would have been predictable. See MPEP 2143(I)(B).
As to claim 3, Dehaen teaches a method for preparing a multi-modality molecular imaging probe comprising coordination reaction steps of dissolving an inorganic gadolinium salt and a DTPA derivative (pg 10006, col 2, lines 26-30; pg 10007, Scheme 2) and performing coordinating the complex (pg 10006, line 28; pg 10007, Scheme 2) and coordination steps of dissolving the gadolinium complex and a transition-metal complex precursor (pg 10007, Scheme 2; pg 10007, lines 3-14) to give the multi-modality molecular imaging probe.
Regarding the first coordination reaction, Dehaen teaches a first coordination reaction with steps of dissolving an inorganic gadolinium salt and a DTPA derivative (pg 10006, col 2, lines 26-30; pg 10007, Scheme 2) and performing coordinating the complex (pg 10006, line 28; pg 10007, Scheme 2).
Dehaen does not teach the same DTPA derivative.
Pope teaches direct attachment of the DTPA to the aromatic ring complex using an amidation reaction between a primary amine on the aromatic ring complex with a dianhydride protected DTPA (pg 4819, Scheme 1; pg 4823, col 1, lines 34-51; and pg 4823, col 2, lines 5-12). Dehaen teaches attachment of the DTPA to 1,10-phenanthroline using a Suzuki cross-coupling reaction between a 1,10-phenanthroline and DTPA. The prior art contained a product which differed from the claimed product by the substitution of some components (step, element, etc.) with other components. The substituted components and their functions were known in the art. Therefore, a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable. See MPEP 2143(I)(B).
Regarding the second coordination reaction, Dehaen teaches a second coordination reaction having the steps of performing coordinating the complex (pg 10006, line 28; pg 10007, Scheme 2) and coordination steps of dissolving the gadolinium complex and a transition-metal complex precursor (pg 10007, Scheme 2; pg 10007, lines 3-14) to give the multi-modality molecular imaging probe. Dehaen teaches a ruthenium-based precursor (pg 10007, Scheme 2; pg 10007, col 1, line 5).
Dehaen does not teach Iridium as the transition metal.
Ko teaches the iridium complex precursor (pg 197, Figure 3(a), reaction step b, line 1). Given that Dehaen, Pope, and Ko are drawn to transition metal compounds for luminescence, and that the precursors of Dehaen and Ko vary in the transition metal used, a person having ordinary skill in the art would be motivated to make a simple substation of one known element for another to obtain predictable results. The prior art contained a method which differed from the claimed method by the substitution of an element with another element. The substituted components and their functions were known in the art. Therefore, a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable. See MPEP 2143(I)(B).
Additionally, Ko teaches the various moieties of the iridium complex precursor: 2-phenylpyridine (pg 195, Fig 1(a), structure 1e) and with halogen substituents (pg 195, Fig 1(a), structure 1g) and with alkyl substituents (pg 195, Fig 1(a), structure 1d); benzoquinoline (pg 195, Fig 1(a), structure 1c); 2-phenylquinoline (pg 195, Fig 1(a), structure 1a); 2-phenylbenzothiazole (pg 195, Fig 1(a), structure 1h).
As to claim 5, Dehaen teaches an equimolar ratio of gadolinium salt with the DTPA derivative (pg 10006, col 2, lines 26-30). An equimolar ratio is a 1:1 ratio. The claimed molar ratio range is described as, “a ratio of an amount in moles of the inorganic gadolinium salt to a sum of amounts in moles of the inorganic gadolinium salt and the diethylenetriaminepentaacetic acid derivative is in a range of (0.2-0.8) : 1.” This is equivalent to a mole ratio range of 1:4 to 4:1. The prior art value lies inside the claimed range. Since claim 3 is rendered obvious by the teachings of Dehaen, Pope, Ko, and Fu and claim 5 is dependent on claim 3, claim 5 is rendered obvious by the combined teachings of Dehaen, Pope, Ko, and Fu.
As to claim 6, Dehaen teaches the preparation of the multi-modality molecular imaging probe by combining ruthenium complexes to lanthanide complexes in a mole ratio from 1:1 to 2:1 respectively (pg10007, Scheme 2; pg 10007, col 1, lines 3-11). The claimed molar ratio range is described as, “a ratio of an amount in moles of the gadolinium complex to a sum of amounts in moles of the gadolinium complex and the iridium complex precursor is in a range of (0.3-0.7) :1.” The prior art range and the claimed range overlap. Since claim 3 is rendered obvious by the teachings of Dehaen, Pope, Ko, and Fu and claim 6 is dependent on claim 3, claim 6 is rendered obvious by the combined teachings of Dehaen, Pope, Ko, and Fu.
As to claim 7, Dehaen teaches a first coordination reaction between DTPA and a gadolinium salt performed at a temperature of 50°C for 24h (pg 10012, col 1, lines 61-64).
As to claim 8, Dehaen teaches a second coordination reaction between the gadolinium complex and the luminescent complexes at reflux of ethanol:water (1:1 v/v) for 5 hrs. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A). The optimization would have been routine as changes in the solvent, or mole ratios or time cause different results in yield. Therefore, a person having ordinary skill in the art would be motivated to adjust the temperature and the time of reaction in order to optimize the coordination reaction.
As to claim 10, Dehaen teaches a first coordination reaction between DTPA and a gadolinium salt performed at a temperature of 50°C for 24h (pg 10012, col 1, lines 61-64).
As to claim 11, Dehaen teaches a second coordination reaction between the gadolinium complex and the luminescent complexes at reflux of ethanol:water (1:1 v/v) for 5 hrs. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP 2144.05(II)(A). The optimization would have been routine as changes in the solvent, or mole ratios or time cause different results in yield. Therefore, a person having ordinary skill in the art would be motivated to adjust the temperature and the time of reaction in order to optimize the coordination reaction.
As to claim 12, Dehaen teaches a multi-modality molecular imaging probe having a structure with (1) a DTPA center complexed to gadolinium (pg 10007, Scheme 2); (2) two 1,10-phenanthroline derivatives attached to the DTPA through a phenyl linker (pg 10006, Figure 1; pg 10006, Scheme 1; pg 10007, Scheme 2) obtained by a Suzuki cross-coupling reaction (pg 10006, col 2, lines 11-16); (3) a transition metal attached to the 1,10-phenanthroline derivative and bound to additional moieties (pg 10007, Scheme 2); and, (4) chloride counterions (pg 10007, Scheme 2).
Dehaen does not teach the compound without the phenyl linker between the DTPA and 1,10-phenanthroline derivative.
Dehaen does not teach iridium.
Dehaen does not teach all the moieties to attach to the iridium.
Dehaen does not teach the counterion hexafluorophosphate.
Regarding the linker between the DTPA and 1,10-phenanthroline derivative, Pope teaches direct attachment of the DTPA to the aromatic ring complex using an amidation reaction between a primary amine on the aromatic ring complex with a dianhydride protected DTPA (pg 4819, Scheme 1; pg 4823, col 1, lines 34-51; and pg 4823, col 2, lines 5-12). Dehaen teaches attachment of the DTPA to 1,10-phenanthroline using a Suzuki cross-coupling reaction between a 1,10-phenanthroline and DTPA. The prior art contained a product which differed from the claimed product by the substitution of some components (step, element, etc.) with other components. The substituted components and their functions were known in the art. Therefore, a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable. See MPEP 2143(I)(B).
Regarding the use of iridium, Ko teaches a two-metal compound containing iridium(III)-based luminescent complex (title; abstract (lines 2-4); pg 197, Figure 3.(a); pg 197, Scheme 1) and a variety of moieties that can be used to adjust the iridium complex for desired effect (pg 195, Figure 1, structures 1a-1h; pg 196, Figure 2, structures 2a-2h) and methods of synthesis (pg 194, col 2, lines 21-42). Given that Dehaen, Pope, and Ko are drawn to transition metal compounds for luminescence, a person having ordinary skill in the art would be motivated to combine elements from Ko with Dehaen and Pope. The prior art included each element claimed although not necessarily in a single reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. A person having ordinary skill in the art could have combined the iridium elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately. Therefore, a person of ordinary skill in the art would have recognized that the results of the combination were predictable. See MPEP 2143(I)(A).
Regarding the moieties to attach to iridium, Ko teaches 2-phenylpyridine (pg 195, Fig 1(a), structure 1e).
Ko teaches 2-phenylpyridine with fluorine substituents (pg 195, Fig 1(a), structure 1g).
Ko teaches 2-phenylquinoline (pg 195, Fig 1(a), structure 1a).
Ko teaches 2-phenylbenzothiazole (pg 195, Fig 1(a), structure 1h).
The combined teachings of Dehaen, Pope and Ko included each of the above elements claimed although not necessarily in a single reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. A person of ordinary skill in the art could have combined the element as claimed by known methods, and that in combination, each element merely performs the same function as it does separately. Therefore, a person of ordinary skill in the art would have recognized that the result of the combination were predictable. See MPEP 2143(I)(A).
The combined teachings of Dehaen, Pope, and Ko do not teach 2-phenylbenzoxazole.
Fu teaches benzoxazole moieties on iridium is useful for luminescence (pg 5301, Table 1; pg 5302, Scheme 2; pg 5302, Scheme 4; pg 5302, col 1, lines 10-16). Given that Fu contains luminescent iridium compounds with benzoxazoles and Ko contains luminescent iridium compounds with 2-phenyl-benzothiazole, a simple substitution of one known element (oxygen) for another (sulfur) in 2-phenyl-benzothiazole would obtain predictable results. The prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components. The substituted components and their functions were known in the art. Therefore, a person of ordinary skill in the art could have substituted one known element for another, and the result of the substitution would have been predictable. See MPEP 2143(I)(B).
Regarding the counterion hexafluorophosphate, Fu teaches hexafluorophosphate (pg 5302, Scheme 4, step 2). Given that the prior art contained a device (method, product, etc.) which differed from the claimed device by the substitution of some components (step, element, etc.) with other components; and the substituted components and their functions were known in the art, a person of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable. See MPEP 2143(I)(B).
The combined teachings of Dehaen, Pope, Ko, and Fu included each element claimed although not necessarily in a single reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. A person of ordinary skill in the art could have combined the elements as claimed by known methods and that in combination, each element merely performs the same function as it does separately. Therefore, a person of ordinary skill in the art would have recognized that the results of the combination were predictable. See MPEP 2143(I)(A).
As to claim 13, Dehaen teaches a method for preparing a contrast agent for magnetic resonance imaging using a multi-modality molecular imaging probe (pg 10007, Scheme 2; pg 10011, col 2, lines 41-44).
As to claim 14, Dehaen teaches a method for preparing an optical probe for optical imaging, using a multi-modality molecular imaging probe (pg 10007, Scheme 2; pg 10011, col 2, lines 41-44).
Claim(s) 9 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dehaen, Pope, Ko, and Fu as applied to claims 1, 3, 5-8, 10-14 above, and further in view of of Wu, C.; et al. (Wu, C.; Vellaisamy, K.; Yang, G.; Dong, Z-Z.; Leung, C-H.; Liu, J-B.; Ma, D-L. A reaction-based luminescent switch-on sensor for the detection of OH- ions in simulated wastewater. Dalton Trans. 2017, 46, 6677) as evidenced by Shilov, I., Y.; et al. (Shilov, I., Y.; Lyashchenko, A., K.; Anion-Specific Effects on Activity Coefficients in Aqueous Solutions of Sodium Salts: Modeling with the Extended Debye-Huckel Theory, J. Solution. Chem. 2019, 48, 234-247). The teachings of Dehaen, Pope, Ko, and Fu as applied in the previous rejection are incorporated in this rejection.
As to claim 9, Fu teaches counterions the Cl- can be exchanged with other anions, such as PF6 via ammonium hexafluorophosphate (pg 5302, Scheme 4, step 2).
Fu does not teach structures with Br-, I-, or NO3-.
Wu, C.; et al. (hereafter referred to as Wu) is also drawn to a series of iridium-based luminescent complexes (title; pg 6678, Figure 1); studying the ability of iridium complexes to sense hydroxide ions (pg 6678, Figure 2); and examining the effect of various counterions in the complex to the luminescent properties of the iridium complex that have varying effects on the complex properties (pg 6679, col 1, lines 1-7; pg 6679, Figure 4); Wu further teaches that the ions may be exchanged through adding the alternative anions at 100 mM (pg 6679, Figure 4 caption, line 2). Given that both Wu and Fu are drawn to luminescent iridium complexes, a person having ordinary skill in the art would be motivated to combine the prior art elements according to known methods to yield predictable results.
Wu teaches the exchange of PF6- counterions with Br-, I-, and NO3- (pg 6679, col 1, lines 1-7; pg 6679, Figure 4). The sodium salts of bromide, iodide and nitrate are useful in ion pairing with a range of solution behaviors as evidenced by Shilov, et al. (abstract, lines 11-13). The prior art included each element claimed although not necessarily in a single reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. The combined teachings of Pope, Ko, and Fu teach the multi-modality complex and Wu teaches a variety of counterions that can be used iridium-based luminescent compounds. A person having ordinary skill in the art could have combined the elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately. Therefore, a person of ordinary skill in the art would have recognized that the results of the combination were predictable. See MPEP 2143(I)(A).
Claim(s) 4 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dehaen, Pope, Ko, and Fu as applied to claims 1, 3, 5-8, 10-14 above, and further in view of Cohen, S., M.; et al. (Cohen, S. M.; Xu, J.; Radkov, E.; Raymond, K. N. Synthesis and Relaxation Properties of Mixed Gadolinium Hydroxypyridinonate MRI Contrast Agents, Inorg. Chem., 2000, 39, 5747-5756) and Kofod, N.; et al. (Kofod, N.; Thomsen, M. S.; Nawrocki, P.; Sorensen, R. J. Revisiting the assignment of innocent and non-innocent counter ions in lanthanide(III) solution chemistry. Dalton Trans. 2022, 51, 7936). The teachings of Dehaen, Pope, Ko, and Fu as applied in the previous rejections are incorporated in this rejection.
As to claim 4, Dehaen teaches the use of a lanthanide salt (gadolinium triflate) (pg 10007, Scheme 2) to prepare the gadolinium complex.
Dehaen does not teach gadolinium nitrate.
Dehaen does not teach gadolinium chloride.
Dehaen does not teach gadolinium perchlorate.
Regarding gadolinium nitrate and gadolinium chloride, Cohen et al. (Cohen, S.; et al. hereafter referred to as Cohen) is drawn to gadolinium containing MRI contrast agents (title; abstract (lines 1-4)) and methods of synthesizing them (title; pg 5748, col 1, line 19 through pg 5749, col 1, line 4). Given that Dehaen and Cohen are drawn to similar fields containing gadolinium contrast agents, a person having ordinary skill in the art would be motivated to make a simple substitution of one known element for another to obtain predictable results.
With respect to gadolinium nitrate, Cohen teaches Gd(NO-3-)3 to make gadolinium containing complexes (pg 5748, col 2, lines 47-49; pg 5748, col 2, lines 55-56; pg 5748, col 2, lines 61-63).
With respect to gadolinium chloride, Cohen teaches GdCl3 to make gadolinium containing complexes (pg 5748, col 2, lines 69-71).
Regarding gadolinium perchlorate, Kofod, et al. (hereafter referred to as Kofod) is drawn to types of lanthanide salts for use in aqueous solutions and other technology areas (title; abstract (lines 1-3, 11-14); pg 7939, Table 1). Kofod examines the type of lanthanide salts and compares them to lanthanide ligand interactions (pg 7937, col 1, lines 7-19; pg 7937, Table 1). Kofod teaches that lanthanide-perchlorate properties are between lanthanide chloride and lanthanide triflate (pg 7937, Table 1). Given that Dehaen is drawn to using lanthanide triflate salts and Cohen is drawn to using lanthanide chloride salts for synthesizing gadolinium-containing complexes; and, given that Kofod lists variety of lanthanide salts where lanthanide perchlorate properties are between lanthanide triflate and lanthanide chloride, then a person having ordinary skill in the art would be motivated to make a simple substitution of one known element for another to obtain predictable results. See MPEP 2143(I)(B).
The prior art of Dehaen, Pope, Ko, Fu, Cohen, and Kofod included each element claimed although not necessarily in a single reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. A person of ordinary skill in the art could have combined the elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately. Therefore, a person of ordinary skill in the art would have recognized that the results of the combination were predictable. See MPEP (2143(I)(A).
Response to Arguments
Applicant states that the references do not appear to teach all aspects of the instant claims as a whole, particularly, the compound without the phenyl linker between the DTPA and 1,10-phenanthroline derivative. Applicant states the DTPA(ph-phen)2 as a whole is critical to achieve the intended purpose of Dehaen and therefore, the ph and phen of ph-phen cannot be separated without undermining the function contemplated by Dehaen. Applicant argues that there would be no motivation for a person skilled in the art to remove the ph or phen in the ph-phen group since such a modification would undermine the core function contemplated in Dehaen.
Respectfully, the applicants’ arguments are not persuasive. A person of skill would have considered it obvious to try to link the 1,10 phenanthroline linker directly to the DTPA chelator based not on Dehaen alone. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
In response to whether the proposed modification undermines the operation of Dehaen, MPEP 2143.01(VI) states “[i]f the proposed modification or combination of the prior art would change the principle of operation of the prior art invention being modified, then the teachings of the references are not sufficient to render the claims prima facie obvious.” In the present case, the principal of operation is a dual functional compound capable of fluorescence and MRI. Therefore, even when the phenyl linker is removed or substituted with another linker, the 1,10-phenanthroline fluorescent complex and the DTPA MRI core are still present, therefore the principal of operation remains unchanged.
Applicant acknowledges that Pope teaches direct attachment of the DTPA to the aromatic ring complex using an amidation reaction. Applicant states the aromatic ring complex is significantly different from the moiety of Dehaen. Applicant argues the linker and 1,10-phenanthroline chelating moiety of Dehaen would be substituted with the linker and fluorescent moiety of Pope rather than just the linkers between the fluorescent moiety and the DTPA core of each art.
Respectfully, the applicants’ arguments are not persuasive. As discussed above, a person of ordinary skill in the art would find it obvious to exchange the linkers of the fluorescent 1,10-phenantholine moiety of Dehaen with the linker of the fluorescent aromatic ring complex of Pope.
The applicant argues the removal of the phenyl linker is impermissible hindsight.
Respectfully, the applicants’ arguments are not persuasive. Necessarily, "[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper. See MPEP 2145(X)(A). In this case, given just the prior art presented in the case, a person of ordinary skill in the art could have realized that 1,10-phenanthroline complex fluorescent moiety of Dehaen could be directly attached to the DTPA core as done in Pope. Additionally, there is no requirement that an "express, written motivation to combine must appear in prior art references before a finding of obviousness. See MPEP 2143(X)(A).
Applicants argue that the additional art of Ko, Fu, Wu, Shilov, Cohen, and Kofod fail to cure the deficiencies above and that they are silent to the inspiration of claim 1.
Respectfully, the applicants’ arguments are not persuasive. As discussed above, the teachings of Dehaen and Pope suggest substituting a fluorescent moiety linker for another would still result in a molecule with a 1,10-phenanthroline complex for fluorescence and a DTPA core for MRI.
The rejections are maintained.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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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/EVAN M LEWOCZKO/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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