DETAILED ACTION
This Office action details a non-final action on the merits for the above referenced application No. Claims 1-18 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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 24 Jun. 2026 has been entered.
Status of Claims
Claims 1 and 8 are amended. Claims 8, and 11-16 are withdrawn. Claim 18 is new.
Response to Amendment
The amendments filed on 24 Jun. 2026 have been entered.
Response to Arguments
In view of Applicants amendments, the rejection of claims 1-7, 9-10 and 17 under 35 USC 103 as being unpatentable over Zhang et al. (ACS Appl. Mater. Interfaces; published 2017), in view of Majkowska-Pilip et al. (Nanomat.; published 13 Jun. 2020) and Chen et al. (ACSNano; published 27 Mar. 2017) is withdrawn.
New Grounds of Rejection
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) 1-7, 9-10, and 17-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Zhang et al. (ACS Appl. Mater. Interfaces; published 2017), in view of Majkowska-Pilip et al. (Nanomat.; published 13 Jun. 2020) and Chen et al. (ACSNano; published 27 Mar. 2017).
Zhang et al. teach extending the use of highly porous and functionalized MOFs to Th(IV) capture (see title). Zhang et al. teach that a highly porous and stable MOF, UiO-66 and its carboxyl derivatives (UiO-66-COOH and UiO-66-(COOH)2) were synthesized and explored for the first time for Th(IV) capture from a weak acid solution. The absorbability towards Th(IV) is greatly enhanced by introduction of carboxyl groups into UiO-66. It is concluded that UiO-66-COOH and UiO-66-(COOH)2 sorb Th(IV) through the coordination of carboxyl anions into the pores of the MOFs (see abstract). Zhang et al. teach nuclear energy. Among these radionuclides much attention has been drawn towards thorium. Thorium can serve as a suitable model related to tetravalent actinides (pg. 25216). MOFs have been widely used in biomedical imaging and drug delivery (pg. 25217). As for the carboxylated UiO-66s, the average particle sizes is ~ 1 µm (pg. 25218). It was found that the Th(IV) uptake by the three MOFs follows the order of UiO-66-(COOH)2>UiO-66-COOH>UiO-66 at all of the test pHs, matching the amount order to free carboxyl groups in the MOFs (pg. 25219). The carboxyl derivatives of UiO-66 especially UiO-66-(COOH)2 were found to be excellent sorbents towards Th(IV) in terms of the large Th(IV) uptake of more than 350 mg/g at pH 3.0, in short equilibrium time of less than 30 min (pg. 25222). (Th(IV) absorbed into UiO-66-COOH and UiO-66-(COOH)2 read of MOFs wherein the MOF comprises: (i) a repeating 3D network inorganic monomers (ZrCl4) and organic monomers (1,2,4-benzenetricarboxylic acid, H4BTEC), forming pores and at least one free carboxyl groups extending into a pore and at least one metal wherein the metal is thorium and wherein the thorium is absorbed into at least one of the pores by the carboxyl group.)
Zhang et al. do not teach that the Th(IV) adsorbed within at least one of the pores of UiO-66-COOH and UiO-66-(COOH)2 particles by at least one -COOH group that extends into the part is thorium-227 or the radium-223 that generates thorium-227 to form therapeutic particles having a therapeutic effect, optionally in vivo, and optionally for use as a medicament. Zhang et al. do not further teach that at least one molecule for modifying the external surface of the therapeutic particle connected to the external surface of the therapeutic particle wherein the at least one molecule is PEG. Zhang et al. do not further teach that the therapeutic particle is a nanoparticle or that at least one targeting moiety such as an antibody is present or expressly teach a pharmaceutically acceptable carrier.
Majkowska-Pilip et al. teach nanoparticles in targeted alpha therapy (see title). Majkowska-Pilip et al. teach that there are important reasons why nanoparticles are used in a radionuclide therapy including following: (i) release of daughters from the radioisotopes, (ii) lack of appropriate bifunctional ligands for effective binding of α-emitters, and (iii) application in targeted nano brachytherapy (see pg. 3). Radiolabeled nanoparticles are in a microscopically dispersed in liquid form and can be injected intra- or peritumorally by syringe and needle (pg. 7). Majkowska-Pilip et al. teach functionalized nanomaterials labeled with alpha-emitting radionuclides such as 223Ra and 227Th and in some cases the nanomaterials are attached to a targeting vector such as trastuzumab (antibody) or J591 antibody (table 2). Radium chloride ([223Ra]RaCl2) is the first α-particle emitting therapeutic agent approved by the FDA for bone metastatic castration-resistant cancers (pg. 8). Majkowska-Pilip et al. teach 227Th as an α-emitter studied in cancer therapy. The daughter of 227Th is 223Ra, which is the first in class α-emitter approved for castration resistant prostate cancer. Gadolinium vanadate nanoparticles were proposed as carriers for 227Th. The ability of the GdVO4 core shell nanoparticles to retain radionuclides gives them the potential to increase specific activity and the possibility to functionalize to make them suitable for targeted therapy because of proton relaxivity for using MRI (pg. 18).
Chen et al. teach in vivo targeting and PET imaging of tumor with intrinsically radioactive metal-organic frameworks nanomaterials (see title). Chen et al. teach that due to the chemical versatility, enormous porosity and tunable degradability of nMOFs, they have been adopted as carriers for delivering imaging and/or therapeutic cargos. 89Zr-Ui-66 was further functionalized with pyrene-derived PET and conjugated with a peptide ligand F3 to nucleolin for targeting of triple-negative breast tumors. DOX was loaded onto UiO-66 with a relatively high loading capacity and served as a therapeutic cargo. Toxicity evaluation confirmed that properly PEGylagted UiO-66 did not impose acute or chronic toxicity to the test subjects. The intrinsically radioactive nMOF can find broad application in cancer theranostics (see abstract). Chen et a. teach that surface engineering with PEG could not only improve the stability and dispersity of UiO-66 in biological media, but also provide further functionalization sites for integration of tumor targeting molecules (pg. 4317). The UiO-66 nMOFs were 50-90 nm based on TEM measurement (see pg. 4318). Chen et al. teach DOX loading and release (pg. 4319). Chen et al. teach in vivo tumor targeting and PET imaging (pgs. 4320-4321; Fig. 3). Chen et al. teach investing the potential of the nanoconjugates for radiation/chemotherapy (pg. 4324). Chen et al. teach a physiological medium such as water and saline (pg. 4324).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify particles of Zhang et al. (UiO-66-COOH and UiO-66-(COOH)2 particles for (radio)thorium capture wherein at least one thorium is adsorbed within at least one of the pores by at least one -COOH group that extends into the pore) so that the radiothorium is thorium-227 and/or its progeny radium-223 , a first in class approved alpha emitter, to produce a therapeutic particle having a therapeutic effect optionally in vivo and a particle for use as a medicament optionally with a pharmaceutical carrier as taught by Zhang et al. and Majkowska-Pilip et al. because those radionuclides would have been expected to advantageously enable alpha therapy of cancer tissue in vitro or in vivo using a carrier particle having a high density of chelating groups capable of retaining the radionuclides. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Zhang et al. so that there is at least one PEG molecule for modifying the external surface of the particle connected to the external surface of the particle as taught by Chen et al. because the at least one PEG molecule would have been expected to advantageously enable improved stability and dispersity of the particle biological media. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Zhang et al. so that the obvious therapeutic particle is a nanoparticle as taught by Chen et al. because it would have been expected to advantageously enable utilization of the nMOF as in vivo cancer treatment.
It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Zhang et al. so that the obvious therapeutic particle is attached to a targeting moiety such as an antibody as taught by Majkowska-Pilip et al. and Chen et al. because the targeting moiety would have been expected to advantageously enable targeted delivery of the particle whereby improving selectivity.
Applicant’s Arguments
Applicants assert that the recited modifying in amended claim 1 facilitates transport, prevents agglomeration and/or provides targeting functionality by increasing the target flexibility and spatial distance between a MOF and its target. This structural feature is not taught by Zhang. Zhang is not a therapeutic radiopharmaceutical reference. The references to drug delivery concern conventional drug delivery. The reference concerns environmental/aqueous uptake of natural thorium ions by MOFs UiO-66-COOH and UiO-66-(COOH)2 at macroscopic concentrations and loadings. Zhang’s particles are approximately micron-scale and they are not therapeutic nanoparticles. Zhang’s MOF cannot perform the intended use of the therapeutic particle of claim 1. The only way to make Zhang therapeutically plausible is to redesign it by reducing the particle size, reducing the radionuclide loading, adding a physiologic surface stabilizer, and evaluating serum/in vivo retention. The hypothetical redesign is completely unpredictable. Chen teaches a radiolabelled imaging MOF, not a therapeutic MOF nanoparticle in which therapeutic radionuclides are retained and adsorbed pore payload. The comparative data in the specification should be considered because the data address the real technical problem: retention and in vivo behaviour of therapeutic radionuclides in a nanoparticulate MOF system.
Applicant's arguments filed 24 Jun. 2026 have been fully considered but they are not persuasive. Zhang provides highly porous UiO-66-COOH and UiO-66-(COOH)2 MOFs for radionuclide application. At pg. 25216, Zhang teaches radionuclides and much attention has been drawn to thorium. At pg. 25217, Zhang teaches biomedical imaging and drug delivery. A person of ordinary skill in art is a person of ordinary creativity, not an automaton. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007). A person of ordinary skill in the art familiar with thorium radionuclides and/or radiopharmaceutical applications would have understood the UiO-66-COOH and UiO-66-(COOH)2 MOFs of Zhang that selectively capture Th(IV) through coordination of carboxyl anions in the pores of MOFs have radiopharmaceutical applications. The sorption capacity for Th(IV) into UiO-66-(COOH)2 represents one of the largest values for Th(IV) capture by solid phase extraction. Majkaowska-Pilip teach that thorium-227 has medical applications enabling the treatment of cancer by alpha-therapy. Majkaowska-Pilip describes the use of gadolinium vanadate particles to capture thorium-227. Their retention of radium-223 was high. Accordingly Majkaowska-Pilip, the ability of GdVO4 nanoparticles to retain radionuclides gives them the potential to increase specific activity and the possibility to functionalize to make them suitable for targeted therapy. Majkaowska-Pilip teaches nanoparticles and brachytherapy. A recognized advantage is the strongest reason to combine. It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify functionalized MOFs of Zhang designed to capture thorium radionuclides by capturing the thorium-227 radionuclide and its daughter radium-223 radionuclide such that the particles are therapeutic particles having a therapeutic effect in vivo and for use as a medicament as taught by Majkaowska-Pilip because those particles would have been expected to advantageously enable radiopharmaceutical applications including alpha therapeutic cancer. Chen teaches nMOF comprising radionuclides and for radiopharmaceutical applications. Chen teaches, suggests and motivates at least one PEG molecule for modifying the external surface of the nMOF connected to the external surface of the nMOF. According to Chen, the PEG advantageously improves stability and dispersity in biological media and provides functionalization sites. It would have been obvious to a person of ordinary skill in the art before the effective filing date further modify the MOFs of Zhang designed to function in aqueous media so that at least one PEG molecule for modifying the external surface of a UiO-66 MOF is connected to the external surface of the MOF as taught by Chen because the at least one PEG molecule would have been expected advantageously provide improved stability and dispersity and enable functionalization site. Identifying an optimal amount of thorium-227 for the obvious 227Th sorbed MOFs is a matter of routine optimization and not a complete redesign of the UiO-66-COOH and UiO-66-(COOH)2 MOFs of Zhang. Regarding applicants’ assertion of unexpected results, the comparative data in the specification has been considered and found ineffective for the reasons discussed in the Office action filed on 35 Mar. 2026. The UiO-66-COOH and UiO-66-(COOH)2 MOFs of Zhang designed to capture thorium radionuclides is the closest prior art. None of the examples in the specification contain a comparison with the UiO-66-COOH and UiO-66-(COOH)2 MOFs of Zhang to describe an unexpected result over the closest prior art.
Conclusion
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/SEAN R. DONOHUE/
Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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