DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 1-17 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 .
Status of Claims
Claims 1-11 and 15-16 are amended. Claims 8, and 11-16 are withdrawn. Claim 17 is new.
Response to Amendment
The amendments filed on 3 Mar. 2026 have been entered.
Response to Arguments
In view of Applicants amendments, the rejection of claims 1-7 and 9-10 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 (Nanomat.; published 13 Jul. 2020) is withdrawn.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 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 Jul. 2020) and Chen et al. (ACSNano; published 27 Mar. 2017; see attached 892).
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). Much attention has been drawn towards thorium, typically as 232Th. 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) sorbed UiO-66-COOH and UiO-66-(COOH)2 are therapeutic particle optionally for use as a medicament and wherein the at least one radionuclide is thorium-227 or its decay radionuclide radium-223 and that the particle has a therapeutic effect optionally in vivo. 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). 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 the particles of Zhang et al. (Th(IV) sorbed UiO-66-COOH and UiO-66-(COOH)2) so that the particles are therapeutic particles optionally nanoparticles and for use as a medicament and so that the 227Th and its decay radionuclide 223Ra replaces the Th that is absorbed in one or the pores by a carboxyl group that extends into the pore and such that the particle has a therapeutic effect optionally in vivo and optionally further comprises a pharmaceutically acceptable carrier as taught by Zhang et al., Majkowska-Pilip et al. and Chen et al. because those 227Th sorbed UiO-66-COOH and UiO-66-(COOH)2 (nano)particles would have been expected to enable alpha therapy of cancer tissue in vitro or in vivo using a non-toxic carrier having a high density of chelating groups capable of retaining Th in aqueous solution. 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 such as an antibody would have been expected to advantageously enable targeted delivery the therapeutic particle whereby improving tissue selectivity.
Applicants Arguments
Applicants assert that Zhang provide absolutely no connection to use MOFs as carriers for highly unstable α-emitting radionuclides. Zhang is directed to absorbing stable Th(IV) into porous MOFs to develop MOF for environmental remediation and/or water treatment. Zhang is not directed to radiotherapy, not directed to 223Ra or 225Ac and not directed to in vivo pharmaceutical use. A person of ordinary skill would not have had any reason to combine Zhang with Majkowska-Pilip to arrive at the claimed therapeutic particle comprising a MOF and at least one radionuclide. This reference does not suggest using MOFs much less UiO-66-COOH/UIO-66-(COOH)2 as carriers for these radionuclides. The review indicates that even carefully engineered dense nanoparticles face significant daughter escape. Majkowska-Pilip relies on a physical range stopping, surface conjugation of chelates or antibodies and does not disclose or suggest the claimed invention. Applicants assert no reasonable expectation of success. The chemical and radiological issues associated with Ra2+, Ac3+ and 227Th and recoil daughters are not addressed in Zhang. Bulk sorption behavior at mg/g levels in nitric acid is not predictive of retention of 223Ra/225Ac and recoil daughters at tracer levels in serum and in vivo. There would have been no reasonable expectation of success of arriving at a therapeutic particle of claim 1 based on the proposed substitution. Applicants assert unexpected results. Examples 2 and 3 demonstrate that UiO-66-(COOH)2 adsorb 92-99% of Ba and retain it in human serum of 11 d. In the example 7, the UiO-66-(COOH)2 shows 59-97% 223Ra adsorption depending on MOF quantity and 94% retention over 5 d in serum. In example 8, the 223Ra-loaded UiO-66-(COOH)2 nanoparticles when injected displayed liver accumulation and markedly reduce bone uptake compared to RaCl2. In examples 9 and 10, high doses of empty UI-66-(COOH)2-PEG nanoparticles show no toxicity in vivo and in vitro viability assays show no toxicity in HT29 and HCT116 cells up to over 48 h. Examples 1 and 4-6 confirm the feasibility of the claimed antibody functionalized therapeutic particles.
Applicant's arguments filed 3 Mar. 2026 have been fully considered but they are not persuasive. The recitations of “therapeutic particle” and “therapeutic particle has a therapeutic effect” in amended claim 1 are functional limitations analogous to an intended use or purpose.
A recitation of the intended use or purpose of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. If the prior art structure is capable of performing the intended use, then it meets the claim. In this case, the mere substitution of Th sorbed into the UiO-66-COOH and UiO-66-(COOH)2 with 227Th would read on the claimed therapeutic particle wherein the particle has a therapeutic effect since those particles would be capable therapeutic assessment in vitro and at least brachytherapy in vivo.
Zhang provides for Th(VI) sorbed UiO-66-COOH and UiO-66-(COOH)2 wherein each of UiO-66-COOH and UiO-66-(COOH)2 comprise a high density of coordinating COOH groups that trap the Th(VI) in the pores of the MOFs such that the Th(VI) does not substantially leach from the MOFs in aqueous solution. At pg. 25217, Zhang teaches the use of MOFs in biomedical imaging and drug delivery and so Zhang relates to the field of pharmaceutical applications including radiopharmaceutical applications. A person of ordinary skill in the art reading Zhang would have reasonably contemplated the use of the MOFs therein in pharmaceutical applications including radiopharmaceutical application. Majkowska-Pilip teaches 227Th and its decay radionuclide 223Ra as having pharmaceutical application in targeted alpha therapy. Majkowska-Pilip teaches 227Th and 223Ra as cations and motivates the use of nanoparticles as carriers for alpha emitters to sequester recoils in the decay chain. Given the high density of coordinating COOH groups of in the MOFS of Zhang that retain Th(VI) in aqueous solution, a person of ordinary skill in the art would have expected the MOFs of Zhang to be suitable carriers of 227Th and 223Ra. Chen describes the UiO-66 MOFs as being suitable for in vivo applications and biomedical imaging. The Ui-66 did not impose acute or chronic toxicity. 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 further modify Zhang by substituting the Th(IV) in the Th sorbed UiO-66-COOH and UiO-66-(COOH)2 with 227Th and/or its decay radionuclide 223Ra because the substituting would have been expected to advantageously enable alpha therapy.
Unexpected results require a comparison with the closest prior art in order to be effective to rebut a prima facie case of obviousness. See In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979). None of examples 1-10 in specification contain a comparison with the Th(IV) sorbed UiO-66-COOH and UiO-66-(COOH)2 in Zhang to describe an unexpected result over the prior art of Zhang. Expected beneficial results are evidence of obvious. Chen teaches the UiO-66 MOFs as not imposing acute or chronic toxicity. In addition, Chen teaches the UiO-66 MOFs as suitable for conjugation and targeted in vivo applications. Zhang teaches that the UiO-66-COOH and UiO-66-(COOH)2 are capable coordinating cationic metals due to the high density of coordinating COOH groups. A person of ordinary skill in the art would have expected UiO-66-COOH and UiO-66-(COOH)2 to be suitable carriers of 277Th for therapeutic applications to provide a therapeutic effect.
Conclusion
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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/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
/SEAN R. DONOHUE/
Examiner, Art Unit 1618