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 .
Applicants' arguments, filed October 17, 2025, 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.
Response to Arguments
Applicant’s arguments with respect to the prior art rejection of pending claims based WO 2018/028645 in view of additional references have been considered but are moot in light of the new grounds of rejection set forth below with a new reference that teachings the presence of just one of 5-sulfosalicylci acid (5-SSA) or 5-nitroslicyclic acid (5-NSA) in the claimed composition and therefore addresses the arguments that the previous rejections did not teach this feature.
Applicants also argue that the inventors have identified a problem that was not known in the field and had a reason to add an additional imaging radionuclide with an activity of 0.1 mCi – 100 mCi, increasing the cost of materials and manufacturing steps for the carbon microsphere (CMS) suspension. As yttrium [90Y] microspheres can only provide low-quality SPECT and PET images, contrast agents needed to be administered separately due to the inconsistent in vivo distribution and metabolism. Adding additional imaging radionuclide with an activity of 0.1 mCi – 100 mCi to a therapeutic CMS suspension, tumor tissue near the visualizable CMS underwent obvious fibrotic necrosis indicating successful visualizable CMS treatment because both local radiotherapy and real-time imaging can be achieved. As the inventors have identified the problem of contrast agents being administered separately and solved the unknown problem by adding an additional imaging radionuclide with the therapeutic radionuclide, the claims are non-obvious.
These arguments are unpersuasive. Arguments without factual support are mere allegations and are not found persuasive. The Examiner is not clear as to the what the exact unidentified problem was. If the problem that was identified is that the same material labeled with different materials had different biodistribution and localization, that problem was previously known (e.g., p 858, col 2, ¶ 2 of Cutler et al. that accompanies this action). There are some examples in the specification as originally filed relating to effects when a composition as claimed but that evidence is not reasonably commensurate in scope with the claims as the material was adsorbed onto/into the carbon microspheres (CMS) and the instant claims do not require such an association of materials with the CMS as they are just required to be present in the same composition. Only claim 4 recites particular elements for the radioisotopes but no specific isotopes are required and there is no explanation as to how the results obtained would also be expected for any therapeutic and any imaging radionuclide. Additionally, the rationale in an obviousness rejection does not need to the same as reasoning used by Applicant if the resulting combination would have been arrived at by different reasoning and Applicants have not addressed the reasoning set forth in the previous Office Action.
Applicants also argue unexpected advantageous properties not possessed by any of the cited references. Data regarding the yttrium preparations from WO’645 is cited and compared with data from the specification as originally filed (see p 18 of the remarks filed October 17, 2025 for all the cited information). A difference in adsorption rate and release rate exhibiting low radioactive uptake in non-target tissue has unobvious and unexpected advantageous properties of localized radiotherapy and real-time imaging of a solid-tumor lesion compared to the nearest cited reference of WO’645.
These arguments are unpersuasive. Note that the initial statements on p 18 reference comparison with the closest prior art are correct but the summary statement later in the document referring to the nearest cited reference is incorrect as the comparison need not be made with the closest cited prior art if other prior art is closer. There is no discussion of what the expected results would be when the radionuclide(s) are complexed with a different organic molecule. Without knowing what the expected results would be, it cannot be determined if the results with 5-SSA and/or 5-NSA are in fact unexpected. Data from an actual side by side comparison is required as there can be differences in the materials, procedures or people carrying out the experiments so merely comparing data obtained from two different sources at different times and concluding the differences observed are in fact unexpected is not sufficient to demonstrate unexpected results. The cited data is different but there is also no discussion of what the expected results would be and they appear to involve different chelators for the radionuclides (EDTA versus the salicyclic acid compounds currently claimed). Without a side-by-side comparison and a discussion of what the expected results would be, the weight of the evidence in support of the alleged unexpected results does not outweigh the prima facie case of obviousness set forth below.
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 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/028645 (WO’645, all citations from machine translation that accompanied the Office Action mailed July 28, 2025) in view of Wadas et al. (Chem Rev, 2010) and Aydin et al. (Turk J Chem, 2006).
WO’645 discloses a tumor radiotherapy drug in particular with medical yttrium-90 carbon microspheres (¶ [0001]). Radioactive yttrium is complexed with the chelator EDTA (ethylenediaminetetraacetate) with carbon microspheres as the carrier (¶ [0007]). The diameter of the carbon microspheres can vary and be in the nanometer range, 20 – 100 µm or even over 100 µm (¶¶ [0018] – [0022]). Yttrium-90 carbon microspheres with a particle size of 20 μm – 30 μm are mainly used for arterial perfusion embolization radiotherapy of liver cancer and those with a particle size of 30 μm – 100 μm can be used for vascular-rich tumors such as lung cancer, kidney cancer, tongue cancer, breast cancer, cervical cancer (¶ [0026]). In vivo preparations contain 50 mCi – 600 mCi (¶ 0026]). The microspheres are administered by means of an interventional catheter, a syringe or an in vivo implantation (¶ [0027]) which requires the presence of carrier such as a liquid solution to render the microspheres capable of being administered via a catheter or a syringe.
The presence of the imaging radionuclide 89Zr is not disclosed.
Wadas et al. discloses the advantages of single-photon emissions computer tomography (SPECT) and positron emissions tomography (PET) using a contrast agent labeled with a γ-emitting radionuclide (p 2858, col 2, ¶ 2). Radiometals such as Zr have been investigated for the potential to combine their favorable decay characteristics with the biological characteristics of the targeting molecule to become a useful radiopharmaceutical (p 2859, col 2, ¶ 2 and table 2). As a consequence of its extreme hardness, a strong preference of Zr(IV) for polyanionic hard donor chelators can be expected and is borne out by the impressive stability constant of Zr with EDTA (p 2877, col 1, ¶ 3). 89Zr has been used to label a monoclonal antibody bearing the chelator moiety DTPA (p 2877, col 1, ¶ 3).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to add the imaging radionuclide 89Zr to the yttrium-90 microspheres of WO’645. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because both compositions are useful for the imaging and treatment of tumors and cancer. Here the composition of WO’645 permits treatment of the tumor and is complexed via the organic molecule EDTA. Wadas et al. discloses the utility of 89Zr for SPECT and PET imaging and that it forms a complex of impressive stability with EDTA. One of ordinary skill would reasonably expect to be able to also complex 89Zr with the carbon microspheres of WO’645 via EDTA to prepare constructs that are imageable due to the 89Zr and are also colocalized with the therapeutic yttrium-90 radionuclide to see exactly where treatment is taking place. One of ordinary skill in the art is aware that liquid carriers are often used to administer compositions by syringe or catheter as disclosed by WO’645 and can readily prepare a suspension as claimed. The size ranges and amount of radioactivity at least overlap with those of the instant claims. The amount of a specific ingredient in a composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve the desired results and there is no evidence of record as to the criticality of the claimed ranges.
EDTA is used for the purposes of chelating the radionuclides and not 5-SSA or 5-NSA as required by the instant claims.
Aydin et al. studied the complexes of yttrium(III) with 5-SSA or 5-NSA (whole document, e.g., title). Various studies such as La(III) and other lanthanide binding with 5-SSA has been previously studied but not 5-NSA (p 145). At acidic and neutral pH values, Y(III) coordinates to both 5-SSA and 5-NSA in 1:1 or higher molar ratios with neutral and basic pH values resulting in 1:2 or higher ratio complexes (p 152, item 1). The formed yttrium complexes with 5-SSA and 5-NSA have a higher stability than the complexes formed with SA and 5-HSA (salicyclic acid and 5-hydroxysalicyclic acid respectively) or those formed with calcium, a result that may be utilized for in vitro and in vivo studies since the ionic radia of Ca(II) and Y(III) are roughly equal (p 152, items 2 and 6).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use chelates of at least 90Y with 5-SSA or 5-NSA that were then mixed with the carbon microspheres of WO’645 along with 89Zr as taught by Wadas et al. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Aydin et al. discloses that 5-SSA or 5-NSA form stable complexes with yttrium(III) and suggests utilization for in vitro and in vivo studies. Different chelator-metal complexes will have different stabilities and one of ordinary skill in the art can select from amongst known chelator-metal complexes depending on the desired effects for the composition being prepared.
Claim(s) 2 is rejected under 35 U.S.C. 103 as being unpatentable over WO 2018/028645, Wadas et al. and Aydin et al. as applied to claims 1 and 4 above, and further in view of Fang et al. (Angew Chem Int Ed, 2010).
WO’645, Wadas et al. and Aydin et al. are discussed above.
WO’645 does not explicitly describe the carbon microspheres having micro and meso pores.
Fang et al. discloses that other groups have synthesized mesoporous carbon microspheres with the diameter over 50 mm (p 7987, col 2, ¶ 1) and report the synthesis of mesoporous carbon nanoparticles with spherical morphology and uniform size (p 7987, col 2, ¶ 2). These mesoporous materials also contained micropores (see table 1). Their open-framework structures, large surface area and porosity, and nanosize make ordered mesoporous nanoparticles useful in adsorption and cellular delivery amongst others (p 7987, col 1, ¶1). Carbon nanoparticles are nontoxic, biocompatible, and nonimmunogenic, which allows them to be used extensively in cellular delivery (p 7987, col 1, ¶ 1).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use carbon microspheres with meso and micropores as the base of the composition rendered obvious by WO’645 and Wadas et al. that permits imaging of the carbon microspheres also bearing the therapeutic radionuclide after administration to a subject. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because the presence of pores of various sizes increases the surface area where materials such as the radionuclides can attach to and there is no evidence of record as to unexpected results arising from the presence of micro- and meso-pores in the carbon microsphere.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 2 and 4 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 4, 6, 7, 9, 10, 12, 19 and 20 of copending Application No. 17/916,091 in view of WO 2018/028645; WO’645, all citations from machine translation that accompanied the Office Action mailed July 28, 2025) and Wadas et al. (Chem Rev, 2010) optionally further in view of Fang et al. (Angew Chem Int Ed, 2010) The claims of US’091 result in the preparation of metal nuclide loaded carbon microspheres complexed with an organic molecule (such as 5-SSA or 5-NSA, see claim 3) and a metal ion (such as yttrium, samarium, holmium or lutetium, see claim 4) (claim 1).
That the metal ion is a therapeutic radionuclide, the presence of a second radionuclide as an imaging radionuclide and the presence of a solution as required by the instant claims is not claimed.
WO’645, Wadas et al. and Fang et al. are discussed above.
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to use a radionuclide in the composition of US’091 such as the yttrium-90 of WO’645 and the imaging radionuclide 89Zr. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because both compositions are useful for the imaging and treatment of tumors and cancer. Here the composition of US’091 with yttrium-90 permits treatment of the tumor and is complexed via the organic molecule EDTA. Wadas et al. discloses the utility of 89Zr for SPECT and PET imaging and that it forms a complex of impressive stability with EDTA. One of ordinary skill would reasonably expect to be able to also complex 89Zr with the carbon microspheres of US’091 and WO’645 via EDTA to prepare constructs that are imageable due to the 89Zr and are also colocalized with the therapeutic yttrium-90 radionuclide to see exactly where treatment is taking place. One of ordinary skill in the art is aware that liquid carriers are often used to administer compositions by syringe or catheter as disclosed by WO’645 and can readily prepare a suspension as claimed. The size ranges and amount of radioactivity at least overlap with those of the instant claims. The amount of a specific ingredient in a composition is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve the desired results and there is no evidence of record as to the criticality of the claimed ranges.
If the meso and micro pores of claim 1 are not present in the materials of US’091, Fang et al. renders obvious the presence of such pores use carbon microspheres with meso and micropores as the base of the composition rendered obvious by US’091, WO’645 and CN’576 that permits imaging of the carbon microspheres also bearing the therapeutic radionuclide after administration to a subject. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because the presence of pores of various sizes increases the surface area where materials such as the radionuclides can attach to and there is no evidence of record as to unexpected results arising from the presence of micro- and meso-pores in the carbon microsphere.
This is a provisional nonstatutory double patenting rejection.
Applicants state that when the application is in condition allowance and this rejection is maintained, Applicant will respond accordingly.
Therefore this rejection is maintained for the reasons set forth above.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Nissa M Westerberg whose telephone number is (571)270-3532. The examiner can normally be reached M - F 8 am - 4 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Michael Hartley can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Nissa M Westerberg/Primary Examiner, Art Unit 1618
Prosecution Insights