DETAILED ACTION
This Office action details a final action on the merits for the above referenced application No. Claims 1-2, 4, 6-11, and 14-20 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 1-2, 4, 6, 8-11, and 16 are amended. Claims 3, 5, and 12-13 are cancelled. Claims 17-20 are new.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 21 May 2026 has been considered by the examiner.
Response to Amendment
The amendments filed on 21 May 2026 have been entered.
Response to Arguments
In view of Applicants amendments, the rejection of claim 13 under 35 USC 101 because the claimed recitation of use without setting forth any steps involved in the process is withdrawn.
In view of Applicants amendments, the rejection of claims 1-16 under 35 USC 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter is withdrawn.
In view of Applicants amendments, the rejection of claims 1-16 under 35 USC 103 as being unpatentable over Gray et al. (WO 02/34300 A1; published 2 May 2002), in view of Ju et al. (CN 113198041 A-English translation; published 3 Aug. 2021) is withdrawn.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) 1-2, 4, 6-11, and 14-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Tang et al. (CN115607694A-English translation; published 17 Jan. 2023; see attached 892), in view of Ju et al. (CN 113198041 A-English translation; published 13 May 2022) and Guangzhi et al. (RSC Adv.; published 2017; see attached 892).
Tang et al. teach radioactive carbon microspheres as well as preparation method and application thereof (title). Tang et al. teach selective internal radiation therapy ([0002]). Tang et al. teach 90Y resin microspheres which used polystyerene-divinylbenzene as a carrier ([0004]). Tang et al. teach that radioactive carbon microspheres of the invention have a high radionuclide loading rate and low static and vibration loss rates which effectively improves the safety of radioactive carbon microspheres during transportation and storage and enhances the medical application possibilities of radioactive carbon microspheres ([00006]). The method for preparing the radioactive carbon microspheres includes the steps of method 2 that mixes porous carbon microspheres with a solution containing a precipitant, then adding a solution containing a radioactive nuclide to a reaction solution. The reactive is complete. The precipitant may be tartaric acid solution ([0020]). Method for preparing the porous carbon microspheres includes calcining resin microspheres (e.g. phenolic resin microspheres or polystyrene microsphere. The preferred calcination temperature is 400-800oC ([0025]) and the calcination time is 3 to 6 h and more preferably 4 h ([0026]) and the preferred calcination atmosphere is Ar ([0027]). The polystyrene microspheres can be conventional in the art such as polystyrene-divinylbenzene microspheres, like polystyrene microspheres of DuPont AmberChrom XT30 ([0035]). Tang et al. teach a particle size of 10-60 microspheres. Tang et al. teach example 2 where polystyrene microspheres (DuPont AmberChrom TM XT30; crosslinked polystyrene-divinylbenzene microspheres with crosslinking degree of 2% to 10%) were calcined at 400oC for 4 h in an Ar atmosphere (temperature was increased from room temperature to 200oC at 10oC/min, then increased to 400oC at 3oC/min held for 4 h and then cooled at a rate of 10oC/min) to prepare porous carbon microspheres The SEM image of the porous carbon microspheres is shown in Fig. 4;(example 2). The porous carbon microspheres prepared in the above examples or comparative examples were soaked in 0.3 mol/L dilute nitric acid for 2 h then washed 3X with deionized water and dried before using. 0.15 g of porous carbon microspheres were mixed with a precipitant solution and YCl3 solution to obtain a reaction solution with a volume of 3 mL. In loading method 2, first add the precipitant solution and porous carbon microspheres allowing the precipitant to fully enter the mesopores of the porous carbon microspheres then add the YCl3. When the precipitant is tartaric acid and sodium phosphate, porous carbon microspheres loaded with γ-tartaric acid complex are first added to sodium phosphate solution and shaken for 1 h. After washing and drying, porous carbon microspheres are obtained. The microspheres were soaked in saline for 6d (suspension, water for injection; [0062]-[0066]). Tang et al. teach Y90 ([0070]). Figure 5 shows the particle size distribution.
Tang et al. do not expressly teach a suspension or a method of its preparation comprising radioactive microspheres wherein the radioactive microspheres having a non-spherical ratio of 5% of less wherein the non-spherical ratio means that the ratio of the number of non-spherical radioactive microspheres to the total number of radioactive microspheres in the suspension, the non-spherical radioactive microspheres with a minimum radius of less than 75% of the radius of the initial microsphere and the radius of the initial microsphere means the mean radius of the radioactive microsphere in the suspension. Tang et al do not expressly teach 300-700 MBq. Tang et al. do not expressly teach a method for treating a tumor.
Ju et al. teach visualized monodispersed embolization microspheres with internal radiotherapy properties and their preparation method (see title). Ju et al. teach that existing embolization microspheres have the problem of size inhomogeneity and is not conducive to predicting the movement trajectory of microspheres and may cause false embolization ([0003]). Ju et al. teach 90Y resin microspheres. The radioactive embolization microspheres prepared by the above methods generally suffer from poor sphericity and poor monodispercity (pg. 5). Ju et al. teach embolization microspheres that are spherical with a particle size between 20-100 um, and the coefficient of variation of the particle size of the embolization microsphere does not exceed 5% ([0005]). Ju et al. teach embolization microspheres labeled with radionuclides. The embolization microspheres have good morphology, good sphericity and good monodispersity which can solve the problem of non-uniform size of existing embolization microspheres makes it difficult to predict the movement trajectory of the microsphere and easily cause false embolization ([0030]). Ju et al. teach a 131I-poly GelMA microsphere (embodiments 1-3).
Guangzhi et al. teach preparation and dispersity of carbon nanospheres by carbonizing polyacrylonitrile microspheres (see title). Guangzhi et al. teach that the relationship between preparation conditions and sphere properties were investigated (pg. 16342). Guangzhi et al. teach that as for heating rate, the powders were heated to the same final temperature of 300oC and held for 30 min at 0.1, 0.5, 1, and 3oC min-1. It can be seen that at slow heating rates of 0.1 and 0.5oC min-1. The sphere structure was almost entirely retained after oxidation whereas at fast heating rates of 1 and 3oC min-1 some large particles without spherical morphology were found which may be caused by melting of the spheres. Aggregation occurred more easily at high heating rates. It can be regarded that a slow heating rate of oxidation is better for maintaining the sphere structure and preventing the melting of the spheres. It can be regarded that a slow heating rate of oxidation is better for maintaining the sphere structure and preventing the melting of spheres (pg. 16343).
It would have been obvious to a person of ordinary skill in the art before the effective filing date to modify Tang et al. (suspension of radioactive microspheres wherein the radioactive polystyrene microspheres comprise carbonized resin microspheres and radionuclides loaded on the carbonized microspheres have an average particles size of 10-60 µm wherein the radionuclide is 90Y and the suspension comprises water for injection and a method for preparing the suspension and method of selective internal radiation therapy of a primary or secondary tumor in a target organ) by during the preparation method optimizing the heating rate of the calcination reaction to a slower heating rate such as 2 oC/min of that produces the carbonized resin microspheres as taught by Guangzhi et al and Ju et al. because the optimized heating rate would have been expected to provide entire retention of the sphere structure and reduced melting and aggregation resulting in a low non-spherical ratio such that all spheres have uniform morphology, good sphericity and monodispersity preventing false embolization and more predictable movement. 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). The percentage of non-spherical radioactive microspheres to the total number of radioactive microspheres in suspension and in turn the non-spherical ratio is a result effective variable that a person of ordinary skill in the art would have been motivated to optimize that the time of invention. MPEP 2144.05.II. A person of ordinary skill in the art would have arrived at a low non-spherical microsphere percent and a non-spherical ratio of 5% or 2% or less through routine experimentation in order to arrive at a suspension of particles having an optimal uniform morphology by preventing melting and aggregation and to prevent false embolization and enable more predictable movement. The particle size and percentage thereof of the radioactive microspheres are result effective variables that a person of ordinary skill in the art would have been motivated to optimize of the invention. A person of ordinary skill in the art would have arrived at an average particle size between 25 µm and 40 µm in order to arrive at average particle sizes suitable for SIRT. The amount of radioactivity per mL of the suspension is a result effective variable that a person of ordinary skill in the art would have optimized at the time of invention. A person of ordinary skill in the art would have arrived at 90Y with an activity of 300-700 MBq/mL in order to arrive an optimal therapeutic amount for suitable for treatment of tumors by radioembolization. It would have been obvious to a person of ordinary skill in the art before the effective filing date to further modify Tang et al. so that material of the resin microsphere is a polystyrene resin partially crosslinked with divinylbenzene as taught by Tang et al. because that polystyrene resin would have been expected to provide an equivalent polystyrene resin material advantageous known use in radioembolization.
Applicants Arguments
Applicants assert that neither Gray nor Ju disclose carbonized resin microspheres. Neither Gray not Ju disclose microspheres having a non-spherical ration of 5% and their advantages for enhancing therapeutic efficacy. Gray and Ju do not provide any teaching or suggestion as to the advantages of microspheres with a non-spherical ratio of 5% or less to reduce local inflammation, increase intratumoral distribution, and decrease extratumoral distribution. The claimed variable was not recognized in the prior art to be a result-effective variable. Coefficient of variation and non-spherical ratio are not related. When all microspheres have identical particle sizes, there can still be both non-spherical and spherical particles. Put it differently, when all microspheres are non-spherical, the non-spherical ratio is high, but the particle sizes can be equal, resulting in a low coefficient of variation. Ju fails to disclose non-spherical ratio. Applicants assert unexpected results supporting a finding of non-obviousness. When the non-spherical ratio of radioactive microspheres is controlled within 5% or less, the resulting irritation score indicates no or very mild irritation, showing the keeping the non-spherical ratio 5% or less significantly reduces inflammation and improves safety. The results show that examples 6 and 7 (which have a non-spherical ratio of 5% or less) have low irritation scores whereas comparative example 3 (which has a non-spherical radio of 15.1%) shows moderate irritation, a significant increase. Example 7 showed a significantly higher tumor growth inhibition rate compared to comparative example 3 (81.0% vs. 58.0%), further demonstrating that controlling the non-spherical ratio within 5.0% provides better antitumor efficacy.
Applicant's arguments filed 21 May 2026 have been fully considered but they are not persuasive. The non-spherical ratio as defined in the claims and specification is a non-limiting mathematical expression of the number of non-spherical radioactive microspheres out of the total number of radioactive microspheres in suspension. See Diehr, 450 U.S. at 191, 209 USPQ at 15 (citing Benson, 409 U.S. 63, 175 USPQ 673). None of Tang, Ju, and Guangzhi need to expressly recite “non-spherical” ratio in order to make obvious claim 1. The composition and preparation method of Tang differs the composition and preparation method of instant example 7 that exhibits a non-spherical ratio of <5% only because example 7 used a slower heating rate of 2oC per min and because Tang does not expressly teach tartaric acid at 10 mg/mL. However, the heating rate used in the preparation of carbonized microspheres is well-known result effective variable known to retain sphere structure and preventing the melting of the spheres. Guangzhi teaches that a fast-heating rate can cause melting and aggregation. Ju teaches and motivates microsphere suspensions having uniform morphology in order to prevent false embolization and enable more uniform and predictable movement. Accordingly, a person of ordinary skill in the art would have had reason and motivation to measure the amount non-spherical microspheres in the radioactive carbonized microsphere suspension of Tang and then optimize conditions heating rate and reagent concentration to arrive a suspension having uniform size and morphology with a minimal number of non-spherical spherical microspheres. The person of ordinary skill in the art would have been motivated to arrive at a suspension having a minimal number of non-spherical microspheres from which non-spherical ratio can be calculated in order to arrive at a suspension with uniform size and morphology whereby preventing false embolization and enabling more predictable movement.
Expected beneficial results are evidence of obviousness. See In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). A person of ordinary skill in the art would have expected a slower heating rate used in the carbonization reaction to enable maintaining sphere structure and prevent melting such that after calcining there are a minimal number of non-spherical microspheres. From Jud, a person of ordinary skill in the art would have expected a suspension having more uniform size and spherical morphology would perform better in biological assays related to selective internal radiation therapy by delivering more particles to the tumors with fewer false embolization and improving therapeutic efficacy. The showing of unexpected result must be reviewed to see if the results occur over the entire claimed range. See In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). The instant specification as [00070] asserts that in the examples the microspheres used in the sulfonation treatment were AmberChrom XT. The microspheres used in the carbonization treatment are polystyrene-divinylbenzene microspheres commercially available from Qingdao Hongpu Biotechnology Co. Sulfonated polystyrene microspheres were Aminex 50W-X4 with an average size of 30 µm. In contrast, claim 1 does limit the material, radionuclide or activity amount of the carbonized resin microsphere. For example, different materials would have been expected to different densities which would affect particle distribution and performance in biological assays including therapeutic efficacy. In addition, different radionuclides would be expected to result in a different therapeutic outcome at least due to the mode of decay and their adherence to the radioactive resin microspheres.
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 SEAN R DONOHUE whose telephone number is (571)270-7441. The examiner can normally be reached on Monday - Friday, 8:00 - 5:00 EST.
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 on (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 an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SEAN R. DONOHUE/
Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
Prosecution Insights