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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 July 13, 2026 has been entered.
Applicants' arguments, filed July 13, 2026, have been fully considered but they are not deemed to be fully persuasive. Applicants arguments regarding Fritzberg et al. (US 4897255) are moot because Fritzberg et al. (US 4897255) are no longer being used in any ground of rejection. The following rejections and/or objections constitute the complete set presently being applied to the instant application.
Claim Rejections - 35 USC § 112 Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5, 10, and 13 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “the primary phase forms a bulk of the volume of the multiphase microsphere.” The term “a bulk” does not have a clear and commonly accepted definition in the art. Neither the claim nor the specification provides definition or specific range to inform a person of ordinary skill in the art of the scope of this term with reasonable certainty. Applicant has appended functional language to the claim reciting “…that imparts an ability on the multiphase microsphere to embolize within a capillary during radioembolizaion.” However, the addition of this functional limitation fails to cure the indefiniteness of the term “a bulk.” Merely reciting a desired functional results or technical effect (i.e. the ability to embolize a capillary) does not provide a definitive structural boundary to the physical volume of the primary phase. For example, a primary phase occupying 51% of the volume may achieve embolization, as might one occupying 85% or 95%. Accordingly, because the claim relies on purely result-oriented language without defining what precise percentage, fraction, or ratio of the total volume constitute “a bulk”, the metes and bounds of the claimed invention cannot be reasonably ascertained, rendering claim 1 indefinite.
The dependent claims fall therewith.
Clarification and/or amendment is required.
For the purposes of applying art below, a bulk volume is being interpreted as more than 50% of the total volume of the multiphase microsphere.
Applicants argue that Applicant submit clarification amendments to address the rejection.
This argument is unpersuasive. As discussed above, the amendment to add the functional limitation does not cure the indefiniteness of the term “a bulk.” To overcome this rejection, Applicant is advised to amend claim 1 by replacing the indefinite term “a bulk” with a specific, objective numerical range or proportion that finds clear support in the original disclosure/specification.
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.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Song et al. (US 2007 0141339; cited on IDS filed Apr 20, 2021) in view of Lin et al. (Journal of Controlled Release, 2011), Mosconi et al. (World journal of hepatology, 2015; cited on PTO-892), and Häfeli (Physics and chemistry basis of biotechnology, 2001; cited on PTO-892).
Song discloses that polymer (resin) particles comprise an interior region and a coating (abstract; ¶ 182; FIG 3; FIG 4), and are microns in size (¶ 13), which read on multiphase microspheres. These microspheres read on instant claim 1, wherein the interior region reads on the first secondary phase and the coating reads on the primary phase. Song discloses that the particle can contain therapeutic agents such as radioactive species (radioisotopes, radioactive molecules) (abstract; ¶ 152; ¶ 157), which reads on a radioactive isotope or a compound including at least one radioactive element of instant claim 1. Song discloses that one or more of radioactive isotopes can be loaded into the first secondary phase, and the primary phase can be substantially free of radioactive isotopes (¶ 152; ¶ 185), which reads on only the first secondary phase comprising at least one of a radioactive isotope of instant claim 1. Song also discloses a multiphase microsphere including smaller sub-particles (FIG. 5) prepared by a double-emulsion process (¶¶ 199-201; FIGs 9A-9F) in Example 3 (¶¶ 229-234). The multiphase microsphere contains smaller SIBS-fluorescein particles and only the smaller sub-particles contain the fluorescein which is used as a substitute for a therapeutic agent, which reads on only the first secondary phase comprising at least one of a radioactive isotope of instant claim 1. Song discloses that the first resin is a bioerodible and/or bioabsorbable material (¶ 182), which reads on a bioresorbable resin or a biodegradable resin of instant claim 2. Song discloses that the first resin is a swellable material, for example, a hydrogel (¶ 182; ¶ 184), which reads on a water-swellable polymer of instant claim 3. Song discloses that the first resin can be the same as the second resin (¶ 186), which reads on the first resin and the second resin are identical of instant claim 4.
Song dose not disclose that the primary phase forms a bulk of the volume of the multiphase microsphere that imparts an ability on the multiphase microsphere to embolize within a capillary during radioembolization, and that a likelihood of leaching of the radioactive material from the microsphere is decreased. Song dose not disclose a radioactive isotope comprising a beta emitting isotope or a gamma emitting isotope.
Lin discloses a polymer nanoparticle comprising an amphiphilic diblock copolymer, a poly(acrylic acid)-b-polystyrene (PAA-b-PS) core (reads on the first secondary phase) and a poly(acrylic acid) (PAA) shell (reads on the primary phase) (ABSTRACT). Lin discloses that the ratios of shell to core volume can be adjusted from 0.44 to 2.1 and the shell-to-core volume ratio shows an impact on the rates and extents of doxorubicin (DOX, drug located in the core) release, with the volume occupied by the primary phase shell relative to the volume occupied by the first secondary phase core correlating inversely with the diffusion-based release of drug (ABSTRACT).
Mosconi discloses radioembolization with Yttrium-90 (a beta emitting isotope) microspheres in hepatocellular carcinoma (title). Mosconi discloses that the particles used for radioembolization must be small enough to allow optimal access into the tumor nodules and deposition within the tumor plexus, without creating ischemia, but large enough to prevent the passage of microspheres through the capillary bed into the venous circulation leaving the liver (page 740, column 1, ¶ 1).
Häfeli discloses alpha- and beta-emitting radioactive microspheres for therapeutic uses such as radioembolization (abstract). Häfeli discloses that the advanced drug delivery systems utilizing microsphere for the encapsulation of drugs (radioisotopes) have the advantage of protecting the encapsulated drug from the in vivo environment (page 214, ¶ 2).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to modify the microspheres of Song by configuring the primary phase to form a bulk of the volume of the multiphase microsphere to embolize within a capillary and decrease a likelihood of leaching of the radioactive material such as Yttrium-90. A person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Lin teaches that increasing the proportions of shell-to-core volume can be the critical parameter for decreased kinetics of drug release, and Mosconi teaches that the optimal size of the microsphere is important for embolization by capillary blockage and a beta emitting isotope such as Yttrium-90 can be used for radioembolization. A person of ordinary skill in the art would have been motivated to optimize the size of the microsphere by adjusting the volume of primary phase in order to embolize within a capillary during radioembolization, and tune the drug loading capacities and drug release rates according to the intended application of the drug delivery system. It would be obvious that Song’s multiphase microsphere comprising radioactive isotopes-free primary phase and the encapsulated first secondary phase comprising radioactive isotope can decrease a likelihood of leaching if the radioactive material from the microsphere because Häfeli teaches that such microspheres can prevent the release of the encapsulated drug. Configuring the primary shell phase to form the bulk volume of the microsphere is a straightforward, routine design choice that a POSITA would readily contemplate to achieve predictable, functional results. As taught by Mosconi, optimal capillary retention requires specific physical dimensions. Increasing the primary phase volume to form the bulk of the sphere is an obvious structural way to achieved the required total diameter for capillary blockage without increasing the dosage of the active radioisotope core. As taught by Lin and Häfeli, increasing the thickness/volume of the outer matrix increases the diffusion barrier, inherently retarding and preventing leaching of the radioactive material. Therefore, utilizing the primary phase as the bulk volume to simultaneously achieve targeted capillary embolization and physical leaching protection represents nothing more than routine structural optimization and the predictable application of known prior art principles. Accordingly, applying the teachings of Lin, Mosconi, Häfeli to the microspheres of Song constitutes no more than the predictable use of prior art elements according to their established functions, thus rendering claims obvious.
Applicant argues that Song does not disclose or reasonably suggest the claimed features, such as that the primary phase forms the bulk volume of the multiphase microsphere, the first secondary phase is surrounded by the primary phase, the first secondary phase comprises a second resin, and only the first secondary phase comprises radioactive material, as recited in amended claim 1. Applicant argues that Song mentions radioactive species only as possible agents among many other possible therapeutic agents. Applicant argues that Lin does not remedy the deficiencies of Song. Applicant argues that the DOX of Lin is a chemotherapy agent, not a radioactive material, and that the overall nanoparticles of Lin including both the shell and core are loaded with DOX molecules. Applicant argues that neither Lin nor Song discloses or reasonably suggested the microsphere as recited in amended claim 1.
This argument is unpersuasive. As discussed above, Song in view of Lin, Mosconi, and Häfeli renders the amended claim 1 obvious. Song teaches radioactive isotope can be loaded into the first secondary phase of multiphase microspheres while the primary phase (coating) can be substantially free of radioactive isotope. Further, a person of ordinary skill in the art would have been motivated to make a microsphere featuring a drug-loaded core and a drug-free shell in order to control drug release rates, safeguard the drug, or mitigate initial burst effects based on the specific requirements of the delivery system. Lin teaches the bulk volume of the primary phase can reduce the drug release rate. Lin explicitly discloses that DOX molecules can be packaged within the core (abstract) as the intended primary encapsulation reservoir for DOX. The fact that minor residual drug binds to the outer shell does not negate Lin’s primary technical teaching that the volume/thickness of the outer primary phase (PAA shell) governs diffusion-based mass transport from the inner core. Physical diffusion across a polymer shell follows universal physical laws regardless of whether the payload is DOX or a radioisotope. The fact that it would have been equally obvious to use other possible therapeutic agents from Song does not make the use of radioactive species any less obvious. Further, Mosconi teaches Yttrium-90 and Häfeli teaches beta-emitting isotopes for radioembolization. A POSITA seeking to perform radioembolization would naturally select a radioactive agent such as Yttrium-90 as taught by Song, Mosconi, and Häfeli. Combining teachings of Song (multiphase radioembolization sphere), Lin (volumetric shell-to-core ratios for diffusion control), Mosconi (the size parameters for capillary blockage), Häfeli (radioisotope encapsulation to prevent leaching) would have been obvious to a person of ordinary skill in the art seeking to minimize radiation leakage while maintaining effective capillary embolization size by adjusting the bulk volume of primary phase. The alleged reduction in leaching and controlled embolization represent the expected, predictable outcome of increasing outer layer volume and sizing the sphere for targeted vasculature. Further, Applicant has provided no experimental evidence or comparative data demonstrating any unexpected, synergistic, or non-obvious result beyond what a POSITA would routinely expect from the predictable combination of prior art elements.
Claims 10 and 13 are rejected under 35 U.S.C. 103 as being unpatentable over Song, Lin, Mosconi, and Häfeli as applied to claims 1-5 above, further in view of Richard (US 2009 0092677; cited on IDS filed Apr 20, 2021) and Stithit et al. (Journal of Microencapsulation, 2008).
In addition to the teachings of Song discussed above, Song discloses a multiphase microsphere can include pore(s) and/or a cavity (a hollow central region in the particle) (¶ 183; ¶ 247; ¶ 248; FIG 30).
Lin, Mosconi, and Häfeli are discussed above.
None of Song, Lin, Mosconi, and Häfeli disclose that a multiphase microsphere further comprises a second secondary phase comprising a gas and that the microsphere is neutrally buoyant in human blood.
Richard discloses multi-component particles comprising one polymeric (resin) component in the form of spherical core and another polymeric (resin) component in the form of a shell (¶ 16; FIG. 1) and are microns in size (¶ 18), which read on multiphase microspheres. Richard discloses that the overall density of the microspheres may be matched to the density of aqueous phase that suspends the microspheres by adjusting the density of the microspheres, producing neutral buoyancy for the microspheres (¶ 42).
Stithit discloses a buoyant theophylline microspheres prepared by encapsulating some bubbles from carbon dioxide gas in the hardening droplets and forming the internal cavities in the microspheres in order to reduce the density of microspheres and provide a floating capacity for drug release system (page 728, Formation of microspheres).
It would have been obvious to the person of ordinary skill in the art before the effective filing date of the claimed invention to incorporate additional phase containing gas encapsulation into the microspheres of Song, Lin, Mosconi, and Häfeli for improved radioisotope delivery system. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Richard teaches that density of microspheres can be adjusted for producing neutral buoyancy and Stithit teaches that gas encapsulation can be used to adjust the density of microspheres. Song also teaches the microspheres containing a therapeutic agent can be porous. Further, a person of ordinary skill in the art would have been motivated to make a multiphase microsphere comprising additional phase comprising a gas for controlled drug release, enhanced bioavailability, and reduced aggregation according to the specific requirements of the delivery system. Accordingly, applying the teachings of Richard and Stithit to the microspheres of Song, Lin, Mosconi, and Häfeli constitutes no more than the predictable use of prior art elements according to their established functions, thus rendering claims 10 and 13 obvious.
Applicant argues that Stithit does not remedy the deficiencies of Song, Lin, and/or Richard with respect to amended claim 1 and that none of Song, Richard, and/or Stithit discloses or reasonably suggest at least a second secondary phase surrounded by the primary phase as recited in claim 10 form which claim 13 depends, and which depends from amended claim 1. Applicant argues that one skilled in the art would not have been motivated to combine Richard or Song with Stithit because Richard or Song is silent regarding multiphase particles including a first secondary phase comprising radioactive isotope and a second secondary phase comprising gas, and Stithit describes a formation process including carbon dioxide not mentioned in Richard or Song.
This argument is unpersuasive. As discussed above, Song in view of Lin, Mosconi, and Häfeli renders the amended claim 1 obvious. As discussed above, Song discloses a multiphase microsphere can include pore(s) and/or a cavity. Richard explicitly addressed the need to adjust microsphere density to match fluid conditions and achieve proper buoyancy. Richard teaches that density of microspheres can be adjusted for producing neutral buoyancy and Stithit teaches that gas encapsulation using carbon dioxide can be used to adjust the density of microspheres. A POSITA seeking to achieve or optimize the buoyance taught by Richard would naturally look to Stithit, which explicitly teaches lowering microsphere density by entrapping gas bubbles inside the primary matrix during solvent evaporation. Selecting Stithit’s gas-entrapping technique to adjust the density of Richard’s radioactive microsphere represents nothing more than choosing a predictable solution from a finite number of know design options. It would have been obvious to the person of ordinary skill in the art to make a multiphase microsphere comprising additional pore (as taught by Song) formed by gas such as carbon dioxide (as taught by Stithit) in order to produce neutral buoyancy (as taught by Richard) for controlled drug release, enhanced bioavailability, and reduced aggregation according to the specific requirements of the delivery system. Accordingly, applying the teachings of Richard and Stithit to the microspheres of Song, Lin, Mosconi, and Häfeli constitutes no more than the predictable use of prior art elements according to their established functions. Further, Applicant has provided no objective evidence of unexpected results sufficient to overcome this prima facie case of obviousness.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Richard (US 2009 0092677; cited on IDS filed Apr 20, 2021) in view of Song et al. (US 2007 0141339; cited on IDS filed Apr 20, 2021), Lin et al. (Journal of Controlled Release, 2011), Mosconi et al. (World journal of hepatology, 2015; cited on PTO-892), and Häfeli (Physics and chemistry basis of biotechnology, 2001; cited on PTO-892).
In addition to the teachings of Richard discussed above, Richard discloses the microspheres which read on instant claim 1, wherein the core component reads on the first secondary phase and the shell component reads on the primary phase. Richard discloses that the multiphase microspheres include one or more therapeutic agent such as radionuclide (¶ 28; ¶ 29), which reads on a radioactive isotope or a compound including at least one radioactive element of instant claim 1. Richard discloses that the first resin is a biodegradable polymer (¶ 23; ¶ 24), which reads on a bioresorbable resin or a biodegradable resin of instant claim 2. Richard discloses that the first resin is a hydrogel (¶ 24; ¶ 25), which reads on a water-swellable polymer of instant claim 3.
Richard does not disclose that primary phase forms a bulk of the volume of the multiphase microsphere that imparts an ability on the multiphase microsphere to embolize within a capillary during radioembolization, and that a likelihood of leaching of the radioactive material from the microsphere is decreased. Richard does not disclose that the first resin and second resin are identical. Richard dose not disclose a radioactive isotope comprising a beta emitting isotope or a gamma emitting isotope.
Song, Lin, Mosconi, and Häfeli 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 modify the microspheres of Richard to by configuring the radioisotope-free primary phase to form a bulk of the volume of the multiphase microsphere to embolize within a capillary and decrease a likelihood of leaching of the radioactive material such as Yttrium-90 in encapsulated first secondary phase, and identical first and second resins. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Song teaches radioactive isotope can be loaded into the first secondary phase of multiphase microspheres while the primary phase can be substantially free of radioactive isotope, and same polymers can be used for the first and second resins; Lin teaches that increasing the proportions of shell-to-core volume can be the critical parameter for decreased kinetics of drug release; and Mosconi teaches that the optimal size of the microsphere is important for embolization by capillary blockage and a beta emitting isotope such as Yttrium-90 can be used for radioembolization. It would be obvious that Richard’s multiphase microsphere comprising radioactive isotopes-free primary phase and the encapsulated first secondary phase comprising radioactive isotope can decrease a likelihood of leaching if the radioactive material from the microsphere because Häfeli teaches that such microspheres can prevent the release of the encapsulated drug. Further, a person of ordinary skill in the art would have been motivated to make a microsphere featuring a drug-loaded core and a drug-free shell in order to control drug release rates, safeguard the drug, or mitigate initial burst effects based on the specific requirements of the delivery system. A person of ordinary skill in the art would have been motivated to adjust the volume ratio of primary phase and first secondary phase in order to tune the drug loading capacities and drug release rates according to the intended application of the drug delivery system. A person of ordinary skill in the art would have been motivated to use same resins for the primary phase and the first secondary phase in order to achieve enhanced structural integrity/stability, uniformed biocompatibility/degradation, and simplified manufacturing. Accordingly, applying the teachings of Song, Lin, Mosconi, and Häfeli to the microspheres of Richard constitutes no more than the predictable use of prior art elements according to their established functions, thus rendering claims obvious.
Applicant argue that neither Song nor Lin assists Richard in disclosing or reasonably suggesting all the features of amended independent claim 1. Applicant argue that Richard describes the particles containing at least two different polymeric components and that Richard only loosely mentions radionuclides as possible therapeutic agents among many others.
This argument is unpersuasive. As discussed above, Richard in view of Song, Lin, Mosconi, and Häfeli renders the amended claim 1 obvious. As discussed above, Richard in view of Song teaches the first resin and second resin can be identical. The fact that it would have been equally obvious to use other possible therapeutic agents from Richard does not make the use of radionuclides any less obvious. Further, Mosconi teaches Yttrium-90 and Häfeli teaches beta-emitting isotopes for radioembolization. A POSITA seeking to perform radioembolization would naturally select a radioactive agent such as Yttrium-90 as taught by Richard, Mosconi, and Häfeli.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JONG HWAN BAEK whose telephone number is (571)272-0670. The examiner can normally be reached Mon - Thu, 9 am - 3 pm ET.
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 G 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.
/JONG HWAN BAEK/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
Prosecution Insights