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 .
Response to Arguments
Applicant's arguments, filed February 12, 2026, 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.
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 the bulk volume of the multiphase microsphere.” The term “bulk volume” 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. Accordingly, the metes and bounds of the claimed invention cannot be reasonably ascertained, thus rendering claim 1 indefinite.
The dependent claims fall therewith.
Clarification and/or amendment is required.
For the purposes of applying art below, bulk volume is being interpreted as more than 50% of the total volume of the multiphase microsphere.
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 1-4 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; 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.
Regarding the new limitation in the independent claim that the primary phase forms the bulk volume of the multiphase microsphere of instant claim 1, Song does not disclose that the primary phase forms the bulk volume.
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) 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 (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).
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 making the primary phase form the bulk volume to reduce the drug release rate. The 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. Further, 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. Accordingly, applying the teachings of Lin to the microspheres of Song constitutes no more than the predictable use of prior art elements according to their established functions, thus rendering claim 1 obvious.
While a new ground of rejection is set forth above, the previously applied Song reference is still used in the new ground of rejection. Applicant argues that Song does not disclose or reasonably suggest the claimed features such as the primary phase forms the bulk volume of the multiphase microsphere, the first secondary phase surrounded by the primary phase, the first secondary phase comprising a second resin and only the first secondary phase comprising at least one of a radioactive isotope as recited in amended claim 1. Applicant argues that Song mentions radioactive species only as possible agents among many other possible therapeutic agents.
This argument is unpersuasive. As discussed above, Song in view of Lin 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 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. Further, 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. 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.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Song et al. (US 2007 0141339; cited on IDS filed Apr 20, 2021) and Lin et al. (Journal of Controlled Release, 2011; cited on PTO-892) as applied to claims 1-4 above, further in view of Fritzberg et al. (US 4897255).
In addition to the teachings of Song discussed above, Song discloses that therapeutic agents (cytostatic agents) can be nuclides as disclosed in Fritzberg (¶ 157).
Lin is discussed above.
Neither Song nor Lin discloses that a radioactive isotope comprises a beta emitting isotope or a gamma emitting isotope.
Fritzberg discloses a radiolabeled polypeptide comprising 99mTc for diagnosis and therapy (col. 5, lines 26-30; claim 2). 99mTc is an example of gamma emitting isotope.
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 gamma emitting isotope such as 99mTc as a radioactive isotope of the microspheres of Song and Lin. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Fritzberg teaches that a gamma emitting isotope such as 99mTc can be used for diagnosis and therapy. Further, the specific choice of the radioisotope being a beta or gamma emitting isotope is straightforward for the skilled person, and a person of ordinary skill in the art would have been motivated to select from various radioactive isotopes as the selection would be a matter of routine optimization based on the intended therapeutic or diagnostic application of the microsphere. Accordingly, applying the teachings of Fritzberg to the microspheres of Song and Lin constitutes no more than the predictable use of prior art elements according to their established functions, thus rendering claim 5 obvious.
Applicant argues that Fritzberg does not assist Song in disclosing or reasonably suggesting all the features of amended independent claim 1. Applicant argues that one skilled in the art would not be motivated to combine Fritzberg and Song, and that claim 5 is not obvious over Song in view of Fritzberg because Fritzberg is silent about particles or microspheres and Song only mentions radioactive species as possible agents among many other possible therapeutic agents.
This argument is unpersuasive. As discussed above, Song in view of Lin renders the amended claim 1 obvious. As discussed above, Song discloses that the microsphere can be used for agents disclosed in Fritzberg. It would have been obvious to use the agents of Fritzberg for the microsphere of Song as taught by Song. Fritzberg discloses the use of a gamma emitting isotope such as 99mTc for diagnosis and therapy. Song discloses the use of microsphere comprising radioactive isotopes as a therapeutic agents. Both teaches the use of isotopes for radiopharmaceutical applications. Further, the specific choice of the radioisotope being a beta or gamma emitting isotope is straightforward for the skilled person, and a person of ordinary skill in the art would have been motivated to select from various radioactive isotopes as the selection would be a matter of routine optimization based on the intended therapeutic or diagnostic application of the microsphere. 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.
Claim(s) 10 and 13 is/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) and Lin et al. (Journal of Controlled Release, 2011; cited on PTO-892) as applied to claims 1-4 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 is discussed above.
Neither Song nor Lin discloses 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 and Lin for improved drug 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 and Lin 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 and/or Richard with respect to 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 renders the amended claim 1 obvious. As discussed above, , Song discloses a multiphase microsphere can include pore(s) and/or a cavity. 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. 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 and Lin constitutes no more than the predictable use of prior art elements according to their established functions.
Claims 1-4 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) and Lin et al. (Journal of Controlled Release, 2011; 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 the primary phase forms the bulk volume of the multiphase microsphere and only the first secondary phase surrounded by the primary phase comprises a radioactive isotope. Richard does not disclose that the first resin and second resin are identical.
Song and Lin 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 make the primary phase form the bulk volume and only the first secondar phase comprises radioactive isotope, and first resin and second resin are identical. 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 the bulk volume of the primary phase can reduce the drug release rate. 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 and Lin to the microspheres of Richard constitutes no more than the predictable use of prior art elements according to their established functions, thus rendering claims 1 and 4 obvious.
Applicant argue that Song does not assist 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 and Lin 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.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Richard (US 2009 0092677; cited on IDS filed Apr 20, 2021), Song et al. (US 2007 0141339; cited on IDS filed Apr 20, 2021), and Lin et al. (Journal of Controlled Release, 2011; cited on PTO-892) as applied to claims 1-4 above, further in view of Fritzberg et al. (US 4897255).
Richard, Song, and Lin are discussed above.
None of Richard, Song, and Lin discloses a radioactive isotope comprises a beta emitting isotope or a gamma emitting isotope.
Fritzberg is 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 gamma emitting isotope such as 99mTc as a radioactive isotope of the microspheres of Richard, Song, and Lin. The person of ordinary skill in the art would have been motivated to make those modifications and reasonably would have expected success because Fritzberg teaches a gamma emitting isotope such as 99mTc can be used for diagnosis and therapy. Further, the specific choice for the radioisotope being a beta or gamma emitting isotope is straightforward for the skilled person, and a person of ordinary skill in the art would have been motivated to select from various radioactive isotopes as the selection would be a matter of routine optimization based on the intended therapeutic or diagnostic application of the microsphere. Accordingly, applying the teachings of Fritzberg to the microspheres of Richard, Song, and Lin constitutes no more than the predictable use of prior art elements according to their established functions, thus rendering claim 5 obvious.
Applicant argues that none of Richard, Fritzberg and/or Song discloses or suggests all the features of amended independent claim 1. Applicant argues that one skilled in the art would not be motivated to combine Fritzberg and Richard, and that claim 5 is not obvious over Richard in view of Fritzberg because Fritzberg is silent about particles or microspheres and Richard mentions radionuclides as possible therapeutic agents among many others.
This argument is unpersuasive. As discussed above, Richard in view of Song and Lin renders the amended claim 1 obvious. As discussed above, Fritzberg discloses the use of a gamma emitting isotope such as 99mTc for diagnosis and therapy. Richard discloses the use of microsphere comprising radioactive isotopes as a therapeutic agents. Both teaches the use of isotopes for radiopharmaceutical applications. Further, the specific choice of the radioisotope being a beta or gamma emitting isotope is straightforward for the skilled person, and a person of ordinary skill in the art would have been motivated to select from various radioactive isotopes as the selection would be a matter of routine optimization based on the intended therapeutic or diagnostic application of the microsphere. The fact that it would have been equally obvious to use other possible therapeutic agents from Richard does not make the use of radioactive species any less obvious.
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 JONG HWAN BAEK whose telephone number is (571)272-0670. The examiner can normally be reached Mon - Thu, 9 am - 3 pm ET.
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/JONG HWAN BAEK/Examiner, Art Unit 1618
/Nissa M Westerberg/Primary Examiner, Art Unit 1618
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