DETAILED ACTION
Applicants’ arguments, filed June 5, 2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Status
Claims 1-17 are pending and under examination.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The abstract of the disclosure is objected to because it is too short in length (28 words). A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b).
While the Applicant states in the remarks filed June 5, 2026 that Applicant will submit a corrected abstract with said response, the examiner notes that no such amended abstract was filed. Therefore, the above objection is maintained.
Claim Interpretation
Claims 1 and 9-12 recite microspheres “for use with radioactive microspheres during a radioembolization treatment.” As claim 1 is drawn to the microsphere itself and claims 9-12 are drawn to methods of preparing the microsphere as the product, the examiner interprets this phrase to be a statement of the intended use of the microspheres. Per MPEP § 2111.02(II), if a statement in the preamble of the claim recites a purpose or intended use, it must be evaluated whether or not the recited purpose or intended use results in a structural difference between the claimed invention and the prior art. With respect to this, the examiner notes that this specific intended use does limit the structure to some degree, as some biodegradable or radiopaque materials may not be suitable for such a use. For example, highly toxic materials would not be suitable for use in a method of treatment. However, MPEP § 2111.02(II) further states that to satisfy an intended use limitation which is limiting, prior art capable of performing the intended use as recited in the preamble meets the claim. This is regardless of whether or not the art teaches the same specific intended use. Indeed, the use need not be explicitly taught by the reference. Claims 1 and 9-12 already possess several structural limitations defining the microspheres, requiring radiopaque nanoparticles and biodegradable material. The examiner interprets the intended use to narrowly further limit these structural features. To the examiner’s understanding, in order for a microsphere comprising a biodegradable material and radiopaque nanoparticles to be capable of performing the intended use as recited (use with radioactive microspheres during a radioembolization treatment), the microsphere must be capable of being administered to a subject in any way and it must not be highly toxic to the subject. Microspheres that meet these criteria will be considered to meet the limitation of the recited intended use.
Claims 1 and 9-12 also recite “the biodegradable is configured to biodegrade to reduce imaging interference between successive radioembolization treatments.” The examiner notes that per the IUPAC Gold Book, a biodegradable material is a substance that undergoes biodegradation (IUPAC Gold Book 09593). Therefore, all biodegradable materials are understood to be configured to biodegrade. The examiner interprets the phrase “to reduce imaging interference between successive radioembolization treatments” to describe the necessary result of the biodegradation. It is not apparent that there are situations in which biodegradation of such a microsphere would not exert this effect. Therefore, the examiner interprets the scope of this limitation to include any biodegradable material.
Claims 1, 9-12, and 17 require the microsphere to be “micron-sized.” The examiner interprets this to mean that the diameter of the microsphere is on a scale that is typically measured in microns. Thus, the examiner interprets the scope of “micron-sized” to be equivalent to 1-999 microns, as values under 1 micron or above 999 microns would be more appropriately described with the units of nanometers and millimeters, respectively.
Claims 1, 9-12, and 17 recite that the microsphere has a density configured to match a density of glass or polymer radioactive treatment microspheres loaded with yttrium-90. In this context, the examiner interprets the broadest reasonable interpretation of the term “match” to mean that the density values of the two microspheres are either equal or similar to each other. Furthermore, the examiner interprets that having “a density configured to match a density of a glass or polymer radioactive treatment microsphere loaded with yttrium-90” means that the radiopaque microsphere must possess a density value that “matches” that of any glass or polymer yttrium-90 loaded microsphere. It is the density value of the radiopaque microsphere that must match a density value of a radioactive microsphere. Additionally, the claim is drawn to the radiopaque microsphere alone and not a radioactive microsphere. If a radiopaque microsphere in one reference has a density that is equal or similar to the density of a glass or polymer radioactive treatment microsphere loaded with yttrium-90 in a different reference, the examiner will interpret the radiopaque microsphere of the first reference to meet this claim limitation. Even if the first reference does not specifically teach that the radiopaque microsphere has an equal or similar density to that of a radioactive treatment microsphere through direct comparison, the fact that it is taught to have a density value that is equal or similar to a radioactive treatment microsphere disclosed in the prior art means that the density values match.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 12-17 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claims contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventors, at the time the application was filed, had possession of the claimed invention.
Claims 12-17 are drawn to methods of making microspheres. These claims require providing a radiopaque material wherein the radiopaque material comprises nanoparticles of at least one of tantalum, gold, barium, strontium, gallium, or iodine. Furthermore, these claims require the radiopaque nanoparticles to be synthesized through addition of a surfactant to a raw radiopaque material. The examiner notes that in the art of nanoparticle synthesis, it is well-understood that surfactants can be used in the preparation of metal nanoparticles. Song (Song, T.; et al., Nanoscale, 2021) teaches that nanoparticles can be synthesized by many wet-chemical methods, including precipitation, hydrothermal, solvent-thermal, sol-gel, polyol, thermal decomposition, seed-mediated growth, and galvanic replacement reactions (pg. 3896, Section 2, first paragraph). Song Figure 1 depicts that surfactants can play several roles in the synthesis of metal nanoparticles. However, as indicated by Song, it is noted that the practitioners in the art of nanoparticle chemistry uses surfactants in the preparation of nanoparticles specifically made of metals. The examiner notes that iodine is not a metal, but a nonmetal halogen. While iodine nanoparticles are known in the art, they are synthesized through the iodination of organic carbon-based molecules and polymers and incorporation in polymeric nanoparticles. Hainfeld (Hainfeld, J. F.; et al., Sci. Rep., 2018) teaches an example in which triiodobenzene is coated with PEG and crosslinked to form nanoparticles (pg. 2, Figure 1c; and pg. 7, Nanoparticles). This is evidence that iodine nanoparticles are synthesized by means other than adding a surfactant to a raw iodine material.
The examiner notes that the instant disclosure lacks reduction to practice, clear depiction, or disclosure of relevant identifying characteristics of a method of preparing iodine nanoparticle by the addition of a surfactant to a raw iodine material. The instant specification teaches that the radiopaque material may be iodine and that it may be in the form of pure metals, metal oxides, alloys, compounds, or any other suitable chemical formulation ([0014]). The instant specification also teaches that radiopaque nanoparticles may be made through the addition of a surfactant to a raw radiopaque material ([0019]). The examiner notes that the instant specification does not provide specific guidance regarding a means of preparing particularly iodine nanoparticles through the addition of a surfactant to a raw iodine material. Therefore, the examiner concludes that claims 12-17 contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventors at the time the application was filed had possession of the claimed invention in its full scope.
Claim Rejections - 35 USC § 112(b)
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.
Claim 16 is 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 16 requires the radiopaque material to be provided as a metal-organic complex. However, claim 12, from which claim 16 depends, requires the radiopaque material to comprise nanoparticles of at least one of tantalum, gold, barium, strontium, gallium, or iodine synthesized through addition of a surfactant to a raw radiopaque material. It is not clear whether the limitation of claim 16 is meant to describe that the radiopaque material is provided as a metal-organic complex instead of being provided as a nanoparticle or if the radiopaque nanoparticle is supposed to be a component of a metal-organic complex. Furthermore, if it is the latter, it is not clear how the nanoparticle is to be connected to or related to the metal organic complex. For these reasons, the claim could have multiple reasonable interpretations at conflict with each other, rendering the scope of the claim indefinite. For the purpose of examination, the examiner will interpret any complexation between a metal and an organic chemical group related in any way to the radiopaque material to read on this limitation.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 13 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 13 requires the radiopaque material to be provided by synthesizing radiopaque nanoparticles through the addition of a surfactant to a raw radiopaque material. However, claim 12, upon which claim 13 depends, already requires the radiopaque material to comprise nanoparticles synthesized through the addition of a surfactant to a raw radiopaque material. Thus, it is understood that claim 13 fails to further limit the claim upon which it depends.
Applicant may cancel the claim, amend the claim to place the claims in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
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 1-3, 5, 7-9, 11-13, and 17 are rejected under 35 U.S.C. 103 as being unpatentable over Duran (Duran, R.; et al., Theranostics, 2016) in view of Kim (Kim, D. H.; et al., Sci. Rep., 2016), Sharma (Sharma, K. V.; et al., J. Vasc. Interv. Radiol., 2010), and Jernigan (Jernigan, S. R.; et al., J. Vasc. Interv. Radiol., 2015).
Duran teaches radiopaque beads for embolotherapy (pg. 28, Abstract). More specifically, Duran teaches radiopaque beads with a poly(vinyl alcohol) (PVA) core modified with triiodobenzyl moieties (pg. 30, Figure 1; and pg. 29-30, Radiopaque Beads Synthesis). Duran describes the PVA beads as biocompatible (pg. 30, left column, lines 18-20). Duran describes the triiodonated benzyl group as a radiopaque compound (pg. 30, left column, lines 23-26). Duran teaches that after attaching the radiopaque group to the PVA bead, the modified bead was filtered and washed (pg. 30, right column, first paragraph). Duran prepared beads of four different size ranges: 40-90 µm, 70-150 µm, 100-300 µm, and 300-500 µm (pg. 34, Table 1 and Figure 2). The densities of these beads varied from 1.21-1.36 g/mL and correlated with bead size (pg. 34, Table 2). Duran teaches that the non-radiopaque comparator LC-beads have a density of 1.05 g/mL and conclude that the radiopaque material conferred a denser bead structure (pg. 34, Results, Second paragraph). Duran teaches that the beads of these sizes can pass through multiple sizes of catheters, though the larger particles do not effectively get delivered through narrow catheters (pg. 35, left column, first paragraph and Table 3). Duran further teaches that the radiopaque PVA beads can effectively be used to perform X-ray and CT imaging of rabbits (pg. 33, In Vivo Imaging; pg. 36, Figure 6; and pg. 37, Figure 7).
Duran does not teach a biodegradable radiopaque microsphere wherein the radiopaque material comprises nanoparticles of at least one of tantalum, gold, barium, strontium, gallium, or iodine. Nor does Duran explicitly teach a microsphere with a density configured to match a density of glass or polymer radioactive treatment microspheres loaded with yttrium-90.
Kim teaches polymer microspheres loaded with gold nanorods for transcatheter therapy imaging (pg. 1, Abstract). More specifically, Kim teaches microspheres composed of an alginate polymer, iron-based magnetic clusters, and gold nanorods (pg. 2, fifth paragraph). Kim teaches that the gold nanorods were synthesized by adding CTAB (cetyltrimethyl ammonium bromide) to an aqueous gold solution (pg. 2, fourth paragraph). Kim describes the nanorods as possessing radiopaque properties, enabling CT imaging (pg. 8, first paragraph). Kim also describes that gold nanoparticles are generally biocompatible, provide greater contrast than iodinated contrast agents, and are less influenced by the environment than iodinated contrast agents (pg. 8, first paragraph, last seven lines). Kim also teaches the alginate polymer matrix of the microsphere as biodegradable (pg. 6, Discussion, line 17). Kim teaches that the biodegradable radiopaque microspheres have diameters around 20-40 µm (pg. 5, Figure 1d). Kim teaches that the radiopaque microspheres can be used for CT imaging in a rat model (pg. 7, Figure 4).
Sharma teaches radiopaque embolization microspheres for CT imaging (pg. 865, Abstract). More specifically, Sharma teaches lipiodol-loaded PVA microspheres (pg. 866, Materials and Methods, first paragraph). Sharma teaches that lipiodol is denser than water, resulting in the lipiodol-loaded microspheres being denser than the unloaded PVA (pg. 868, left column, third paragraph, first sentence). Sharma teaches that the density of the microspheres can be altered by varying the amount of lipiodol loaded into the polymer microsphere, which may be desirable to decrease how much the microspheres settle in suspension (pg. 871, right column, second paragraph). Sharma suggests an alternative means to optimizing the density of the microspheres is to use a different, more radiopaque agent (pg. 871, right column, second paragraph, lines 29-32). Sharma teaches that the radiopaque PVA microspheres produce CT signal at multiple concentrations of lipiodol (pg. 869, Figure 2). Sharma teaches the lipiodol-loaded PVA microsphere can effectively be used for CT imaging during transcatheter embolization of swine liver (pg. 871, Figure 5).
Jernigan teaches an analysis of the impact of microsphere density and diameter on tissue penetration (pg. 897, abstract). Jernigan teaches that yttrium-90 loaded microspheres used for internal radiation therapy are commercially available with resin or glass matrices (pg. 897, Introduction, first paragraph). Jernigan teaches that the density of commercial yttrium-90 loaded glass microspheres is 3.4 g/mL whereas the density of the yttrium-90 loaded resin microspheres is 1.6 g/mL (pg. 897, right column, first paragraph). Jernigan prepared a hepatic arterial system model (Figure 1 and Figure 3) to analyze the difference in flow between microparticles possessing different properties. The model glass microspheres of Jernigan have a density of 2.52 g/mL, whereas the model resin microspheres have a density of 1.57 g/mL (pg. 900, Table 1). Jernigan found that the resin microspheres traveled further than did the glass microspheres (pg. 902, Figure 6). Jernigan concludes that microsphere density likely impacts radioembolitic microsphere tissue penetration (pg. 904, left column, last paragraph). Jernigan notes that the model glass microspheres were less dense than the known commercial yttrium-90 loaded glass beads, but suggests that the difference in penetration between resin and glass microspheres may be more pronounced in the commercial products (pg. 904, left column, third paragraph).
A person of ordinary skill in the art would have recognized that Duran, Kim, Sharma, and Jernigan all teach microspheres that can be used in various forms of embolization. It would be recognized that Duran, Kim, and Sharma all teach biodegradable radiopaque microspheres. It would be recognized that Duran and Sharma teach iodine-containing moieties as the radiopaque component while Kim teaches a gold nanoparticle instead. It would also be recognized that Sharma suggests iodine-based contrast components can be substituted for other agents with greater contrast. It would also be recognized that Duran and Sharma teach that microsphere density can vary with diameter and radiopaque material loading and that Jernigan teaches that particle density likely influences tissue penetration.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the biodegradable radiopaque microsphere of Duran to substitute the triiodobenzyl group with the gold nanoparticles of Kim because these are both radiopaque groups that serve the same purpose in the polymer microspheres of Duran and Kim to enable imaging of the particles and the materials can be substituted with predictable results (MPEP § 2143(I)(B)). This would yield the predictable outcome of a gold nanoparticle coated PVA radiopaque and biodegradable microsphere.
Furthermore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the biodegradable radiopaque gold nanoparticle-PVA microsphere of the combination of Duran and Kim to optimize its density by varying the radiopaque material loading and particle diameter as taught by Duran and Sharma, as Jernigan teaches that the density of embolization microspheres influence the tissue penetration and distribution (MPEP § 2143(I)(G)). This would predictably yield a biodegradable radiopaque microsphere having a density matching that of an yttrium-90 loaded treatment microsphere.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the microspheres of Duran because Sharma suggests that iodine containing moieties can be replaced by more radiopaque agents (pg. 871, second paragraph, lines 29-32). Furthermore, chemists are able to functionalize many groups, which would enable attachment of the gold nanoparticles to the surface of the PVA microsphere of Duran in place of the triiodobenzyl group. There would also be a reasonable expectation of success in varying the density of this biodegradable radiopaque microsphere because Duran and Sharma teach that varying particle size and radiopaque material loading can change the density of such microspheres.
The skilled artisan would have been motivated to substitute the triiodobenzyl group with gold nanoparticles because Kim teaches that gold nanoparticles provide greater contrast than iodinated contrast agents and have good biocompatibility (pg. 8, first paragraph, lines 15-16). The skilled artisan also would have been motivated to optimize the density of the biodegradable radiopaque microspheres because Jernigan teaches that microsphere density influences distal penetration in vitro, suggesting differences in vasculature and tissue penetration in living systems.
Regarding claim 1, Duran teaches a microsphere with a PVA core modified with a radiopaque material on the surface (pg. 30, Figure 1). Kim teaches a microsphere containing radiopaque gold nanorods (pg. 2, paragraphs 4 and 5). As described above, the combined teachings of Duran and Kim would result in a PVA microsphere modified with gold nanorods on the surface. While neither Duran nor Kim explicitly teach using these microspheres with radioactive microspheres during a radioembolization treatment, this claim is drawn to the composition of matter itself, and not the method of use. Furthermore, as described in the Claim Interpretation above, this preamble phrase is interpreted to be a statement of intended use. As Duran and Kim teach that PVA microspheres and polymer microspheres containing gold nanorods are capable of use in embolization and can be administered to living systems (Duran, Figures 6 and 7) (Kim, Figure 4), these materials are understood to be not highly toxic and capable of being administered. Therefore, the modified PVA microsphere is understood by the examiner to be capable of being used with radioactive microspheres during a radioembolization treatment.
Additionally, MPEP § 2111.01(IV) states that the Applicant may be their own lexicographer. In [0013] and [0051], applicant provides a list of examples of biodegradable materials that includes poly(vinyl alcohol) (PVA). Therefore, the examiner interprets the scope of the “biodegradable material” to encompass PVA. Duran teaches radiopaque PVA microspheres (pg. 30, Figure 1), thus teaching a biodegradable material. Kim teaches that gold nanorods are radiopaque materials (pg. 8, second paragraph, lines 13-14). As the term nanoparticle does not require a spherical three-dimensional shape, the examiner interprets a nanorod to be a nanoparticle. Therefore, Kim teaches a radiopaque material comprising nanoparticles of gold.
As described above, PVA is biodegradable. As described in the Claim Interpretation section, all biodegradable materials are configured to biodegrade. Furthermore, the examiner interprets “to reduce imaging interference between successive radioembolization treatments” to be a result of the process of biodegradation. While Duran and Kim are silent to the imaging interference between radioembolization treatments, the combined teachings read on the required structural limitations of the claim. Per MPEP 2112(III), when the prior art is silent to a function or property of a composition and the composition is the same as that of the claim, the examiner may still make a proper rejection under 35 U.S.C. 103. If the biodegradable microsphere biodegrades, it would result in a change in imaging interference.
Furthermore, Duran teaches the radiopaque PVA microspheres as having diameters of 40-90 µm, 70-150 µm, 100-300 µm, and 300-500 µm (pg. 34, Table 1 and Figure 2). These are all measured in microns. Thus, the gold nanoparticle PVA microspheres taught by the combination of Duran and Kim are considered to be micron-sized. Even if the gold nanoparticles are larger than the triiodobenzyl moieties of Duran, being on the scale of nanometers, these nanoparticles would not meaningfully change the diameter of the Duran PVA microspheres as measured in microns to the point that the microspheres are no longer appropriately measured in microns (see above Claim Interpretation).
Duran teaches the density of the radiopaque PVA microspheres varied from 1.21-1.36 g/mL and correlated with bead size (pg. 34, Table 2). Jernigan teaches that the density of commercial yttrium-90 loaded glass microspheres is 3.4 g/mL whereas the density of the yttrium-90 loaded resin microspheres is 1.6 g/mL (pg. 897, right column, first paragraph). Per the above Claim Interpretation section, the examiner interprets the term “match” to include in scope that the radiopaque microspheres have a similar density to that of radioactive treatment microspheres loaded with yttrium-90. The examiner notes that 1.36 g/mL and 1.6 g/mL (resin radioactive microspheres) are similar values. Furthermore, Duran teaches that density increases as microsphere diameter decreases (pg. 34, Table 2) and Sharma teaches that density increases with increased radiopaque material loading (pg. 871, right column). The examiner notes that this teaches that the density of radiopaque microspheres varies with size and the concentration of the radiopaque material in the microsphere. Per MPEP § 2144.04(IV)(A), changes in size are obvious; and per MPEP § 2144.05(II)(A), differences in concentration generally do not support patentability, as this is can be achieved through routine optimization. As Jernigan teaches that the density of microspheres influences their distance traveled in a fluidic system (pg. 902, Figure 6), the skilled artisan would be motivated to optimize the density of the gold nanoparticle modified PVA microspheres taught by the combination of Duran and Kim by adjusting microsphere size and radiopaque material concentration. This means that the density of the biodegradable radiopaque microspheres may exceed 1.36 g/mL and be even more similar and possibly equal to the 1.6 g/mL density of radioactive resin microspheres through routine optimization. Therefore, achieving a matching density is rendered obvious.
For the above reasons, the combined teachings of Duran, Kim, Sharma, and Jernigan render claim 1 obvious.
Regarding claim 2, Kim teaches radiopaque nanorods (pg. 2, fourth paragraph; and pg. 8, first paragraph). As stated above, the examiner interprets nanorods to be within the scope of the meaning of nanoparticles. Therefore, the combined teachings of Duran, Kim, Sharma, and Jernigan render claim 2 obvious.
Regarding claim 3, Duran teaches chemically linking the PVA biodegradable core to the radiopaque material through a linker (pg. 30, Figure 1). As described above, the substitution of the triiodobenzyl moiety for the gold nanoparticles of Kim would result in a surface-linked radiopaque gold nanoparticle. Therefore, the combined teachings of Duran, Kim, Sharma, and Jernigan render claim 3 obvious.
Regarding claim 5, Duran teaches the radiopaque material being attached to the exterior of the PVA biodegradable core (pg. 30, Figure 1). As described above, the substitution of the triiodobenzyl moiety for the gold nanoparticles of Kim would result in a surface-linked radiopaque gold nanoparticle. As the gold nanoparticles would be present in a plurality on the exterior of the biodegradable material, the examiner interprets this to be within the scope of “coated.” The examiner interprets the broadest reasonable interpretation of the biodegradable material being coated by the radiopaque material to include situations in which the radiopaque material is on the exterior of the biodegradable material and does not require a complete gapless shell to be formed around the biodegradable material. Therefore, the combined teachings of Duran, Kim, Sharma, and Jernigan render claim 5 obvious.
Regarding claim 7, Duran teaches a microsphere comprising PVA (pg. 30, Figure 1). Therefore, the combined teachings of Duran, Kim, Sharma, and Jernigan render claim 7 obvious.
Regarding claim 8, Kim teaches radiopaque gold nanoparticles (pg. 2, fourth paragraph; and pg. 8, first paragraph). Therefore, the combined teachings of Duran, Kim, Sharma, and Jernigan render claim 8 obvious.
Regarding claim 9, Duran teaches a method of linking a biodegradable material to a radiopaque material through a linker (pg. 29-30, Radiopaque Beads Synthesis). As described above, the combined teachings of Duran and Kim result in a biodegradable PVA microsphere linked to radiopaque gold nanoparticles on the surface. As described above, this product is a micron-sized microsphere that is capable of being used with radioactive microspheres during a radioembolization treatment and is configured to biodegrade, which would result in reduced imaging interference. Furthermore, as described above, the density of the microsphere is relatively similar to that of the commercially available yttrium-90 resin microsphere (Duran, pg. 34, Table 2) (Jernigan, pg. 897, right column, first paragraph) and adjustment of the density to be more similar would amount to routine optimization. Therefore, the combined teachings of Duran, Kim, Sharma, and Jernigan render claim 9 obvious.
Regarding claim 11, Duran teaches a method of linking a biodegradable material to a radiopaque material through a linker on the outer surface of the microsphere (pg. 29-30, Radiopaque Beads Synthesis). As described above, the combined teachings of Duran and Kim result in a biodegradable PVA microsphere linked to radiopaque gold nanoparticles on the surface. As described above, this is interpreted to be within the scope of “coating,” as the radiopaque gold nanoparticles form a layer on the outer surface surrounding the biodegradable material, even if it is not a complete encapsulation. As described above, this product is a micron-sized microsphere that is capable of being used with radioactive microspheres during a radioembolization treatment and is configured to biodegrade, which would result in reduced imaging interference. Furthermore, as described above, the density of the microsphere is relatively similar to that of the commercially available yttrium-90 resin microsphere (Duran, pg. 34, Table 2) (Jernigan, pg. 897, right column, first paragraph) and adjustment of the density to be more similar would amount to routine optimization. Therefore, the combined teachings of Duran, Kim, Sharma, and Jernigan render claim 11 obvious.
Regarding claim 12, Duran teaches a method of providing a radiopaque material (triiodobenzyl moiety), combining the radiopaque material with a biodegradable material (PVA) to prepare a biodegradable radiopaque microsphere, and filtering and washing the product (pg. 29-30, Radiopaque Beads Synthesis). As described above, PVA is a biodegradable material and is therefore configured to biodegrade, and the reduction in imaging interference is an effect of the degradation. Furthermore, the filtering and washing steps of Duran are interpreted by the examiner to read on “finish processing” as recited in claim 12. Additionally, as described above, the combined teachings of Duran and Kim result in a PVA microsphere modified with gold nanoparticles on the surface. Kim teaches radiopaque nanorods (pg. 2, fourth paragraph; and pg. 8, first paragraph). As stated above, the examiner interprets nanorods to be within the scope of the meaning of nanoparticles. Kim teaches that the nanoparticles are synthesized by the addition of cetyltrimethylammonium bromide to an aqueous solution of gold (pg. 2, fourth paragraph, lines 9-11). The examiner notes that cetyltrimethylammonium bromide is a surfactant. The examiner interprets the addition of cetyltrimethylammonium bromide to the aqueous solution of the gold salt to read on the limitation of a nanoparticle of at least one of tantalum, gold, barium, strontium, gallium, or iodine synthesized through addition of a surfactant to a raw radiopaque material. Additionally, as described above, this product is a micron-sized microsphere that is capable of being used with radioactive microspheres during a radioembolization treatment. Furthermore, as described above, the density of the microsphere is relatively similar to that of the commercially available yttrium-90 resin microsphere (Duran, pg. 34, Table 2) (Jernigan, pg. 897, right column, first paragraph) and adjustment of the density to be more similar would amount to routine optimization. Therefore, the combined teachings of Duran, Kim, Sharma, and Jernigan render claim 12 obvious.
Regarding claim 13, as described above, the combined teachings of Duran and Kim result in a biodegradable PVA microsphere modified with radiopaque gold nanoparticles on the surface. Kim teaches radiopaque nanorods (pg. 2, fourth paragraph; and pg. 8, first paragraph). As stated above, the examiner interprets nanorods to be within the scope of the meaning of nanoparticles. Kim teaches that the nanoparticles are synthesized by the addition of cetyltrimethylammonium bromide to an aqueous solution of gold (pg. 2, fourth paragraph, lines 9-11). The examiner notes that cetyltrimethylammonium bromide is a surfactant. The examiner interprets the addition of cetyltrimethylammonium bromide to the aqueous solution of the gold salt to read on the limitation of synthesizing radiopaque nanoparticles through addition of a surfactant to a raw radiopaque material. Therefore, the combined teachings of Duran, Kim, Sharma, and Jernigan render claim 13 obvious.
Regarding claim 17, as described above, the combined teachings of Duran, Kim, Sharma, and Jernigan render claim 12 obvious. Furthermore, Duran teaches filtering and washing the biodegradable radiopaque microsphere (pg. 29-30, Radiopaque Beads Synthesis), which the examiner interprets to be a “finish processing step.” Furthermore, Duran teaches the radiopaque PVA microspheres as having diameters of 40-90 µm, 70-150 µm, 100-300 µm, and 300-500 µm (pg. 34, Table 1 and Figure 2). These are all measured in microns. Thus, the gold nanoparticle PVA microspheres taught by the combination of Duran and Kim are considered to be micron-sized. Even if the gold nanoparticles are larger than the triiodobenzyl moieties of Duran, being on the scale of nanometers, these nanoparticles would not meaningfully change the diameter of the Duran PVA microspheres as measured in microns to the point that the microspheres are no longer appropriately measured in microns (see above Claim Interpretation). Additionally, Duran teaches that the 40-90 µm and 70-150 µm biodegradable radiopaque microspheres have narrow size distributions as measured with an optical microscope (pg. 34, Figure 2), which the examiner interprets to be within the scope of “uniform size distribution” due to the relatively narrow range and relatively symmetric shape of the distribution in the histogram plot. Furthermore, as described above, the density of the microsphere is relatively similar to that of the commercially available yttrium-90 resin microsphere (Duran, pg. 34, Table 2) (Jernigan, pg. 897, right column, first paragraph) and adjustment of the density to be more similar would amount to routine optimization. Therefore, the combined teachings of Duran, Kim, Sharma, and Jernigan render claim 17 obvious.
Claims 14-16 are rejected under 35 U.S.C. 103 as being unpatentable over Duran, Kim, Sharma, and Jernigan, as applied to claims 1-3, 5, 7-9, 11-13, and 17 above, and further in view of Kamra (Kamra, T.; et al., J. Colloid Interface Sci., 2016) and Ino (Ino, J. M.; et al., Biomatter, 2013).
As described above, the combination of the teachings of Duran, Kim, Sharma, and Jernigan result in a biodegradable radiopaque microsphere comprising a biodegradable PVA core microsphere modified by gold nanoparticles on the surface. Furthermore, Duran teaches a method of making microspheres in which a radiopaque material is attached to the outer surface of a biodegradable material on the surface of the PVA microsphere (pg. 29-30, Radiopaque Bead Synthesis; and Figure 1). As described above, the combined teachings of Duran, Kim, Sharma, and Jernigan render the method of claim 12 obvious.
The combined teachings of Duran, Kim, Sharma, and Jernigan do not explicitly teach forming a complex between the radiopaque nanoparticles and the biodegradable PVA core through a biodegradable linker.
Kamra teaches covalent immobilization of polymer nanoparticles to a gold surface (pg. 1, Abstract). More specifically, Kamra teaches modifying a gold surface with mercaptoundecanoic acid, activating the carboxylic acid with EDC/NHS, and then attaching polymer particles with primary amine groups on the surface (pg. 3, Scheme 1; and pg. 3-4, Section 2.6). Kamra teaches that this EDC/NHS approach has various advantages such as high conversion efficiency, mild reaction conditions, easily separable byproducts, and compatibility with organic materials (pg. 2, right column, second paragraph).
Ino teaches functionalization of PVA hydrogels (pg. 1, Abstract). More specifically, Ino teaches treating a PVA material with hydrogen and nitrogen plasma (pg. 4, Plasma Treatment). Ino teaches that this plasma treatment introduces primary amines on the surface of the PVA material (pg. 3, Figure 1; and pg. 2, right column, first full paragraph). Ino teaches that such modification enhanced cell growth on the PVA material (pg. 6, Figure 5), indicating increased biocompatibility.
A person of ordinary skill in the art would have recognized that the combination of Duran and Kim teaches linking a polymer particle to a gold nanoparticle. It would also be recognized that Kamra similarly teaches a specific means to covalently link a gold material to a polymer particle through EDC/NHS coupling. It would further be recognized that Ino teaches that PVA can be modified to have an amine-functionalized surface.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the linkage between the PVA microsphere and gold nanoparticle of Duran, Kim, Sharma, and Jernigan to be linked through the EDC/NHS coupling as taught by Kamra after modifying the PVA microsphere to be amine-functionalized, as taught by Ino. This is because these techniques were known in the art and one of skill in the art could have combined these methods with no change in their respective functions (MPEP § 2143(I)(A)). The combination would have yielded the predictable outcome of a method of preparing a biodegradable radiopaque microsphere in which radiopaque gold nanoparticles are attached to the outside of a biodegradable PVA microsphere through covalent amide linkages.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the method in these ways because Ino teaches the efficacy of plasma-based amine functionalization of PVA and Kamra teaches the efficiency and benefits to EDC/NHS coupling of two materials in the context of a gold material and an amine-presenting polymer particle.
The skilled artisan would have been motivated to modify the method in this way because Kamra describes that EDC/NHS coupling has many advantages (pg. 2, right column, first full paragraph) including high efficiency and compatibility with organic materials.
Regarding claim 14, as described above, the combined teachings of Duran, Kim, Sharma, and Jernigan render the method of claim 12 obvious. While Duran teaches linking a radiopaque material to a radiopaque material (pg. 30, Figure 1), Duran does not explicitly teach a biodegradable linker structure that can be used to attach radiopaque gold nanoparticles to the surface of the PVA microspheres. Kamra teaches a means of covalently linking polymer particles to a gold material through modifying a gold surface with mercaptoundecanoic acid, activating the carboxylic acid with EDC/NHS, and then attaching polymer particles with primary amine groups on the surface (pg. 3, Scheme 1; and pg. 3-4, Section 2.6). Though this was done with a gold surface, since the gold nanoparticles of Kim are also a gold material, it would be expected that the thiol attachment to the gold particles would also work. Additionally, Ino teaches that PVA can be modified to have amine groups on the surface through plasma treatment (pg. 3, Figure 1), indicating that PVA can be modified to be suitable for the EDC/NHS coupling taught by Kamra. The result of the combination of the teachings of these references would be an amine-modified PVA microsphere covalently linked to the gold nanoparticles through a linker comprising an amide group and a thiol-based attachment to the gold nanoparticle. This linker contains an amide group, which is biodegradable. This can be interpreted to read on “a radiopaque material and a biodegradable linker complex” in two ways. In one way, the linker contains an amide group, thus making it a biodegradable linker. As the radiopaque nanoparticle is attached to the linker through the sulfur group, it can be understood to be a complex between the radiopaque material and a biodegradable linker. In another interpretation, the radiopaque gold nanoparticle has been incorporated into a complex with the biodegradable PVA microsphere and this complex is formed through the use of an amide-containing (thus, biodegradable) linker. With either interpretation, this combined method reads on this limitation of claim 14. Therefore, the combined teachings of Duran, Kim, Sharma, Jernigan, Kamra, and Ino render claim 14 obvious.
Regarding claim 15, as described above, the combined method and product of Duran, Kim, Sharma, Jernigan, Kamra, and Ino results in an amine-modified biodegradable microsphere surface modified with radiopaque gold nanoparticles which are attached through NHS/EDC coupling to form a biodegradable linker. Kamra teaches that this NHS/EDC coupling is formed by the combination of a carboxyl group and an amine group (pg. 3, Scheme 1). Therefore, the combined teachings of Duran, Kim, Sharma, Jernigan, Kamra, and Ino render claim 15 obvious.
Regarding claim 16, as described above, the combined method and product of Duran, Kim, Sharma, Jernigan, Kamra, and Ino results in an amine-modified biodegradable microsphere surface modified with radiopaque gold nanoparticles which are attached through NHS/EDC coupling to form a biodegradable linker. The examiner interprets the broadest reasonable interpretation of “metal-organic complex” to be any complex formed between a metal material and an organic chemical group. As PVA is an organic biodegradable polymer, this full structure could be described as a complex between a radiopaque material and an organic material. Separately, Kamra teaches complexing a gold material with a thiol-containing organic group to build the linker between the gold material and the polymer particle (pg. 3, Scheme 1). This interaction is a complexation of the metal material and an organic moiety, which also reads on the concept of a metal-organic complex. Therefore, the combined teachings of Duran, Kim, Sharma, Jernigan, Kamra, and Ino render claim 16 obvious.
Claims 1, 2, 4, 6, 8, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Kim in view of Duran, Sharma, Jernigan, and Alrfooh (Alrfooh, A.; et al., Nucl. Med. Mol. Img., 2021).
As described above, Kim teaches polymer microspheres loaded with gold nanorods for transcatheter therapy imaging (pg. 1, Abstract). More specifically, Kim teaches microspheres composed of an alginate polymer, iron-based magnetic clusters, and gold nanorods (pg. 2, fifth paragraph). Kim teaches that the gold nanorods were synthesized by adding CTAB (cetyltrimethyl ammonium bromide) to an aqueous gold solution (pg. 2, fourth paragraph). Kim describes the nanorods as possessing radiopaque properties, enabling CT imaging (pg. 8, first paragraph). Kim also describes that gold nanoparticles are generally biocompatible, provide greater contrast than iodinated contrast agents, and are less influenced by the environment than iodinated contrast agents (pg. 8, first paragraph, last seven lines). Kim also teaches the alginate polymer matrix of the microsphere as biodegradable (pg. 6, Discussion, line 17). Kim teaches that the biodegradable radiopaque microspheres have diameters around 20-40 µm (pg. 5, Figure 1d). Kim teaches that the microsphere product encapsulates the gold nanorods (pg. 4, fifth paragraph, lines 15-17). Kim teaches that the radiopaque microspheres can be used for CT imaging in a rat model (pg. 7, Figure 4).
Kim does not explicitly teach a biodegradable radiopaque microsphere having a density configured to match a density of glass or polymer radioactive treatment microspheres loaded with yttrium-90.
As described above, Duran teaches radiopaque beads for embolotherapy (pg. 28, Abstract). More specifically, Duran teaches radiopaque beads with a poly(vinyl alcohol) (PVA) core modified with triiodobenzyl moieties (pg. 30, Figure 1; and pg. 29-30, Radiopaque Beads Synthesis). Duran describes the PVA beads as biocompatible (pg. 30, left column, lines 18-20). Duran describes the triiodonated benzyl group as a radiopaque compound (pg. 30, left column, lines 23-26). Duran prepared microbeads with densities varied from 1.21-1.36 g/mL, which correlated with bead size (pg. 34, Table 2). Duran teaches that the non-radiopaque comparator LC-beads have a density of 1.05 g/mL and conclude that the radiopaque material conferred a denser bead structure (pg. 34, Results, Second paragraph). Duran further teaches that the radiopaque PVA beads can effectively be used to perform X-ray and CT imaging of rabbits (pg. 33, In Vivo Imaging; pg. 36, Figure 6; and pg. 37, Figure 7).
As described above, Sharma teaches radiopaque embolization microspheres for CT imaging (pg. 865, Abstract). More specifically, Sharma teaches lipiodol-loaded PVA microspheres (pg. 866, Materials and Methods, first paragraph). Sharma teaches that lipiodol is denser than water, resulting in the lipiodol-loaded microspheres being denser than the unloaded PVA (pg. 868, left column, third paragraph, first sentence). Sharma teaches that the density of the microspheres can be altered by varying the amount of lipiodol loaded into the polymer microsphere, which may be desirable to decrease how much the microspheres settle in suspension (pg. 871, right column, second paragraph). Sharma suggests an alternative means to optimizing the density of the microspheres is to use a different, more radiopaque agent (pg. 871, right column, second paragraph, lines 29-32). Sharma teaches that the radiopaque PVA microspheres produce CT signal at multiple concentrations of radiopaque agent (pg. 869, Figure 2). Sharma teaches the lipiodol-loaded PVA microsphere can effectively be used for CT imaging during transcatheter embolization of swine liver (pg. 871, Figure 5).
As described above, Jernigan teaches an analysis of the impact of microsphere density and diameter on tissue penetration (pg. 897, abstract). Jernigan teaches two examples of yttrium-90 loaded microspheres used for internal radiation therapy that are commercially available with resin or glass matrices (pg. 897, Introduction, first paragraph). Jernigan teaches that the density of commercial yttrium-90 loaded glass microspheres is 3.4 g/mL whereas the density of the yttrium-90 loaded resin microspheres is 1.6 g/mL (pg. 897, right column, first paragraph). Jernigan prepared a hepatic arterial system model (Figure 1 and Figure 3) to analyze the difference in flow between microparticles possessing different properties. The model glass microspheres of Jernigan have a density of 2.52 g/mL, whereas the model resin microspheres have a density of 1.57 g/mL (pg. 900, Table 1). Jernigan found that the resin microspheres traveled further than did the glass microspheres (pg. 902, Figure 6). Jernigan concludes that microsphere density likely impacts radioembolitic microsphere tissue penetration (pg. 904, left column, last paragraph). Jernigan notes that the model glass microspheres were less dense than the known commercial yttrium-90 loaded glass beads, but suggests that the difference in penetration between resin and glass microspheres may be more pronounced in the commercial products (pg. 904, left column, third paragraph).
Alrfooh provides a summary of known radionuclide agents and carriers for transarterial radioembolization agents (pg. 162, Abstract). Alrfooh describes that yttrium-90 is a well-known radionuclide used in radioembolization therapy (pg. 163, Table 1; pg. 164, Table 2; pg. 165, Table 3), disclosing that yttrium-90 loaded resin microspheres have a strong embolizing effect (pg. 165, left column, last paragraph). Alrfooh also summarizes known carrier molecules used in microsphere preparation, indicating that known radioembolization microparticles have glass, resin, or polymer carriers (pg. 163, Table 1). Alrfooh states that a vast array of carriers made of a variety of materials have been studied in the form of microspheres (pg. 164, Carrier Microspheres, first paragraph). Alrfooh provides a summary and analysis of known polymers used in preparing embolization microspheres, their advantages, and disadvantages (pg. 166, Table 5), including biodegradable PVA (pg. 167, right column, third paragraph). Alrfooh also describes that alginate microspheres are also studied in the context of embolization microspheres as a carrier particle material (pg. 169, right column, Alginate Microspheres).
A person of ordinary skill in the art would have recognized that Kim, Durant, Sharma, Jernigan, and Alrfooh all teach microspheres that can be used in various forms of embolization. It would be recognized that Kim, Duran, and Sharma all teach biodegradable radiopaque microspheres. It would also be recognized that Duran and Sharma teach that microsphere density can vary with diameter and radiopaque material loading and that Jernigan teaches that particle density likely influences tissue penetration. It would also be recognized that Alrfooh describes that radioembolization particles, such as those loaded with yttrium-90, can be prepared using a variety of carrier materials, including alginate.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the biodegradable radiopaque microspheres of Kim to have a density matching that of glass or polymer yttrium-90 loaded microspheres; as Sharma suggests varying radiopaque material concentration changes microsphere density, Duran suggests varying microsphere diameter changes microsphere density, Alrfooh teaches that radioactive treatment microspheres can be prepared with many different polymer materials, and Jernigan teaches that the density of microsphere can influence penetration (MPEP § 2143(I)(G)). This combination would predictably result in a biodegradable radiopaque microsphere having a density matching that of glass or polymer yttrium-90 loaded microspheres.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the density of the biodegradable radiopaque microspheres of Kim because Duran and Sharma teach that varying particle size and radiopaque material loading can change the density of such microspheres.
The skilled artisan would have been motivated to optimized the density of the biodegradable radiopaque microspheres because Jernigan teaches that microsphere density influences distal penetration in vitro, suggesting differences in vasculature and tissue penetration in living systems.
Regarding claim 1, Kim teaches a microsphere containing gold nanorods encapsulated in alginate (pg. 4, fifth paragraph). Kim teaches that gold nanorods are radiopaque materials (pg. 8, second paragraph, lines 13-14). As the term nanoparticle does not require a spherical three-dimensional shape, the examiner interprets a nanorod to be a nanoparticle. Therefore, Kim teaches a radiopaque material comprising nanoparticles of gold. Kim also teaches the alginate polymer matrix of the microsphere as biodegradable (pg. 6, Discussion, line 17). As described in the Claim Interpretation section, all biodegradable materials are configured to biodegrade. Furthermore, the examiner interprets “to reduce imaging interference between successive radioembolization treatments” to be a result of the process of biodegradation. While Kim are silent to the imaging interference between radioembolization treatments, the biodegradable alginate polymer microsphere reads on the required structural limitations of the claim. Per MPEP 2112(III), when the prior art is silent to a function or property of a composition and the composition is the same as that of the claim, the examiner may still make a proper rejection under 35 U.S.C. 103. If the biodegradable microsphere biodegrades, it would result in a change in imaging interference between successive radioembolization treatments. Additionally, Kim teaches that the average diameter of the biodegradable radiopaque microspheres was 25 µm (pg. 4, fifth paragraph; and pg. 5, Figure 1d). Thus, these microspheres are considered to be micron-sized (see above Claim Interpretation).
While neither Kim does not explicitly teach using these biodegradable radiopaque microspheres with radioactive microspheres during a radioembolization treatment, this claim is drawn to the composition of matter itself, and not the method of use. Furthermore, as described in the Claim Interpretation above, this preamble phrase is interpreted to be a statement of intended use. As Kim teaches that alginate microspheres encapsulating gold nanoparticles are capable of use in embolization and can be administered to living systems (pg. 3, last paragraph; pg. 5, last paragraph; and pg. 7, Figure 4), these materials are understood to not be highly toxic and be capable of being administered to subjects. Therefore, the alginate-gold nanoparticle biodegradable radiopaque microsphere of Kim is understood by the examiner to be capable of being used with radioactive microspheres during a radioembolization treatment.
Kim does not explicitly teach a density value of the alginate polymer-gold nanoparticle biodegradable radiopaque microspheres. Though the examiner notes that, as it is a physical and existing microsphere, it possesses a density value. Jernigan teaches that the density of commercial yttrium-90 loaded glass microspheres is 3.4 g/mL whereas the density of the yttrium-90 loaded resin microspheres is 1.6 g/mL (pg. 897, right column, first paragraph). However, Alrfooh teaches that a variety of polymers can be used as microsphere carriers for radioembolization (pg. 166, Table 5; and pg. 167, Polymer-based microspheres). Alrfooh discloses that several polymers, including alginate, can be used for embolic microspheres (pg. 166, Table 5; and pg. 169, Alginate Microspheres). This suggests that alginate microspheres could also be loaded with yttrium-90. As Jernigan describes that the carrier material (glass vs. resin) can influence radioembolization microsphere density, the teachings of Alrfooh suggest that yttrium-90 loaded microspheres made of other polymeric carrier materials would possess a range of densities other than 1.6 g/mL and 3.4 g/mL. Thus, the scope of densities of glass or polymer microspheres loaded with yttrium-90 is understood by the examiner to be broader than the values of 1.6 g/mL and 3.4 g/mL. Furthermore, Duran teaches the density of a radiopaque PVA polymer microspheres varied from 1.21-1.36 g/mL and that that density increases as microsphere diameter decreases (pg. 34, Table 2). Additionally, Sharma teaches that density increases with increased radiopaque material loading (pg. 871, right column). Per MPEP § 2144.04(IV)(A), changes in size are obvious; and per MPEP § 2144.05(II)(A), differences in concentration generally do not support patentability, as this is can be achieved through routine optimization. As Jernigan teaches that the density of microspheres influences their distance traveled in a fluidic system (pg. 902, Figure 6), the skilled artisan would be motivated to optimize the density of the gold nanoparticle encapsulating alginate microspheres taught by Kim by adjusting microsphere size and radiopaque material concentration. This means that a range of densities of the biodegradable radiopaque microspheres could be achieved through routine optimization. Per the above Claim Interpretation section, the examiner interprets the term “match” to include in scope that the radiopaque microspheres have a similar density to that of glass or polymer radioactive treatment microspheres loaded with yttrium-90. As the density of the biodegradable radiopaque microspheres of Kim may be optimized to achieve a range of values, and as polymer microspheres loaded with yttrium-90 within the scope of the claim may be made with a range of materials, including alginate (the same polymer as the microspheres of Kim), achieving a matching density is rendered obvious.
For the above reasons, the combined teachings of Kim, Duran, Sharma, Jernigan, and Alrfooh render claim 1 obvious.
Regarding claim 2, Kim teaches radiopaque nanorods being incorporated in a biodegradable radiopaque microsphere (pg. 2, fourth paragraph; and pg. 8, first paragraph). As stated above, the examiner interprets nanorods to be within the scope of the meaning of nanoparticles. Therefore, the combined teachings of Kim, Duran, Sharma, Jernigan, and Alrfooh render claim 2 obvious.
Regarding claim 4, Kim teaches that the biodegradable alginate material encapsulates the radiopaque gold nanorods in the microsphere (pg. 4, fifth paragraph, lines 15-17). Therefore, the combined teachings of Kim, Duran, Sharma, Jernigan, and Alrfooh render claim 4 obvious.
Regarding claim 6, Kim teaches a microsphere comprising alginate (pg. 2, fifth paragraph). Therefore, the combined teachings of Kim, Duran, Sharma, Jernigan, and Alrfooh render claim 6 obvious.
Regarding claim 8, Kim teaches radiopaque gold nanoparticles (pg. 2, fourth paragraph; and pg. 8, first paragraph). Therefore, the combined teachings of Duran, Kim, Sharma, and Jernigan render claim 8 obvious.
Regarding claim 10, Kim teaches a method of preparing microspheres comprising a biodegradable alginate polymer and radiopaque gold nanoparticles (pg. 2, fifth paragraph). Kim teaches that this method results the encapsulation of the radiopaque gold nanoparticles in the alginate microsphere (pg. 4, fifth paragraph, lines 15-17). Therefore, this is a method of making a microsphere comprising encapsulating a radiopaque material with a biodegradable material. As described above, this product is a micron-sized microsphere that is capable of being used with radioactive microspheres during a radioembolization treatment and is configured to biodegrade, which would result in reduced imaging interference. Furthermore, as described above, the density of the microsphere being configured to match that of a glass or polymer radioactive treatment microsphere loaded with yttrium-90 is obvious through routine optimization, change in size, and the scope of the polymers that may be used as carriers in the yttrium-90 loaded microspheres. Therefore, the combined teachings of Kim, Duran, Sharma, Jernigan, and Alrfooh render claim 10 obvious.
Response to Arguments
In the reply filed June 5, 2026, Applicant stated in response to the specification objection for an abstract too short in length that a corrected abstract would be submitted with the response. As stated above, no such abstract was provided to the examiner. Therefore, the examiner maintains this objection to the specification.
In the reply filed June 5, 2026, Applicant puts forth that the previously cited prior art references of the prior office action (Qie, Cilliers, Zhou, Meng, and Idris) do not anticipate the pending claims.
First, applicant asserts that the prior art references fail to teach or suggest a microsphere for use with radioactive microspheres during a radioembolization treatment or a biodegradable material configured to biodegrade to reduce imaging interference between successive radioembolization treatments. Applicant submits that the preamble “for use with radioactive microspheres during a radioembolization treatment” should be given patentable weight because it is “necessary to give life, meaning, and vitality” to the claim body limitations, particularly the limitations that the biodegradable material is configured to biodegrade to reduce imaging interference between successive radioembolization treatments and that the microsphere has a density configured to match glass or polymer radioactive treatment microspheres loaded with yttrium-90. Applicant puts forth that none of Qie, Cilliers, Zhou, Meng, or Idris teach or suggest the claimed use with radioactive microspheres during radioembolization treatment or biodegradation to reduce imaging interference between successive radioembolization treatments.
Second, Applicant asserts that the previously cited references do not teach microspheres comprising radiopaque materials comprising nanoparticles of at least one of tantalum, gold, barium, strontium, gallium, or iodine in the context of radioembolization; as is now required in the amended claim 1.
Third, Applicant asserts that none of the previously cited references teach or suggest a microsphere with the structural characteristics of the microsphere being micron-sized and having a density configured to match a density of glass or polymer radioactive treatment microspheres loaded with yttrium-90 because none of the references is concerned with matching the properties of radioactive treatment microspheres used in radioembolization.
Fourth, Applicant puts forth that claims 9-12 are amended in similar ways to claim 1 as discussed above, requiring the same limitations, in addition to an amendment to claim 12 requiring the nanoparticles be synthesized through addition of a surfactant to a raw radiopaque material. Applicant asserts that the previously cited prior art does not read on these claims or the dependent claims for the reasons put forth above.
With regard to all the arguments presented, as the amended claims necessitated new grounds of rejection as described above, the previous rejections under 35 U.S.C. § 102(a)(1) over Qie, Cilliers, Zhou, Meng, and Idris have been withdrawn. Thus, the arguments with respect to these particular references is moot. However, as several of the above arguments put forth are pertinent to the rejections presented in this office action, the examiner addresses them as follows.
First, as described in the above Claim Interpretation section, the examiner agrees that the preamble “for use with radioactive microspheres during a radioembolization treatment” included in the amended claims carries patentable weight, as it is possible that some microspheres within the scope of the following structural limitations in these claims may not be capable of such use. However, the examiner interprets this preamble to be a statement reciting the purpose or intended use of the claimed microsphere composition of matter or the product resulting from the claimed methods of making such microspheres. As such, MPEP 2111.02(II) further states that to satisfy an intended use limitation which is limiting, prior art capable of performing the intended use as recited in the preamble meets the claim. This is regardless of whether or not the art teaches the same specific intended use. Indeed, the use need not be explicitly taught by the reference. To the examiner’s understanding, in order for a microsphere comprising a biodegradable material and radiopaque nanoparticles to be capable of performing the intended use as recited (use with radioactive microspheres during a radioembolization treatment), the microsphere must be capable of being administered to a subject in any way and it must not be highly toxic to the subject. As described in the above rejections, as the cited prior art teaches microspheres and materials administered to living organisms, these references teach microspheres capable of this intended use and methods of making such microspheres.
Second, Applicant’s arguments with respect to the composition and form of the radiopaque material have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Third, as this argument applies to Qie, Cilliers, Zhou, Meng, and Idris, it is moot due to the new grounds of rejection. As it applies to the current rejections, the examiner puts forth that, as stated in the above Claim Interpretation section, the limitation having “a density configured to match a density of glass or polymer radioactive treatment microspheres loaded with yttrium-90” is understood to require the radiopaque microsphere to have a density that is the same or similar to a density of any yttrium-90 loaded polymer or glass microsphere. The examiner notes that in order for a radiopaque microsphere to have a density that matches that of a radioactive treatment microsphere, it need not be directly compared in an individual reference. If an yttrium-90 loaded microsphere possesses a density of X and a radiopaque microsphere possesses a density that matches X, then the radiopaque microsphere is understood to possess a density matching that of a radioactive treatment microsphere regardless of whether or not the radiopaque microsphere is compared to a radioactive microsphere in the teachings of the art.
Fourth, as described above, the new grounds of rejections necessitated by the amendments to the claims address these amended limitations of claims 9-12 in the same way as described in response to the first set of arguments.
Pertinent Art
As pertinent art, the examiner cites Moulay (Moulay, S., Polym.-Plast. Technol. Mater., 2015). Moulay provides a review of poly(vinyl alcohol) chemical modifications and functionalizations known in the art and their applications (pg. 1289, Abstract). Moulay depicts and refers to several examples in which the alcohol side chain group of PVA is modified to have alternative functionalities such as carbon nanotubes or graphene oxide (Fig. 2), sulfates (Eq. 3), carboxylates (Eq. 4), alkenes (Eq. 5 and Eq. 6), aldehydes (Eq. 8), alkynes or azides (Eq. 12), chelating groups (Fig. 5), thiols or primary amines (Fig. 7 and Fig. 9), sugars (Eq. 17), nanoparticles (Fig. 8), and maleimides (Eq. 27). The examiner notes that this reference demonstrates a wide range of chemistries known in the art to be suitable for modification of PVA materials.
As pertinent art, the examiner cites Quach (Quach, A. D.; et al., J. Am. Chem. Soc., 2011). Quach teaches microspheres modified with gold nanoparticles on the surface (pg. 2028, Abstract). More specifically, Quach teaches polystyrene polymer microspheres modified with carboxylic acid groups on the surface that are covalently attached to gold nanoparticles through EDC coupling (pg. 2029, Scheme 1). The examiner notes that this is analogous to the above teachings of Ino and Kamra in that a gold material is functionalized with an organic group via a thiol-containing organic molecule, enabling the formation of an amide-containing linker between the polymer particle and gold material through EDC coupling. The examiner notes that this reference demonstrates that using such conjugation methods were known in the art prior to the effective filing date of the claimed invention in the context of polymer microspheres and gold nanoparticles.
As pertinent art, the examiner cites Henry (Henry, E. C.; et al., EJNMMI Physics, published March 21, 2022). Henry teaches using radiopaque microspheres to perform dosimetry of yttrium-90 radioembolization by CT imaging (pg. 1, Abstract). More specifically, Henry teaches Eye90 microspheres composed of a radiopaque glass matrix loaded with yttrium-90 (pg. 4, Radiopaque microspheres). Henry teaches that the loaded Eye90 microspheres had a density (3.4 g/mL) similar to that of commercially available glass yttrium-90 loaded microspheres (pg. 4, Radiopaque microspheres, lines 2-3). Henry teaches transcatheter administration of the radioactive and radiopaque microspheres in a rabbit liver model (pg. 6, Rabbit liver model). Henry teaches post-treatment PET/CT imaging of the microspheres in the rabbit model wherein the yttrium-90 generates the PET signal and the radiopaque matrix enables detection by CT imaging (pg. 7, Post-treatment imaging). Henry notes that the Eye90 microspheres did not produce any image artefacts during CT imaging (pg. 22, last paragraph). Henry concludes that radiopaque microspheres enable post-treatment dosimetry in radioembolization (pg. 23-24, Conclusions). The examiner notes that this reference may suggest to the skilled artisan the utility of radiopaque microspheres in connection with radioembolization treatment.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new grounds of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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