DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 17 March 2026 has been entered.
Status of Claims
The amendments and arguments filed 17 March 2026 are acknowledged and have been fully considered. Claims 1-4, 7, 10-12, and 17 are currently pending. Claim 1 is amended; claims 5-6, 8-9, 13-16, and 18 are cancelled; no claims are withdrawn; no claims are new.
Claims 1-4, 7, 10-12, and 17 are examined on the merits herein.
Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn.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, and constitute the complete set presently being applied to the instant application.
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.
Claims 1-4, 7, and 10-12 are rejected under 35 U.S.C. 103 as being unpatentable over Sundar et al. (Int. J. Drug Deliv. 2014, Vol. 6, 24-35; of record) in view of Wassel et al. (Colloids Surf. A, 2007, Vol. 292, 125-130; of record), Tonello et al. (Drug Deliv. Transl. Res., 2016, Vol. 6, 174-183; of record), Cheng et al. (Pharm. Res., 2006, Vol. 23, 557-564), Benoit et al. (Int. J. Pharm., 1999, Vol. 184, 73-84), and Solorio et al. (J. Control. Release, 2012, Vol. 158, 224-232) as evidenced by McKeen (Permeability Properties of Plastics, Third Edition, 2012; of record).
Claim 1 is drawn to a composite microparticle comprising:
a plurality of magnetic nanoparticles, wherein the magnetic nanoparticles are coated with oleic acid, wherein the microparticles comprise about 5 to 80% (w/w) magnetic nanoparticles;
a biologically active agent, wherein the biologically active agent comprises biomolecules selected from the group consisting of: proteins, antibodies, nucleotides, carbohydrates, lipids, and mixtures thereof, wherein the microparticles comprise about 10 to 50% (w/w) biologically active agent; and
a biocompatible polymer matrix comprising a polymer having a melting point higher than normal body temperature and lower than a deactivation temperature of the biologically active agent, wherein the magnetic nanoparticles and biologically active agent are at least partially encapsulated in the polymer matrix, wherein the composite microparticle has the characteristic of melting upon exposure of the plurality of magnetic nanoparticles of the composite microparticle to an alternating magnetic field, wherein the composite microparticle has the characteristic of immediate release of the biologically active agent upon melting.
Claim 2 is drawn to the composite microparticle of claim 1, wherein the magnetic nanoparticles comprise superparamagnetic iron oxide nanoparticles (SPIONs).
Claim 3 is drawn to the composite microparticle of claim 2, wherein the SPIONs are selected from the group consisting of : Fe3O4 and γFe2O3.
Claim 7 is drawn to the composite microparticle of claim 1, wherein the biologically active agent comprises human placental matrix (hPM) (Applicant’s elected species).
Claim 10 is drawn to the composite microparticle of claim 1, wherein the polymer matrix comprises a biocompatible polymer having a melting point of about 38°C or higher.
Claim 11 is drawn to the composite microparticle of claim 1, wherein the polymer matrix comprises a biocompatible polymer having a melting point of about 42°C to 60°C.
Claim 12 is drawn to the composite microparticle of claim 1, wherein the polymer matrix comprises polycaprolactone (Applicant’s elected species).
Sundar et al. teach a targeted drug carrier system comprising polycaprolactone (PCL) microspheres loaded with magnetite (i.e., Fe3O4) and the anticancer drug etoposide (Abstract). Sundar et al. further teach the composite microparticles having a magnetite concentration of between 13.6% (w/w) and 31.5% (w/w) (Table 1 on Pg. 27), overlapping with the instantly claimed range.
As such, Sundar et al. teach a composite microparticle comprising: a plurality of magnetic nanoparticles, wherein the microparticles comprise about 5 to 80% (w/w) magnetic nanoparticles (Fe3O4 SPIONs); a biologically active agent; and a biocompatible polymer matrix (PCL), wherein the magnetic nanoparticles and biologically active agent are at least partially encapsulated in the polymer matrix.
The microparticle of Sundar et al. differs from the instantly claimed invention in the following ways:
the microparticle of Sundar et al. does not comprise magnetic nanoparticles coated in oleic acid;
the microparticle of Sundar et al. does not comprise a biomolecule active agent;
the microparticle of Sundar et al. does not comprise 10 to 50% (w/w) biologically active agent;
Sundar et al. do not teach the melting point of PCL; and
Sundar et al. do not explicitly teach the microparticle having the characteristic of melting upon exposure of the plurality of magnetic nanoparticles of the composite microparticle to an alternating magnetic field, wherein the composite microparticle has the characteristic of immediate release of the biologically active agent upon melting.
Yet, as to 1: Wassel et al. teach similar SPION containing polymer microparticles for the targeted delivery of a drug to a localized site (Pg. 125 right column second paragraph). Wassel et al. further teach “The saturation magnetization of well-dispersed single SPIONs can theoretically be as high as 92 emu/g; the saturation magnetizations of previously described PLGA particles containing SPIONs are typically two to three orders of magnitude lower. Although difficult to ascertain, SPIONs appear to be aggregated, which could be the basis of the low saturation magnetizations reported” (Pg. 126 left column first paragraph) and that high saturation magnetization is required to allow for the direction of the particles using an external magnetic field (Pg. 126 left column second paragraph). Additionally, Wassel et al. teach “Also of importance is limitation of SPION aggregation, which can lead to a reduction in saturation magnetization. Aggregation could also lead to an uneven distribution of the SPIONs within different polymeric particles; that is many SPIONs in a few PLGA particles and no SPIONs in most PLGA particles. If an even distribution of the therapeutic agent is assumed, polydispersity would cause a significant loss of drug use in PLGA particles that were not receptive to external magnetic fields” (Pg. 126 left column second paragraph).
Wassel et al. demonstrate that the use of SPIONs coated in oleic acid results in microparticles with much less aggregation of SPIONs and reduced partitioning of SPIONs from one microparticle to another (Pg. 128 left column first paragraph) as well as improved saturation magnetizations (Pg. 129 left column last paragraph).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the microparticles of Sundar et al. to include SPIONs coated in oleic acid as taught by Wassel et al. It would have been obvious to use the known oleic acid coated SPIONs to improve the similar targeted drug delivery microparticle of Sundar et al. in the same way, by improving the saturation magnetization to yield the predictable result of a microparticle with better targeting via an external magnetic field and decreased loss of drug use, with a reasonable expectation of success.
As to 2: Sundar et al. teach “magnetic PCL magnetic microspheres may have potential as a highly versatile carrier for targeted delivery approach” (Pg. 34 right column “Conclusion”). Sundar et al. further teach that the magnetic PCL microspheres are suitable for sustained release of the drug as demonstrated in Figs. 8-10, releasing 76.25% of the encapsulated drug over 21 days (Pg. 32 right column).
Tonello et al. teach similar sustained release polymeric microparticles for the delivery of hPM for the initiation of angiogenesis over time (Abstract). Tonello et al. further teach the microparticles releasing between 50-95% of the encapsulated hPM over a period of 21 days (Fig. 4 on pg. 180).
Cheng et al. teach magnetically responsive polymeric microparticles for the delivery of proteins (Title) for targeted delivery of an active agent protein (Abstract), wherein the microparticles comprise a biodegradable polymer encapsulating magnetite nanoparticles and insulin (Pg. 558 right column second paragraph), indicating that polymeric microparticles encapsulating SPIONs are a suitable delivery system for bioactive proteins.
Benoit et al. teach the use of polymeric microparticles for the delivery of proteins (Abstract), further teaching that PCL is a suitable polymer for delivery of proteins (Pg. 74 left column fourth paragraph).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the microparticles of Sundar et al. to include hPM as taught by Tonello et al. It would have been obvious to substitute one active agent suitable for delivery by polymeric nanoparticle with similar release profiles for another to obtain the predictable result of a targeted angiogenesis promoting composition. One of ordinary skill in the art would have had a reasonable expectation of success for doing so as polymeric microparticles comprising SPIONs and PCL microparticles are both taught in the prior art to be suitable for delivery of protein active agents.
As to 3: Solorio et al. also teach polymeric microparticles for the delivery of a protein to facilitate tissue growth (Title, Abstract). Solorio et al. further teach the microparticles comprising 400 ng TGF-β1 per mg microparticles (Pg. 226 left column third paragraph; corresponding to 40 wt%) and this concentration of TGF-β1 being suitable for increasing tissue growth (Sec. 3.6 on pg. 228).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the microparticles of Sundar et al. and Tonello et al. to include 40 wt% hPM. It would have been obvious to combine the known microparticles with the known amount of microparticle delivered biomolecule active agent suitable for increasing tissue growth to yield the predictable result of a microparticle comprising an effective amount of hPM for promoting angiogenesis, with a reasonable expectation of success.
As to 4: As evidenced by McKeen, the melting point of polycaprolactone is about 60°C (Chapter 13.5), overlapping with the instantly claimed range.
And, as to 5: As discussed in MPEP 2112(IV), The Federal Circuit stated that while "inherency may support a missing claim limitation in an obviousness analysis", "the use of inherency, a doctrine originally rooted in anticipation, must be carefully circumscribed in the context of obviousness." Id. at 1194-95, 112 USPQ2d at 1952. "[I]n order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis – the limitation at issue necessarily must be present, or the natural result of the combination of elements explicitly disclosed by the prior art." Id. at 1195-96, 112 USPQ2d at 1952.
As discussed in MPEP 2112.01, Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not."
In the instant case, the composite microparticles melting upon exposure of the magnetic nanoparticles to an alternating magnetic field and immediate release of the biologically active agent upon melting are properties inherent to the instantly claimed microparticles as disclosed in the instant specification at pgs. 14-15 as the heat generated by the exposure of the SPIONs to an alternating magnetic field is sufficient to melt the polymer matrix of the microparticle. And as further demonstrated by Applicant at pgs. 42-43 of the instant specification, these properties are inherent to composite microparticles comprising oleic acid coated SPIONs and a biomolecule active agent encapsulated in PCL.
As Sundar et al. in view of Wassel et al., Tonello et al., Cheng et al., Benoit et al., and Solorio et al. teach a composite microparticle comprising a plurality of SPIONs in an amount of between 5 to 80% (w/w), a biologically active agent (hPM), and a biocompatible polymer matrix comprising a polymer having a melting point higher than normal body temperature and lower than a deactivation temperature of the biologically active agent (PCL), the instantly claimed melting upon exposure to an alternating magnetic field and instant release of the biomolecule active agent are the natural result of the combination of elements explicitly disclosed by the prior art.
Based on all of the foregoing, claims 1-3, 7, and 10-12 are rejected as prima facie obvious.
Claim 4 is drawn to the composite microparticle of claim 2, wherein the SPIONs have an average diameter of about 5 nm to about 100 nm.
Sundar et al. further teach the use of magnetite nano powders < 50 nm in preparation of the microspheres (Pg. 25 left column “Materials and Methods”), overlapping with the instantly claimed range.
As such, claim 4 is also rejected as prima facie obvious.
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Sundar et al., Wassel et al., Tonello et al., Cheng et al., Benoit et al., and Solorio et al. as applied to claims 1-4, 7, and 10-12 above, and further in view of Fonte et al. (J. Control. Release, 2016, Vol. 225, 75-86; of record).
The teachings of Sundar et al., Wassel et al., Tonello et al., Cheng et al., Benoit et al., and Solorio et al. have been set forth above.
Claim 17 is drawn to the composite microparticle of claim 1, wherein the microparticles are lyophilized.
Sundar et al., Wassel et al., Tonello et al., Cheng et al., Benoit et al., and Solorio et al. do not teach the microparticles being lyophilized.
However, Fonte et al. teach that “lyophilization is commonly used to improve the long-term stability of nanoparticles” (Sec. 2 on pg. 76).
Therefore, it would have been prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to have modified the composite microparticles of Sundar et al., Wassel et al., Tonello et al., Cheng et al., Benoit et al., and Solorio et al. by lyophilizing them. It would have been obvious to use the known technique of lyophilization to improve the similar microparticles in the same way by increasing the long-term stability, with a reasonable expectation of success.
As such, claim 17 is rejected as prima facie obvious.
Response to Arguments
Applicant's arguments filed 17 March 2026 have been fully considered but they are not persuasive.
Applicant argues on pg. 5 of the Remarks that one of ordinary skill in the art would not consider the teachings of Sundar et al. to arrive at the instantly claimed invention as Sundar et al. teach an extended release of the active as opposed to the instant release use of the instantly claimed invention.
This argument is not persuasive. The instant claims are drawn to a composite microparticle composition, not to a method for instant release of an active compound from a composite microparticle. As Sundar et al., Wassel et al., Tonello et al., Cheng et al., Benoit et al., and Solorio et al. teach the structure of the instant claims, they read on the claims regardless of the intended use of the compositions.
And as discussed in MPEP 2141.01(a)(I), In order for a reference to be proper for use in an obviousness rejection under 35 U.S.C. 103 , the reference must be analogous art to the claimed invention. In re Bigio, 381 F.3d 1320, 1325, 72 USPQ2d 1209, 1212 (Fed. Cir. 2004). A reference is analogous art to the claimed invention if: (1) the reference is from the same field of endeavor as the claimed invention (even if it addresses a different problem); or (2) the reference is reasonably pertinent to the problem faced by the inventor (even if it is not in the same field of endeavor as the claimed invention). Note that "same field of endeavor" and "reasonably pertinent" are two separate tests for establishing analogous art; it is not necessary for a reference to fulfill both tests in order to qualify as analogous art. See Bigio, 381 F.3d at 1325, 72 USPQ2d at 1212. When determining whether the "relevant field of endeavor" test is met, the examiner should consider "explanations of the invention’s subject matter in the patent application, including the embodiments, function, and structure of the claimed invention." Airbus S.A.S. v. Firepass Corp., 941 F.3d 1374, 1380, 2019 USPQ2d 430083 (Fed. Cir. 2019) (quoting Bigio, 381 F.3d at 1325, 72 USPQ2d at 1212). "The field of endeavor is ‘not limited to the specific point of novelty, the narrowest possible conception of the field, or the particular focus within a given field.’") (quoting Unwired Planet, LLC v. Google Inc., 841 F.3d 995, 1001, 120 USPQ2d 1593, 1597 (Fed. Cir. 2016)).
In the instant case, as both the instantly claimed invention and Sundar et al. share a common structure of polymeric nanoparticles encapsulating magnetic nanoparticles and an active agent, Sundar et al. is considered to be from the same field of endeavor as the claimed invention and is proper for an obviousness rejection under 35 U.S.C. 103.
Applicant argues on pgs. 5-6 of the Remarks that one of ordinary skill in the art would not have a reasonable expectation for success in combining the microparticles of Sundar et al. with the hPM active of Tonello et al., further arguing that teaching of magnetic PCL microspheres as a highly versatile drug carrier is a non-enabled disclosure.
This argument is not persuasive. As discussed in the rejection of claims 1-3, 7, and 10-12 above, both polymeric microparticles comprising SPIONs and PCL microparticles were taught in the prior art to be suitable carriers for protein delivery (see Cheng et al. and Benoit et al.), indicating to one of ordinary skill in the art that the PCL microparticles comprising SPIONs taught by Sundar et al. would be a suitable carrier for a bioactive protein such as hPM, which is also taught in the prior art to be suitable for delivery via polymeric microparticles (see Tonello et al.).
And as discussed in MPEP 2121.02 When a prior art reference merely discloses the structure of the claimed compound, evidence showing that attempts to prepare that compound were unsuccessful before the relevant time will be adequate to show inoperability. In re Wiggins, 488 F.2d 538, 179 USPQ 421 (CCPA 1973). However, the fact that an author of a publication did not attempt to make the compound disclosed, without more, will not overcome a rejection based on that publication. In re Donohue, 766 F.2d 531, 226 USPQ 619 (Fed. Cir. 1985).
In the instant case, as PCL microparticles encapsulating a protein and polymeric microparticles encapsulating SPIONs and a protein were both taught in the prior art before the publication of Sundar et al., the teaching of magnetic PCL microspheres as a highly versatile drug carrier is considered to be enabled.
Applicant argues on pgs. 6-7 of the Remarks that the optimization of the concentration of small molecule active ingredient taught by Sundar et al. is not relevant to the claimed concentration of the biomolecule active agent.
This argument is moot in view of the new grounds of rejection over Sundar et al., Wassel et al., Tonello et al., Cheng et al., Benoit et al., and Solorio et al. set forth above.
Applicant argues on pg. 7-8 of the Remarks that the cited references do not teach the composite microparticle having the characteristic of melting upon exposure to an alternating magnetic field or the composite microparticle having the characteristic of immediate release of the biologically active agent upon melting, further arguing that no basis in fact and/or technical reasoning has been provided in support of the determination of inherency.
This argument is not persuasive. While Examiner agrees that Sundar et al., Wassel et al., Tonello et al., Cheng et al., Benoit et al., and Solorio et al. do not teach the composite microparticle having the characteristic of melting upon exposure to an alternating magnetic field or the composite microparticle having the characteristic of immediate release of the biologically active agent upon melting, as discussed in MPEP 2112(I) and 2112(II), "[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer." Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003).
As further discussed in MPEP 2112(IV), "In relying upon the theory of inherency, the examiner must provide a basis in fact and/or technical reasoning to reasonably support the determination that the allegedly inherent characteristic necessarily flows from the teachings of the applied prior art." Ex parte Levy, 17 USPQ2d 1461, 1464 (Bd. Pat. App. & Inter. 1990) (emphasis in original). In PAR Pharmaceutical, Inc. v. TWI Pharmaceuticals, Inc., 773 F.3d 1186, 112 USPQ2d 1945 (Fed. Cir. 2014). As discussed in the rejection of claims 1-3, 7, and 10-12 above, melting upon exposure of the magnetic nanoparticles to an alternating magnetic field and immediate release of the biologically active agent upon melting are properties inherent to the instantly claimed microparticles as disclosed in the instant specification at pgs. 14-15 as the heat generated by the exposure of the SPIONs to an alternating magnetic field is sufficient to melt the polymer matrix of the microparticle. And as further demonstrated by Applicant at pgs. 42-43 of the instant specification, these properties are inherent to composite microparticles comprising oleic acid coated SPIONs and a biomolecule active agent encapsulated in PCL.
As Sundar et al. in view of Wassel et al., Tonello et al., Cheng et al., Benoit et al., and Solorio et al. teach a composite microparticle comprising a plurality of SPIONs in an amount of between 5 to 80% (w/w), a biologically active agent (hPM), and a biocompatible polymer matrix comprising a polymer having a melting point higher than normal body temperature and lower than a deactivation temperature of the biologically active agent (PCL) as recited in instant claim 1, the instantly claimed melting upon exposure to an alternating magnetic field and instant release of the biomolecule active agent are the natural result of the combination of elements explicitly disclosed by the prior art.
Conclusion
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/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
/PAUL HOERNER/Examiner, Art Unit 1611
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