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 .
DETAILED ACTION
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Response to Amendments
Applicant’s amendments, IDS filed on May 20, 2025 and response filed Jun. 22, 2025 have been received and entered into the case.
Status of the Claims
Claims 1, 4-8, 13-15, 17, 24, 29, 30, 32 and 33 are currently pending.
Claims 1, 4, 7, 24, 32 and 33 are amended.
Claims 1, 4-8, 13-15, 17, 24, 29, 30, 31, 34 and 35 are cancelled.
Claims 1, 4-8, 13-15, 17, 24, 29, 30, 32 and 33 have been considered on the merits.
Claim Rejections - 35 USC § 112
The claim rejections under 35 USC § 112, (b) or second paragraph (pre-AIA ), are withdrawn due to amendment.
Claim Rejections - 35 USC § 103
The claim rejections under 35 USC § 103 are withdrawn due to amendment. New claim rejections under 35 USC § 103 have been added to address the claim amendments.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 4-8, 20, 29, 30, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Schonberg et al. (Journal of Neuroscience, 2012) (ref. of record) as evidenced by Rheinländer et al. (Immunology Letters, 2018) (ref. of record), Lee et al. (Advanced Drug Delivery Reviews, 2016), Stec et al. (Journal of Leucocyte Biology, 2007) (ref. of record), and Foey (Immune Response Activation, 2014) (ref. of record) in view of Lin et al. (Nano Letters, 2016).
With respect to claims 1 and 4, Schonberg teaches activated macrophages loaded with fluorescent ferritin (an iron binding protein and a label) (abstract). Since Schonberg teaches activated macrophages the cells would be alive. Macrophages inherently express CD45 as evidenced by Rheinländer. Rheinländer reports that all nucleated cells of the hematopoietic system express CD45 including macrophages (abstract and pg. 22 para. 2). Ferritin is a cage-like multimeric protein as evidenced by Lee (Fig.1, abstract and pg. 158 last para.)
Schonberg does not teach the complex of ferritin and a label is a radioisotope and where the label is entrapped or encapsulated by multimers of the ferritin in the absence of a covalent bond as recited in claim 1 or where the radioisotope is one of those listed in claims 24, 32, and 33.
However, Lin teaches ferritin nanocages can be loaded with molecules for imaging of tissues and tumors including the radioisotope (abstract and pg. 814 last para to pg. 815 para. 2 and Fig. 5). Lin specifically teaches ferritin nanocage that encapsulate 64Cu (abstract and Fig. 1). Lin teaches 64Cu can be directly loaded into the ferritin nanostructures by using the metal binding capabilities of ferritin (metal-coordination bonds) (pg. 816 Col. 1 para. 3). Accordingly, the 64Cu is encapsulated by the multimers of the ferritin in the absence of a covalent bond.
Accordingly, at the effective time of filing of the claimed invention one of ordinary skill in the art would have been motivated to modify the targeted delivery system of Schonberg so that the ferritin contains a radioisotope where the radioisotope is entrapped or encapsulated in the absence of a covalent bond for the benefit of using the targeted delivery system to carry additional substances for additional purposes such as imaging as taught by Lin. It would have been obvious to one of ordinary skill in the art that the ferritin nanocage (multimers of ferritin) taught by Schonberg could encapsulate additional substances including radioisotopes in the absence of a covalent bond, since ferritin nanocages were known to encapsulate such molecules in the absence of covalent bonds as taught by Lin. Furthermore, one of ordinary skill in the art would have a reasonable expectation of success in making such a modification to Schonberg, since Schonberg teaches macrophages containing ferritin and a label, and Lin teaches additional labels including radioisotopes which can be encapsulated within the ferritin nanocage without a covalent bond.
Although, Schonberg does not teach that the macrophage is producible from a CD34+ hematopoietic precursor cells as recited in claim 7, this appears to be an inherent characteristic of monocytes and monocyte-macrophage as evidenced by Stec. Stec reports monocytes are producible from CD34+ hematopoietic precursor cells (abstract).
Similarly, Schonberg does not teach the claimed characteristics of the activated macrophage recited in claims 5-8. However, many of these characteristics appear to be inherent to activated monocyte-macrophage as evidenced by Foey. For instance with respect to claim 5 (ii), Foey reports that a subset of monocytes express CD16 (pg. 122 para. 2). With respect to claim 5 (ii, iv, and vi), Foey teaches activated macrophages express cytokines including IL-12, express CD163, have cytokine secretion, produce iNOS (pg. 122 para. 3 and Fig. 1). With respect to claim 5 (iii and v), Foey teaches the macrophages can phagocytosis (pg. 122 para. 1 and pg. 128 last para.). With respect to claim 6 (i) and 8 (i), Foey teaches M1 inducers include IFN-γ and LPS (pg. 122 last para. to 123 para. 2). With respect to claim 6 (ii), claim 7 (ii) and claim 8 (ii), Foey teaches M2 inducers include IL-4, IL-10, IL-13, TGF-β, M-CSF, immune complexes, glucocorticoids (pg. 123 para. 3 and Fig. 1).
Although Schonberg does not teach the claimed use of the isolated targeted delivery system for use as a diagnostic as recited in claim 29, the activated macrophages loaded with fluorescent ferritin (isolated targeted delivery system) or contrast agent taught by Schonberg and Lee are the same as those claimed by applicant. Thus, the intended use of the macrophages is also inherent in the macrophages of the prior art. It is noted that the intended use of the claimed composition does not patentably distinguish the composition, per se, since such undisclosed use is inherent in the reference composition. In order to be limiting, the intended use must create a structural difference between the claimed composition and the composition of the prior art. In the instant case, the intended use fails to create a structural difference, thus, the intended use is not limiting. Please note that when applicant claims a composition in terms of function, and the composition of the prior art appears to be the same, the Examiner may make rejections under both 35 U.S.C 102 and 103 (MPEP 2112).
With respect to claim 30, Schonberg teaches the macrophages loaded with ferritin resuspended in sterile PBS (a pharmaceutical carrier) for microinjection into rats (pg. 5376 Col. 2 para. 2).
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Claims 24, 32 and 33 are rejected under 35 U.S.C. 103(a) as being unpatentable over Schonberg as evidenced by Rheinländer, Lee, Stec and Foey in view of Lin (as applied to claims 1, 4-8, 20, 29, 30, and 32 above), and further in view of Malecki et al. (US 2012/0083005 A1).
The teachings of Schonberg and Lin can be found in the previous rejection above.
Neither Schonberg or Lin teach the isolated targeted delivery system where the radioisotope is one of those listed in claims 24 and 33, or the additional radioisotopes listed in claim 32. However, Malecki teaches radioactive substances that are commonly used as diagnostic agents include 18F, 67Ga (Auger and X-ray emitting isotope), 68Ga (a gamma radiation emitting isotope), 89Zr , 111In (a gamma radiation and Auger emitting isotope), 99mTc (a gamma radiation, Auger and X-ray emitting isotope), 153Sm, 149Pm, 177Lu, 47Sc, 142Pr, 212Bi, 105Rh, 123I (a gamma radiation, Auger and X-ray emitting isotope), 124I, 131I (a X-ray emitting isotope), 211At, 212Pb (an alpha radiation emitting isotope), 64Cu, 67Cu, and 198Au (0075-0076). At the time of the claimed invention, one of ordinary skill in the art would have been motivated to modify the teachings of Schonberg and Lin in such a way that the radioisotope of isolated targeted delivery system comprising ferritin is one of those claimed for the purpose being able to image cells or tissue as taught by Schonberg and Lin. Furthermore, it would have been obvious to one skilled in the art to have further modified the combined teachings of Schonberg and Lin such that the therapeutic nanoparticle loaded into the macrophage is one of the claimed radioisotopes, since ferritin nanocages for imaging were known to contain radioisotopes for labeling as taught by Lin and the additional radioisotopes are known for imaging as well. Furthermore, one of ordinary skill in the art would have a reasonable expectation of loading macrophages with the claimed radioisotopes encapsulated within iron-binding proteins, since Lin teaches such nanoparticles and Schonberg teaches macrophages loaded with ferritin and a label. Such a modification merely involves the substitution of one known type of radioisotope for another for the targeted delivery systems containing a macrophage, an iron binding protein and a radioisotope.
Claims 13-15 and 17 are rejected under 35 U.S.C. 103(a) as being unpatentable over Schonberg as evidenced by Rheinländer, Lee, Stec and Foey in view of Lin (as applied to claims 1, 4-8, 20, 29, 30, and 32 above), and further in view of Lee et al. (Advanced Drug Delivery Reviews, 2016) and Steinfeld et al. (International Journal of Pharmaceutics, 2006) (ref. of record).
The teachings of Schonberg and Lin can be found in the previous rejection above.
Schonberg does not teach the isolated targeted delivery system further comprising a pharmaceutical active substance that is an anti-cancer drug as recited in claim 13, or where the anticancer drug is one those listed in claims 14, 15 and 17.
However, Lee teaches ferritin nanocages for carriers of drugs and dyes, proteins/peptides and antibody fragments (pg. 158-159 bridging para.). Lee reports non-covalent encapsulation of anticancer drugs in ferritin (pg. 163-164 bridging para.).
Specifically, Lee reports that cisplatin (chemotherapy drug), carboplatin (chemotherapy drug), 5-flurouracil (chemotherapy drug), daunomycin (anthracycline antibiotic used as chemotherapy drug) and doxorubicin (chemotherapy drug) have been encapsulated in ferritin (pg. 159 Col. 1 para. 1).
Additionally, Steinfeld teaches “therapeutic nanoparticles are loaded into immune cells for a target specific and sheltered transport to the diseased site” (pg. 229 Col. 2 para. 2). Steinfeld teaches transport inside immune cells will protect nanoparticles that would be removed by the reticuloendothelial system (pg. 229 Col. 2 para. 4). Steinfeld teaches the nanoparticles are either loaded with green fluorescence dye or doxorubicin (a cytotoxic anthracycline antibiotic used in chemotherapy) (pg. 233 Section 3.7, pg. 230 Section 2.3, and pg. 231 Section 2.6).
Accordingly, at the effective time of filing of the claimed invention, one of ordinary skill in the art would have been motivated to modify the targeted delivery system of Schonberg so that the isolated targeted delivery system contains an anti-cancer drug including carboplatin, cisplatin, doxorubicin and fluorouracil and that is encapsulated with an iron-binding protein such as ferritin for the known benefit of protecting the drug from degradation prior to reaching the target tissue as taught by Lee and Steinfeld. It would have been obvious to one of ordinary skill in the art to modify the targeted delivery system of Schonberg so that the nanoparticle is the anti-cancer drug, doxorubicin with a label, encapsulated with an iron-binding protein such as ferritin and carried within the cell, since anti-cancer drugs, including carboplatin, cisplatin, doxorubicin and fluorouracil and with a label were known to be encapsulated in iron-binding proteins as taught by Lee and Steinfeld teaches the benefits of having immune cells loaded with nanoparticles. Furthermore, one of ordinary skill in the art would have had a reasonable expectation of success in modifying the targeted delivery system of Schonberg so that the nanoparticle contains a pharmaceutically active substance that is an anti-cancer drug, including doxorubicin, encapsulated with an iron-binding protein such as ferritin, since anti-cancer drugs were known to be encapsulated in iron-binding proteins as taught by Lee and both Steinfeld and Schonberg teach the benefits of using cell-based delivery of encapsulated drugs.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the effective time of filing of the invention, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed Jun. 22, 2025 have been fully considered but they are not persuasive.
With respect to the rejections under 35 U.S.C. § 103, Applicant argues that the Declaration under 37 C.F.R § 1.132 from inventor Dr. Tomasz Rygiel submitted on Jan. 3, 2025 presents data demonstrating that the claimed invention is non-obvious and unexpectantly advantageous (Remarks pg. 8 para. 3 to pg. 9). Specifically, Applicant argues that the claimed invention is capable of delivering a complex of ferritin and a radioisotope directly into tumor cells has shown in Fig. 2 (Remarks pg. 9). However, this argument was not found to be persuasive, since this appears to be a feature of macrophages carrying a ferritin payload. In support, Schonberg teaches that activated macrophages loaded with ferritin carrying a fluorescent label are able to transfer the ferritin to NG2+ progenitor cells directly (abstract, pg. 5374-5375 bridging para., and Fig. 6-8). Additionally, it is Fig. 2 shows a complex of FITC-decorated ferritin inside a mouse tumor mass (see 0182 of published application) and not a complex of ferritin and a radioisotope in the absence of a covalent bond as claimed.
Applicant argues that the additional experimental and post-filing data in the Rygiel Declaration further demonstrate that intravenous injection of macrophages containing a radioisotope encapsulated in a ferritin multimer in the absence of a covalent bond are more effective and stable in labeling tumors than an injection of radioisotope encapsulated in a ferritin multimer but not in a macrophage (Remarks pg. 9). Applicant argues that the Rygiel Declaration further states that the advantageous effects of the direct delivery into the tumor cells of the claimed composition include specific delivery of the label, protection of the label from inactivation and clearance, reduced toxicity and side effects, successful delivery of labels with poor pharmacokinetics and the possibility of using lower doses of label (Remarks pg. 9). For the same reasons the previous arguments were not found to be persuasive, these arguments were not found to be persuasive. The ability of macrophages to directly deliver a ferritin complex was known in the art and Schonberg teaches that activated macrophages loaded with ferritin carrying a fluorescent label are able to transfer the ferritin to NG2+ progenitor cells directly (abstract, pg. 5374-5375 bridging para. and Fig. 6-8).
Applicant argues that the Rygiel Declaration further states that the use of the radioisotope, 64Cu, is particularly useful of efficient and stable in vivo labeling of tumors (Remarks pg. 9). In response to applicant's argument that one of the embodiments of the claimed invention is useful to labeling of tumors in vivo, the intended use of the claimed invention, which in this case is not recited, must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art. Here the art in combination teach the claimed composition, therefore the proposed use should be inherent to the ferritin loaded macrophages of the prior art.
Applicant argues that the claims have been amended to be commensurate in scope with the evidence presented (Remarks pg. 10 para. 1-2). However, this argument was not found to be persuasive, since the evidence presented was not found to be convincing as demonstrating an unique property of the composition as explained above.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 extension fee 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.
Examiner Contact Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to EMILY ANN CORDAS whose telephone number is (571)272-2905. The examiner can normally be reached on M-F 9:00-5:30 EST.
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/EMILY A CORDAS/Primary Examiner, Art Unit 1632