FINAL 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 .
Status of the Claims
This action is in response to papers filed 06/22/2026 in which claims 4 and 18-20 were canceled; claims 1-3, 5-12, and 14-16 were withdrawn; and claims 13 and 17 were amended. All the amendments have been thoroughly reviewed and entered.
Claims 13, 17, and 21 are under examination.
Withdrawn Rejection
The rejection of claims 13, 17 and 21 under 35 U.S.C. 103 as being unpatentable over Fan et al (Angew. Chem. Int. Ed., 2016, 55, pages 5477-5482; cited in IDS filed 10/07/2019) in view of Hao et al (Nanotechnology, 2015, 27: 1-14; cited in IDS filed 10/07/2019), Koyakutty et al (19 July 2012; US 2012/0184495 A1) and Lange et al (20 August 2009; US 2009/0209508 A1), is withdrawn, in view of Applicant’s amendment to claims 13 and 17, which had necessitated the 112(a) New Matter rejection. In the event that the new matter material was to be removed in response to the new matter rejection, this 103 rejection may be reinstated. Thus, Applicant’s arguments directed to this 103 rejection, as well as, arguments focusing on the Hao reference on pages 7-13 of the Remarks filed 06/22/2026 are hereby moot.
New Objection
Claim Objections
Claim 13 is objected to because of the following informalities: please remove the second comma (,) in “nanosheet, ,”. Appropriate correction is required.
New Rejection
Necessitated by Applicant’s Claim Amendments
Claim Rejections - 35 USC § 112- NEW MATTER
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 13, 17, and 21 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 claim(s) 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 inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 13 and 17 introduces new matter as the claim recite the limitation: “without a polymeric spacer between the folic acid and the metallic nanosheet.” There is no support in the specification for this negative limitation.
Applicant asserted that support for the amendment can be found in Experimental Example 1 of the specification (see Remarks filed 06/22/2026, page 9).
However, after a thorough review of said Experimental Example 1, as well as, throughout the specification, there appeared to be no support or disclosure in the specification for the negative limitation of the folic acid and the photosensitizer are distributed directly on a surface of a metallic nanosheet “without a polymeric spacer between the folic acid and the metallic nanosheet.”
It is noted that paragraph [0163] under Experimental Example 1 discloses:
[163] Accordingly, it is expected that the FA-MnO2/ZnPc complex may be easily applied to physiological conditions by simple production of the complex even without binding any polymer or adding a surfactant to the complex.
As described above in paragraph [0163] of the specification, the ‘without binding any polymer” is to the binding of an additional polymer to the already formed “complex” so that the complex can be applied to physiological conditions. The negative disclosure of “without binding any polymer” is not pertinent to the formation of the complex. Even if it was pertinent to the formation of the complex, “polymer” as disclosed in paragraph [0163] is not support for “polymer spacer,” as not all polymer in the broad genus of “polymer” can function or used as a spacer in the formation of a complex. It is also noted that any negative limitation or exclusionary proviso must have basis in the original disclosure. Thus, it is also noted that [t]he mere absence of a positive recitation is not basis for an exclusion. However, a lack of literal basis in the specification for a negative limitation may not be sufficient to establish a prima facie case for lack of descriptive support. Ex parte Parks, 30 USPQ2d 1234, 1236 (Bd. Pat. App. & Inter. 1993). See MPEP §2173.05(i). As such, Applicant does not have possession of the negative limitation of “without a polymeric spacer between the folic acid and the metallic nanosheet” as claimed.
Claim 21 is also rejected as said claim 21 is dependent from independent claim 17, thereby also containing the new matter material.
As such, the disclosure does not reasonably convey that the inventor had possession of the subject matter of claims 13 and 17 as amended at the time of filing of the instant application.
Maintained-Modified Rejections
Modification Necessitated by Applicant’s Claim Amendments
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.
Claims 13, 17 and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fan et al (Angew. Chem. Int. Ed., 2016, 55, pages 5477-5482; cited in IDS filed 10/07/2019) in view of Rana et al (Dalton Transactions, 2016, 45: 17401-17408), Koyakutty et al (19 July 2012; US 2012/0184495 A1) and Lange et al (20 August 2009; US 2009/0209508 A1).
Regarding claims 13 and 17, Fan teaches a photosensitizer- MnO2 nanosystem for highly efficient photodynamic therapy, wherein the MnO2 nanosheet absorb photosensitizer chlorin e6 (Ce6), protect it from self-destruction upon light irradiation and efficiently deliver it into cells (Abstract; page 5477, right column; page 5480; page 5481, left column). Fan teaches the Ce6- MnO2 nanosheet is used for treating cancer (Abstract; page 5477, right column; page 5480; page 5481, left column). Fan teaches MnO2 nanosheets can strongly adsorb small organic molecules, such as photosensitizers, via electrostatic interaction and Mn-N coordinate bonds, which can facilitate their endocytosis for intracellular photodynamic therapy (PDT) (page 5477, right column). Fan further teaches MnO2 nanosheets have an intense and broad optical absorption spectrum (~200-600 nm), making them an efficient broad-spectrum fluorescence quencher for the design of fluorescence turn-on probes for monitoring delivery efficiency (page 5477, right column). Fan further teaches MnO2 nanosheets can react with intracellular glutathione (GSH), resulting in the disintegration of the nanosheets and, hence, complete release of photosensitizers for PDT (page 5477, right column). Fan teaches the MnO2 nanosheets were mixed with the photosensitizer such that the photosensitizer is loaded directly on the surface of the MnO2 nanosheets (page 5478, left column, last paragraph to top of right column).
However, Fan does not teach the folic acid being distributed directly on a surface of the metallic nanosheet without a polymeric spacer between the folic acid and the metallic nanosheet; and zinc-phthalocyanine (ZnPc) as the photosensitizer of claims 13 and 17.
Regarding the folic acid being distributed directly on a surface of the metallic nanosheet without a polymeric spacer between the folic acid and the metallic nanosheet of claims 13 and 17, Rana teaches a magnetic nanoparticles (iron oxide nanoparticles) having folic acid conjugated (covalent bonded) on a surface of the iron oxide nanoparticles via EDC-NHS coupling reaction (Abstract; pages 17401-17407). Rana teaches the folic acid conjugated nanoparticles provides higher cellular internalization capability in cancer cells over-expressing folate receptors (Abstract; pages 17401-17407).
It would have been obvious to one of ordinary skill in the art to covalent bond folic acid on a surface of the MnO2 nanosheet of Fan via EDC-NHS coupling, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Rana provided the guidance to do so by teaching that folic acid can be advantageously loaded on the surface of a metal nanoparticle by conjugating (covalent bonding) folic acid via EDC-NHS coupling reaction and such folic acid conjugated nanoparticles provides higher cellular internalization capability in cancer cells over-expressing folate receptors. It is noted that EDC-NHS is not a polymeric spacer, and thereby meeting the claimed “the folic acid …distributed directly on a surface of the metallic nanosheet without a polymeric spacer between the folic acid and the metallic nanosheet,” as recited in claims 13 and 17. Thus, an ordinary artisan interested in providing higher cellular internalization capability in cancer cells over-expressing folate receptors would have looked to conjugating (covalent bonding) folic acid on a surface of the metallic nanosheet of Fan via EDC-NHS coupling reaction with a reasonable predictability that the resultant photosensitizer-MnO2-folic acid nanosheet that would specifically target the folate receptor on the tumor/cancer cells, thereby providing the desired cancer treatment, and achieve Applicant’s claimed methods with reasonable expectation of success.
Regarding the zinc-phthalocyanine (ZnPc) of claims 13 and 17, Koyakutty teaches a photosensitizer-containing metal nanoparticle used for killing cancer cells by photodynamic treatment, wherein the suitable photosensitizers include chlorin e6 (Ce6) and metal phthalocyanine (Abstract; [0001], [0004]-[0008], [00013], [0015], [0018]-[0023], [0027], [0046], [0051], [0059] and [0088]; claims 18, 19, 21 and 24). Lange teaches chlorin e6 (Ce6) and zinc phthalocyanine are known photosensitizers conventional used in photochemotherapeutic treatment of cancer (Abstract; [0005]-[0006], [0018], [0020], [0025], [0079]-[0080], [0117]-[0121]; Table 3).
It would have been obvious to one of ordinary skill in the art to incorporate or substitute zinc phthalocyanine as the photosensitizer on the MnO2 nanosheet of Fan, and produce the claimed invention. One of ordinary skill in the art would have motivated to so because Koyakutty and Lange provided the guidance to do so by teaching that not only chlorin e6 (Ce6) of Fan is suitable as photosensitizers in photodynamic therapy of treating cancer, but zinc phthalocyanine is also a photosensitizer conventionally known in the art to be suitable as photosensitizers in photodynamic therapy of treating cancer, as well as, Fan establishes that MnO2 nanosheets can strongly absorbed photosensitizers by electrostatic interactions and Mn-N coordinate bonds, providing a photosensitizer-MnO2 nanosheet that have enhanced photodynamic therapy efficient (Fan: page 5477, right column). Thus, it would have been merely simple substitution of one known photosensitizer for another to achieve the desired photosensitizer-MnO2 nanosheet with enhanced photodynamic therapy efficient in the treatment of cancer. As such, [t]he selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).
With respect to the claimed “the photosensitizer is releasable from the metallic nanosheet upon degradation of the metallic nanosheet by glutathione (GSH) in the tumor tissue,” as recited in claims 13 and 17, as discussed above, Fan established that MnO2 nanosheets can react with intracellular glutathione (GSH), resulting in the disintegration of the nanosheets and, hence, complete release of photosensitizers for PDT (page 5477, right column). Thus, it would have been reasonably obvious that the zinc phthalocyanine that is incorporated on the MnO2 nanosheet of Fan as the photosensitizer, as guided by Koyakutty and Lange would have been releasable from the metallic nanosheet upon degradation of the metallic nanosheet by glutathione (GSH) in the tumor tissue, as it is well-established by Fan supra MnO2 nanosheets react with intracellular glutathione (GSH), resulting in the disintegration of the nanosheets and, hence, complete release of photosensitizers for photodynamic therapy.
As such, based on the guidance from Rana, Koyakutty and Lange, an ordinary artisan seeking to maximize cancer treatment would have looked to covalently bonding folic acid on a surface of the metallic nanosheet (MnO2 nanosheet) via EDC-NHS coupling reaction, as well as, as mixing the MnO2 nanosheet with photosensitizer such as zinc phthalocyanine so as to form a resultant zinc phthalocyanine-MnO2-FA nanosystem that have specific target to the folate receptor on the tumor/cancer cells, as well as, enhanced photodynamic therapy efficient in the treatment of cancer, and achieve Applicant’s claimed invention with reasonable expectation of success.
Regarding claim 21, Lange teaches zinc phthalocyanine has an irradiated wavelength between 580-630 nm ([0117]-[0121]; Table 3).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 06/22/2026 have been fully considered but they are not persuasive.
Below is the Examiner’s response to Applicant’s arguments as they pertain to the standing 103 rejection over the combined teachings of Fan, Rana, Koyakutty, and Lange.
Applicant argues:
“Rana, which attaches folic acid to iron oxide nanoparticles via EDC-NHS amide coupling with no MnO2 and no PEG, similarly does not teach the claimed direct, polymer-free distribution on an MnO2 nanosheet.” (Remarks, page 7, 1st paragraph).
In response, the Examiner disagrees. The metallic nanosheet of MnO2 nanosheet has been taught by Fan. Rana was used for teaching and rendering obvious the concept of binding folic acid to a surface of a metallic nanosheet (metal nanoparticle) via EDC-NHS coupling reaction so as to provide higher cellular internalization capability in cancer cells over-expressing folate receptors. See 103 rejection, pages 6-8 of this office action. The MnO2 nanosheet of Fan and the iron oxide nanoparticles of Rana are both metal nanoparticles and thus, it is maintained that it would have been obvious to one of ordinary skill in the art to covalent bond folic acid on a surface of the MnO2 nanosheet of Fan via EDC-NHS coupling, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Rana provided the guidance to do so by teaching that folic acid can be advantageously loaded on the surface of a metal nanoparticle by conjugating (covalent bonding) folic acid via EDC-NHS coupling reaction and such folic acid conjugated metal nanoparticles provides higher cellular internalization capability in cancer cells over-expressing folate receptors. It is noted that EDC-NHS is not a polymeric spacer, and thereby meeting the claimed “the folic acid …distributed directly on a surface of the metallic nanosheet without a polymeric spacer between the folic acid and the metallic nanosheet,” as recited in claims 13 and 17. Thus, an ordinary artisan interested in providing higher cellular internalization capability in cancer cells over-expressing folate receptors would have looked to conjugating (covalent bonding) folic acid on a surface of the metallic nanosheet of Fan via EDC-NHS coupling reaction with a reasonable predictability that the resultant photosensitizer-MnO2-folic acid nanosheet that would specifically target the folate receptor on the tumor/cancer cells, thereby providing the desired cancer treatment.
Applicant is noted that the specification discloses that “the metallic nanosheet is introduced into a cancer cell by folate(FA) receptor-mediated endocytosis” (Specification: paragraph [17]), which is exactly the same function/advantage to which Rana uses folic acid conjugated metal nanoparticles, to provide higher cellular internalization capability in cancer cells over-expressing folate receptors. Thus, this is preponderance of evidence to support the Examiner’s obviousness analysis.
Applicant argues:
“Neither Rana (iron oxide nanoparticles are not degraded by GSH) nor Hao (ZnPc in Hao is loaded by physisorption onto MnO2-PEG-FA; its release by GSH is not demonstrated, and folic acid in Hao's structure is covalently tethered to PEG and would not be cleanly released upon MnO2 degradation) satisfies this limitation.” (Remarks, page 7, 2nd paragraph).
In response, the Examiner disagrees. As discussed above, the metallic nanosheet of MnO2 nanosheet has been taught by Fan. As discussed in the standing 103 rejection, Fan has already established the MnO2 nanosheets reacts with intracellular glutathione (GSH), resulting in the disintegration of the nanosheets and, hence, complete release of photosensitizers for PDT (103 rejection, pages 6-7 of this office action).
Applicant argues:
“The Specification reports that the IC50 of FA-MnO2/ZnPc is 38.1 + 2.2 pg/mL, approximately three times lower than the IC50 of free ZnPc alone (115.1 + 3.4 pg/mL) in HeLa cells under identical PDT conditions. (Spec. [Experimental Example 3]; FIG. 5C.) This threefold improvement is an unexpected result that directly reflects the synergy of FA-mediated folate- receptor targeting, MnO2 nanosheet-mediated intracellular ZnPc delivery, and GSH-triggered ZnPc release within the tumor cell. None of the cited references teaches or suggests this combination, let alone this magnitude of improvement.” (Remarks, page 8, 1st paragraph).
In response, the Examiner disagrees. Applicant’s alleged unexpected results as shown in Experimental Example 3 and FIG. 5C with respect to “the IC50 of FA-MnO2/ZnPc is 38.1 + 2.2 pg/mL, approximately three times lower than the IC50 of free ZnPc alone,” are considered, but found insufficient to obviate the standing 103 rejection over the combined teachings of Fan, Rana, Koyakutty, and Lange because as disclosed in Experimental Example 3 and submitted by Applicant, it is the folic acid that is bound to the MnO2 nanosheet which provides the improvement, which is an improvement that not unexpected, but rather reasonable expected. This is because as discussed above, Rana had already recognized the advantage of using folic acid conjugated metal nanoparticles to provide higher cellular internalization capability in cancer cells over-expressing folate receptors. The modification of the MnO2-photosensitizer nanosheets of Fan per Rana to contain bound/conjugated folic acid would be reasonable expected to provide lower cell viability (IC50) when compared to no folic acid, as it is the bounded folic acid that provided the high uptake of the MnO2-photosensitizer nanosheets within tumor cells, thereby providing enhanced accumulation of the photosensitizer upon degradation of the MnO2 nanosheet via GSH, as per Fan supra, the MnO2 nanosheets reacts with intracellular glutathione (GSH), resulting in the disintegration of the nanosheets and, hence, complete release of photosensitizers for PDT.
Applicant argues:
“The Specification demonstrates specific, FA-mediated delivery of ZnPc into FR-positive tumor cells (HeLa and MDA-MB-231) but not into FR-negative cells (A-549), confirmed by fluorescence microscopy and quantitative flow cytometry. (Spec. [Experimental Example 2]; FIGs. 4A-4C, 8.) Pre-saturation of folate receptors with free folic acid completely blocked FA- MnO2/ZnPc uptake, confirming FR-mediated specificity. This selective targeting is absent from the non-FA-targeted MnO2/ZnPc control under identical conditions and is a direct functional consequence of the claimed folic acid-targeted nanosheet platform.” (Remarks, page 8, 2nd paragraph).
In response, the Examiner disagrees. Applicant’s alleged unexpected results as shown in Experimental Example 2 and FIGs. 4A-4C, and 8 with respect enhanced uptake into FR-positive tumor cells due to folic acid-targeted nanosheet, are considered but found insufficient to obviate the standing 103 rejection over the combined teachings of Fan, Rana, Koyakutty, and Lange because as discussed above, the enhanced uptake of MnO2/ZnPc into tumor cells due to the bound folic acid on the nanosheet is not an unexpected result, but rather reasonable expected. This is because as discussed above, Rana had already recognized the advantage of using folic acid conjugated metal nanoparticles to provide higher cellular internalization capability in cancer cells over-expressing folate receptors. The modification of the MnO2-photosensitizer nanosheets of Fan per Rana to contain bound/conjugated folic acid would be reasonable expected to provide lower cell viability (IC50) when compared to no folic acid, as it is the bounded folic acid that provided the high uptake of the MnO2-photosensitizer nanosheets within tumor cells, thereby providing enhanced accumulation of the photosensitizer upon degradation of the MnO2 nanosheet via GSH, as per Fan supra, the MnO2 nanosheets reacts with intracellular glutathione (GSH), resulting in the disintegration of the nanosheets and, hence, complete release of photosensitizers for PDT.
Applicant argues:
“In a human HeLa cancer xenograft mouse model, FA-MnO2/ZnPc combined with laser irradiation produced significant tumor suppression over two weeks at a ZnPc dose of only 0.5 mg/kg 10% of the standard effective dose of 5.0 mg/kg for conventional ZnPc administration. Control groups (FA-MnO2 alone, MnO2/ZnPc with laser, PBS) showed no significant difference in tumor volume. (Spec. [Experimental Example 4]; FIGs. 6B, 6C.) Achieving equivalent or superior anticancer efficacy at one-tenth the conventional dose is a remarkable and unexpected result that flows from the integrated FA-targeting, GSH-responsive release, and ZnPc-based PDT platform of the claimed invention, and is not predicted by any of the cited references.” (Remarks, page 8, 3rd paragraph).
In response, the Examiner disagrees. Applicant’s alleged unexpected results of achieving equivalent or superior anticancer efficacy at one-tenth the conventional dose due to integrated FA-targeting, GSH-responsive release, and ZnPc-based PDT platform are considered, but found insufficient to obviate the standing 103 rejection over the combined teachings of Fan, Rana, Koyakutty, and Lange because the methods of claims 13 and 17 are not commensurate in scope with laser irradiation and the wavelength of the light irradiation, as well as, the effective dose of ZnPC that are used in Applicant’s alleged evidence of unexpected results. Thus, it is noted that per MPEP §716.02(d), [w]hether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support."
Furthermore, Applicant’s alleged unexpected results of achieving equivalent or superior anticancer efficacy at one-tenth the conventional dose due to integrated FA-targeting, GSH-responsive release, and ZnPc-based PDT platform, are also not persuasive because Fan is a photosensitizer-MnO2 nanosheet for enhanced photodynamic therapy when used in addition with light irradiation (Fan: pages 2477-2478), and bounding of folic acid to the photosensitizer-MnO2 nanosheet for enhanced cancer treatment is reasonably obvious and expected. This is because as discussed above, Rana had already recognized the advantage of using folic acid conjugated metal nanoparticles to provide higher cellular internalization capability in cancer cells over-expressing folate receptors. The modification of the MnO2-photosensitizer nanosheets of Fan per Rana to contain bound/conjugated folic acid would be reasonable expected to provide lower cell viability (IC50) when compared to no folic acid, as it is the bounded folic acid that provided the high uptake of the MnO2-photosensitizer nanosheets within tumor cells, thereby providing enhanced accumulation of the photosensitizer upon degradation of the MnO2 nanosheet via GSH, as per Fan supra, the MnO2 nanosheets reacts with intracellular glutathione (GSH), resulting in the disintegration of the nanosheets and, hence, complete release of photosensitizers for PDT.
Applicant argues:
“The Examiner's proposed combination would, as a practical matter, lead a POSA to a PEG- containing MnO2-FA nanosheet system (via Hao's established route), not the claimed polymer- free system. Moreover, the prior art of record includes Hu, which expressly teaches that EDC-type covalent coupling of folic acid produces toxic by-products and hinders folate receptor recognition. A POSA seeking an FA-targeted nanosheet for cancer therapy would thus have had a specific reason to avoid coupling-reagent-mediated FA attachment, further undermining any motivation to apply Rana's approach to Fan's MnO2 nanosheet.” (Remarks, page 11, 1st paragraph).
In response, the Examiner disagrees. Rana does not require pegylation for binding folic acid to the metal nanoparticles. Rana teaches that EDC-NHS system is sufficient to conjugate folic acid to metal nanoparticles, and such folic acid conjugated to the metal nanoparticles via EDC-NHS system are blood compatible. Furthermore, it is noted that claims 13 and 17 does not exclude covalent binding of folic acid to the metallic nanosheet via EDC-NHS, thereby Applicant’s claims 13 and 17 also encompassed a metallic nanosheet that can “produce toxic by-products and hinders folate receptor recognition” per Applicant’s Hu reference.
Accordingly, it is maintained that Rana is properly combined with Fan to render obvious the binding of folic acid to the MnO2 nanosheet of Fan. Thus, as discussed in the standing 103 rejection, it is maintained that it would have been obvious to one of ordinary skill in the art to covalent bond folic acid on a surface of the MnO2 nanosheet of Fan via EDC-NHS coupling, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Rana provided the guidance to do so by teaching that folic acid can be advantageously loaded on the surface of a metal nanoparticle by conjugating (covalent bonding) folic acid via EDC-NHS coupling reaction and such folic acid conjugated nanoparticles provides higher cellular internalization capability in cancer cells over-expressing folate receptors. It is noted that EDC-NHS is not a polymeric spacer, and thereby meeting the claimed “the folic acid …distributed directly on a surface of the metallic nanosheet without a polymeric spacer between the folic acid and the metallic nanosheet,” as recited in claims 13 and 17. As such, an ordinary artisan interested in providing higher cellular internalization capability in cancer cells over-expressing folate receptors would have looked to conjugating (covalent bonding) folic acid on a surface of the metallic nanosheet of Fan via EDC-NHS coupling reaction with a reasonable predictability that the resultant photosensitizer-MnO2-folic acid nanosheet that would specifically target the folate receptor on the tumor/cancer cells, thereby providing the desired cancer treatment. As discussed above, Applicant’s specification discloses that “the metallic nanosheet is introduced into a cancer cell by folate(FA) receptor-mediated endocytosis” (Specification: paragraph [17]), which is exactly the same function/advantage to which Rana uses folic acid conjugated metal nanoparticles, to provide higher cellular internalization capability in cancer cells over-expressing folate receptors. Thus, this is preponderance of evidence to support the Examiner’s obviousness analysis.
Applicant argues:
“No reference in either cited combination discloses ZnPc in combination with an MnO2 nanosheet, let alone the specific Mn-N coordinate bond between them.” (Remarks, page 12, last paragraph to page 13).
In response, the Examiner disagrees. As discussed above in the standing 103 rejection, Koyakutty and Lange provided the guidance to do so by teaching that not only chlorin e6 (Ce6) of Fan is suitable as photosensitizers in photodynamic therapy of treating cancer, but zinc phthalocyanine is also a photosensitizer conventionally known in the art to be suitable as photosensitizers in photodynamic therapy of treating cancer, as well as, Fan establishes that MnO2 nanosheets can strongly absorbed photosensitizers by electrostatic interactions and Mn-N coordinate bonds, providing a photosensitizer-MnO2 nanosheet that have enhanced photodynamic therapy efficient (Fan: page 5477, right column). Thus, it would have been merely simple substitution of one known photosensitizer for another to achieve the desired photosensitizer-MnO2 nanosheet with enhanced photodynamic therapy efficient in the treatment of cancer. As such, [t]he selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.). See 103 rejection, pages 8-10 of this office action.
As a result, for at least the reasons discussed above, claims 13, 17, and 21 remain rejected as being obvious and unpatentable over the combined teachings of Fan, Rana, Koyakutty, and Lange in the standing 103 rejection as set forth in this office action.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/DOAN T PHAN/ Primary Examiner, Art Unit 1613
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