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 .
Status of Application
Claims 1-20 are under examination.
Drawings
The drawings are objected to because of the following reasons:
Figure 3 has an unlabeled scale bar.
Figure 4A and 5 have bars which are unclear which graph is ICG-free and which is ICG-GNP II.
Figure 5 have bars which are unclear which graph is ICG-free and which is ICG-GNP II.
Figure 6A have bars which are unclear which bar is ICG-free and which is ICG-GNP I.
Figure 6C have bars which are unclear which bars belong to ICG-free and which to ICG-GNP I
Figure 6B, 7A, and 7B have scale bars that do not adequately show difference in intensity between high and low.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as "amended." If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either "Replacement Sheet" or "New Sheet" pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 18 is objected to because of the following informalities: there is a typographical error in line 2, "imagining" should be "imaging". Appropriate correction is required.
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 7 and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
The term "strong" in claim 7 is a relative term which renders the claim indefinite. The term "strong" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The electrostatic interaction between the cationic gelatin and the anionic fluorophore are rendered indefinite by this term.
Regarding claim 20, the phrase "such as" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 20 recites the limitation "the fluorophore" in line 3. There is insufficient antecedent basis for this limitation in the claim. The examiner recommends amending from "the fluorophore" to "a fluorophore".
The term "5x less" in claim 20 is a relative term which renders the claim indefinite. The term "5x less" is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The amount of free fluorophore is not defined or claimed nor is the amount of fluorescent nanoparticles claimed. The range of "5x less" is indefinite since it depends on the amount of free fluorophore.
Claim Interpretation
Claim 1 recites "substantial fluorescence" in line 7. The specification defines "substantial fluorescence" as fluorescence that is optically detectable by standard imaging techniques and is distinguishable from encapsulated fluorophores (pg 9, para [0040]). Therefore, for the purposes of examination, the examiner interprets any prior art which shows fluorescence and where the fluorescence is different from the fully encapsulated fluorescence measurement as reading on this claim limitation.
Claim 1 recites "effective size". The specification does not define "effective size". The examiner notes that effective size is referenced in the specification as between 40 nm and 160 nm. However, the "effective size" is not defined. Therefore, for the purposes of examination, the examiner interprets any prior art with any size between 40 and 160 nm made by any method as reading on this claim limitation.
Claim 2 recites a standard deviation of the average hydrodynamic diameter. The examiner notes that this reads on a range of 30-110nm. Therefore, for the purposes of examination, the examiner interprets any hydrodynamic diameter in the range of 30-110 nm as reading on this claim limitation.
Claim 5 recites “peptide bond”. The examiner notes that the specification describes ethylene diamine as a diamine here, and that the diamine forms a amide bond. Therefore, for the purposes of examination, the examiner interprets any prior art conjugating diamines to the gelatin through an amide bond as reading on peptide bonds.
Claim 6 recites “wherein the gelatin matrix is from acid or base hydrolysis of collagen”. This is a product-by-process claim language. Applicant is directed to MPEP 2113(I), “Product-by-Process Claims Are Not Limited To the Manipulations Of The Recited Steps, Only the Structure Implied by the Steps”, which states “[e]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production.” Therefore, the examiner interprets any prior art containing fluorescent nanoparticle as reading on this claim limitation.
Claim 7 recites “configured to”. This is a linking word or phrase modified by functional
language. See MPEP 2181(I). However, the claim sufficiently describes the subject, “cationic gelatin” such that the examiner interprets this linking word or phrase as acceptable.
Claim 7 recites “strong electrostatic interaction”. The examiner notes that the specification does not define “strong electrostatic interaction”. However, the examiner notes that the strong electrostatic interactions are between anions and cations. Therefore, for the purposes of examination, the examiner interprets any prior art containing ionic interactions as reading on this claim limitation.
Claim 8 recites “ICG”. The examiner notes that the specification defines this abbreviation as “indocyanine green” (pg 1, para [0003], line 11). For the purposes of examination, the examiner interprets ICG as indocyanine green.
Claim 13 recites “polypeptides having a dipeptide sequence portion”. The examiner notes that portion means that dipeptide is not the full polypeptide. Therefore, for the purposes of examination, the examiner interprets any prior art containing a peptide with a portion thereof that is a dipeptide that matches the claimed groups, reads on this claim limitation.
Claim 14 recites “receptor-specific ligand”. The specification does not define “receptor-specific ligand”. Therefore, for the purposes of examination, the examiner interprets any prior art with a fluorescent nanoparticle with a ligand which can bind to a specific receptor as reading on this claim limitation.
Claim 16 recites “configured to” in lines 4, 6, and 8. This is a linking word or phrase modified by functional language. See MPEP 2181(I). However, the claim sufficiently describes the subject, “gelatin matrix” such that the examiner interprets this linking word or phrase as acceptable.
Claim 18 recites “imagining” in line 2. The examiner notes that this should be “imaging”. Therefore, for the purposes of examination, the examiner interprets “imagining” as “imaging”.
Claim 20 recites “at a dose that is at least 5x less than the fluorophore that is provided as free fluorophore not encapsulated within the gelatin matrix”. The concentration of the free fluorophore is not a claim limitation; therefore, it could be any concentration. Therefore, the 5x less limitation could also be anything so long as it is 5x less the free fluorophore dose. Therefore, for the purposes of examination, the examiner interprets any prior art containing any dose of the fluorescent nanoparticle as reading on this claim limitation.
Claims 1, 5, 7, 12, 16-17, and 19 recite functional language. A claim term is functional when it
recites a feature "by what it does rather than by what it is". See MPEP 2173.05(g).
Claim 1 recites "selected to provide: quenching of fluorophore encapsulated within the gelatin matrix; a substantial fluorescence for the fluorophore released from the gelatin matrix". This phrase is functional language. For the purposes of examination, the examiner interprets any prior art containing a fluorescent nanoparticle which can quench fluorophore encapsulated within the gelatin matrix or fluorescence for the fluorophore released from the gelatin matrix, regardless of whether it was used for any of these functions, as reading on this claim limitation.
Claim 5 recites “to increase an effective positive change of the gelatin matrix and an increase in cellular uptake”. This is functional language. Therefore, for the purposes of examination, the examiner interprets any fluorescent nanoparticle that could do these functions regardless to whether the prior art says that it does, reads on these claim limitations.
Claim 7 recites, “to encapsulate an anionic fluorophore via a strong electrostatic interaction between the cationic gelatin and the anionic fluorophore”. This is functional language. For the purposes of examination, the examiner interprets any prior art containing a fluorescent nanoparticle which could be configured to perform this function as reading on this claim limitation, regardless as to whether the prior art recites this limitation.
Claim 12 recites “for specific degradation by a cancer cell secreted protease” and “to enhance a tumor selective degradation of the fluorescent nanoparticle” and “to release the encapsulated fluorophore from the gelatin matrix”. These phrases are functional language. Therefore, for the purposes of examination, any prior art containing the fluorescent nanoparticle with a peptide which can perform these functions, regardless as to whether the prior art recites these functions, reads on these claim limitations.
Claim 16 recites “enhances fluorescent particle stability in a biological environment” and “is configured for in vivo near-infrared (NIR) imaging” and “increases an in vivo circulation time of the fluorophore” and “is configured to facilitate delivery fo the fluorescent nanoparticle to and accumulate in tumors” and is configured to enhance fluorescent nanoparticle tumor uptake and gelatin degradation within a tumor environment” and “so that there is minimal fluorescence of fluorophore outside a tumor environment and maximum fluorescence of the fluorophore inside the tumor environment” and “to provide improved tumor detection and contrast”. These phrases are functional language. Therefore, for the purposes of examination, the examiner interprets any prior art containing a fluorescent nanoparticle with the gelatin matrix which can perform these functions, regardless of whether the prior art recites these limitations, as reading on these claim limitations.
Claim 17 recites “for the fluorescent nanoparticles to accumulate and degrade in the tumor, so that at least a portion of the encapsulated fluorophores are released from the gelatin matrix inside the tumor”. This phrase is functional language. Therefore, any prior art containing a method with fluorescent nanoparticles where the nanoparticles could do this step in the method, regardless of whether the prior art recites their ability, reads on this claim limitation.
Claim 19 recites “for removal of tumors having a negative margin”. This is functional language. Therefore, the examiner interprets any prior art containing a method of using fluorescent nanoparticles to visualize tumor boundaries that are capable of this function, regardless of whether the prior art recites this limitation, as reading on this limitation.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 3-4, 6-11, and 16-19 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Li, X.; et al., Core-Satellite Nanomedicines for in vivo Real-Time Monitoring of Enzyme-Activatable Drug Release by Fluorescence and Photoacoustic Dual-Modal Imaging, ACS Nano, 2019, 13, 176-186 and as evidenced by Lu, C-H.; et al., Indocyanine green: An old drug with novel applications, Tzu Chi Medical Journal, 2021, 33, 4, 317-322 and Rose, J. B.; et al. Gelatin-Based Materials in Ocular Tissue Engineering, Materials, 2014, 7, 3106-3135 and Li, X.; et al., Supplementary Information Core-Satellite Nanomedicines for in vivo Real-Time Monitoring of Enzyme-Activatable Drug Release by Fluorescence and Photoacoustic Dual-Modal Imaging, ACS Nano, 2019, 13, 176-186.
Li, X.; et al. (hereafter referred to as Li) is drawn to gelatin-based nanomedicines containing indocyanine green and doxorubicin embedded internally with CuS nanoparticles on the surface (title; abstract). Li teaches nanoparticle medicines have advantages of heightened accumulation disease-site targeting delivery over traditional medicines (pg 177, col 1, par 1, lines 2-7) and incorporation of site-specific features increase clinical development promise (pg 177, col 1, para 1, lines 7-12) and loading nanomedicines directly with fluorophores can help with understanding kinetics of the nanomedicines (pg 177, col 2, para 1, lines 1-8) and a variety of stimuli-activatable nanomedicines have been developed (pg 177, col 2, para 1, lines 16-17). Li teaches an enzyme-activatable core-satellite indocyanine green and doxurubicin loaded gelatin nanoparticles with CuS nanoparticles on the surface (ICG/DOX@Gel-CuS) (pg 177, col 2, para 2, lines 1-5) and preparation of the nanomedicines (pg 178, Figure 1A) and the gelatin is eroded by protease (pg 178, col 1, para 1, lines 1-4) and kinetics of drug release in vivo (pg 178, col 1, para 1, lines 10-16) and that the fluorescence is off until protease releases the indocyanine green enabling fluorescence (pg 178, col 2, para 2, lines 6-15; pg 179, Figure 2A). Li teaches in vivo testing of the nanoparticles (pg 182, Figure 5).
Lu, C-H.; et al. (hereafter referred to as Lu) is drawn to indocyanine green (title; abstract). Lu teaches that indocyanine green is an FDA-approved fluorescent compound and is a fluorophore (abstract). Lu teaches indocyanine green was developed by Kodak during World War II for color imaging purposes and medical applications of ICG were approved by the USFDA in 1959 (pg 317, col 1, para 2, lines 1-4). Lu teaches indocyanine green is a water-soluble cyanine dye and is green when diluted with water (pg 317, col 2, para 2, lines 1-8) and that indocyanine green has two negative charges and one positive charge giving an overall net negative charge (pg 318, Figure 1).
Rose, J. B.; et al. (hereafter referred to as Rose) is drawn to gelatin and uses in the pharmaceutical industry (title; abstract). Rose teaches gelatin is a protein based material derived from the hydrolysis of collagen and is biodegradable, biocompatible, and commercially available at low cost (pg 3107, para 2, lines 1-3) and that gelatin exists as a mixture of water soluble protein fragments and can be manufactured from a variety of animal collagens (pg 3107, para 4, lines 1-5) and that the processing under acidic or basic conditions give either Type A or type B gelatin respectively (pg 3107, para 4, lines 6-9). Rose teaches gelatin can be crosslinked (pg 3109, para 2, lines 1-3).
Li, X.; et al. (hereafter referred to as Li-SI) is drawn to the supplementary information of Li (title). Li-SI teaches materials used (pg 2, para 1), methods of preparing silicon dioxide particles (pg 3, para 2), emission spectra of geltain nanoparticles (pg 6, Figure S6) and surgically removed tumors (pg 8, Figure S8) and difference in average fluorescence signal between free fluorophore and gelatin nanoparticles containing fluorophore (pg 9, Figure S9) and H&E staining of major organs (pg 10, Figure S12).
As to claim 1, Li teaches a fluorescent nanoparticle for imaging tumors (abstract, lines 14-21; pg 182, col 1, para 1, lines 1-8; pg 182, Figure 5) comprising a gelatin matrix (pg 182, col 1, para 1, lines 16-19); a fluorophore encapsulated within the gelatin matrix (pg 178, col 1, para 2, lines 1-8) and ionically-bound to the gelatin matrix (pg 184, para 2, lines 1-2; pg 184, para 3, lines 1-5). And Li teaches that the encapsulation concentration is such that quenching of fluorophore encapsulated within the gelatin matrix, a substantial fluorescence for the fluorophore released from the gelatin matrix (pg 184, col 1, para 3, lines 19-24; pg 179, Figure 2A; pg 182, Figure 5); and wherein the gelatin matrix and fluorophore together form the fluorescent particle (pg 177, col 2, para 2, lines 1-5; pg 177, Scheme 1; pg 178, Figure 1) having an effective size that is between 116.4 nm (pg 178, Figure 1B; pg 178, col 2, para 1, lines 5-6). [W]hen, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art. See MPEP 2131.03.
Regarding the fluorophore is ionically bound to the gelatin, the prior art states that the fluorophore is indocyanine green (pg 184, col 1, para 3, lines 19-24) and the gelatin is Type A gelatin (pg 184, col 1, para 3, lines 1-4). As evidenced by Lu, the indocyanine green has an overall negative charge (Lu, pg 318, Figure 1). As evidenced by Rose, the Type A gelatin has an overall positive charge (Rose, pg 3107, para 4, lines 8-9). Inherently, compounds with negative and positive charges form ionic bonds. Therefore, regarding the ionically bound fluorophore to the gelatin matrix, the combination of indocyanine green (an overall negatively charged fluorophore) is combined with an overall positively charged gelatin matrix, ionic bonding between the two will occur.
As to claim 3, Li teaches the gelatin matrix is a type A gelatin (pg 184, col 1, para 2, lines 1-2; pg 184, col 1, para 3, lines 1-4).
As to claim 4, Li teaches the gelatin matrix is a type A (cationic) gelatin, as evidenced by Rose (Rose, pg 3107, para 4, lines 8-9) and the fluorophore has a net negative charge, as evidenced by Lu (Lu, pg 318, Figure 1).
As to claim 6, Li teaches the fluorescent nanoparticle (abstract, lines 14-21; pg 182, col 1, para 1, lines 1-8; pg 182, Figure 5). As evidenced by Rose, gelatin matrices are from acid or base hydrolysis of collagen (pg 3107, para 4, lines 1-9).
As to claim 7, Li teaches the fluorescent nanoparticle wherein the gelatin matrix is a cationic gelatin (pg 184, col 1, para 2, lines 1-2; pg 184, col 1, para 3, lines 1-4), as evidenced by Rose (Rose, pg 3107, para 4, lines 8-9). And, Li teaches an anionic fluorophore, as evidenced by Lu (Lu, pg 318, Fig 1), encapsulated within the gelatin matrix (pg 178, col 1, para 2, lines 1-8) and ionically-bound to the gelatin matrix (pg 184, para 2, lines 1-2; pg 184, para 3, lines 1-5).
Regarding a strong electrostatic interaction between the cationic gelatin and the anionic fluorophore, the prior art states that the fluorophore is indocyanine green (pg 184, col 1, para 3, lines 19-24) and the gelatin is Type A gelatin (pg 184, col 1, para 3, lines 1-4). As evidenced by Lu, the indocyanine green has an overall negative charge (Lu, pg 318, Figure 1). As evidenced by Rose, the Type A gelatin has an overall positive charge (Rose, pg 3107, para 4, lines 8-9). Inherently, compounds with negative and positive charges form ionic bonds. Therefore, regarding the ionically bound fluorophore to the gelatin matrix, the combination of indocyanine green (an overall negatively charged fluorophore) is combined with an overall positively charged gelatin matrix, ionic bonding between the two will occur.
As to claim 8, Li teaches the fluorescent nanoparticles comprise a fluorophore is indocyanine green (pg 184, col 1, para 3, lines 1-4 and 19-24).
As to claim 9, Li teaches the fluorescent nanoparticles where the fluorophore is a NIR dye that is indocyanine green (pg 184, col 1, para 3, lines 1-4 and 19-24).
As to claim 10, Li teaches a fluorescent nanoparticle wherein the fluorophore encapsulated with the gelatin matrix (pg 178, Figure 1A) and it has an encapsulated fluorescence intensity (pg 179, Figure 2D, 0min curve) that is less than an unencapsulated fluorescence intensity (pg 179, Figure 2D, 60 min curve) without a separate quencher molecule or on the fluorescent nanoparticle (pg 178, col 2, para 2, lines 1-17; pg 179, col 1, para 1, lines 1-6; pg 179, Figure 2A, and 2C-2E).
As to claim 11, Li teaches the fluorescent nanoparticle where the fluorophore encapsulated fluorescence value and an unencapsulated fluorescence value (pg 179, Figure 2A and 2C-E) and the free fluorescence value is greater than the encapsulated fluorescence value by at least a factor of 3 (pg 179, Figure 2D, 0 min curve and 60 min curve; pg 179, Figure 2E, Trypsin (-) curve at 60 min and Trypsin (+) curve at 60 min) at a selected emission wavelength (pg 178, col 2, para 2, lines 9-15) and a fluorophore concentration of 5 µg/mL, which is equivalent to 6.4 µM. The 6.4 µM value falls within the range of the claim. When, as by a recitation of ranges or otherwise, a claim covers several compositions, the claim is ‘anticipated’ if one of them is in the prior art. See MPEP 2131.03(I).
As to claim 16, Li teaches fluorescent nanoparticles wherein the gelatin matrix enhances fluorescent particle stability in a biological environment (pg 178, col 2, lines 14-17; pg 179, Figure 2E, Trypsin (-) curve) and is capable of in vivo NIR imaging (pg 182, Figure 5) and the fluorescent nanoparticles deliver to and accumulate in tumors (pg 182, Figure 5; pg 183, Figure 6).
Additionally, Li teaches an identical fluorescent particle as claimed in claim 1. 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. See MPEP 2112.01(I). Regarding the gelatin matrix enhances fluorescent particle stability in a biological environment; is configured for in vivo NIR imaging; increases an in vivo circulation time of the fluorophore, and facilitate delivery of the fluorescent nanoparticle to and accumulate in tumors, these functional features are inherent to the fluorescent nanoparticle of claim 1. Therefore, any composition sharing the same features of claim 1 will inherently have the same functions as the fluorescent nanoparticle of claim 1.
As to claim 17, Li teaches a method of imaging a tumor (pg 184, col 2, para 4, lines 1-12) comprising injecting a plurality of fluorescent nanoparticles (pg 184, col 2, para 4, line 3) to a patient in need of imaging (pg 184, col 2, para 4, lines 2-4), waiting a time period for the fluorescent nanoparticles to accumulate and degrade in the tumor, so that at least a portion of the encapsulated fluorophores are released from the gelatin matrix inside the tumor (pg 184, col 2, para 4, lines 5-6), applying an excitation wavelength of electromagnetic radiation to excite the fluorophore (pg 184, col 2, para 4, lines 9-12) and measuring an emitted wavelength of electromagnetic radiation generated by the excited fluorophores that have been released from the gelatin matrix to the tumor (pg 184, col 2, para 4, lines 9-12; pg 182, Figure 5), thereby imaging the tumor (pg 182, Figure 5).
As to claim 18, Li teaches near-infra-red imaging for a cancer tumor (pg 182, Figure 5).
As to claim 19, Li teaches the fluorescent nanoparticles provide visualization of a tumor boundary (pg 181, Figure 4; pg 182, Figure 5E) for removal of tumors having negative margins (pg 181, Figure 4; pg 182, Figure 5; pg 183, Figure 6).
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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.
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.
Claim(s) 2 and 20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li, X.; et al., Core-Satellite Nanomedicines for in vivo Real-Time Monitoring of Enzyme-Activatable Drug Release by Fluorescence and Photoacoustic Dual-Modal Imaging, ACS Nano, 2019, 13, 176-186.
Li, X.; et al. (hereafter referred to as Li) is drawn to gelatin-based nanomedicines containing indocyanine green and doxorubicin embedded internally with CuS nanoparticles on the surface (title; abstract). Li teaches nanoparticle medicines have advantages of heightened accumulation disease-site targeting delivery over traditional medicines (pg 177, col 1, par 1, lines 2-7) and incorporation of site-specific features increase clinical development promise (pg 177, col 1, para 1, lines 7-12) and loading nanomedicines directly with fluorophores can help with understanding kinetics of the nanomedicines (pg 177, col 2, para 1, lines 1-8) and a variety of stimuli-activatable nanomedicines have been developed (pg 177, col 2, para 1, lines 16-17). Li teaches an enzyme-activatable core-satellite indocyanine green and doxurubicin loaded getatin nanoparticles with CuS nanoparticles on the surface (ICG/DOX@Gel-CuS) (pg 177, col 2, para 2, lines 1-5) and preparation of the nanomedicines (pg 178, Figure 1A) and the gelatin is eroded by protease (pg 178, col 1, para 1, lines 1-4) and kinetics of drug release in vivo (pg 178, col 1, para 1, lines 10-16) and that the fluorescence is off until pretease releases the indocyanine green enabling fluorescence (pg 178, col 2, para 2, lines 6-15; pg 179, Figure 2A). Li teaches in vivo testing of the nanoparticles (pg 182, Figure 5).
As to claim 2, Li teaches a fluorescent nanoparticle with an effective size is an average hydrodynamic diameter that is between 184-213.9 nm with a 0.9-4.5 nm standard deviation (pg 178, col 2, lines 5-10; pg 178, Figures 1A and 1B). Generally, where the only difference between the prior art and the claims was a recitation of relative dimensions of the claimed device and a device having the claimed relative dimensions would not perform differently than the prior art device, the claimed device was not patentably distinct from the prior art device. See MPEP 2144.04(IV)(A). Alternatively, the claimed range of 50-90 nm is close to the prior art range of a hydrodynamic diameter of 184.0-213.9 nm or a diameter of 116.4-132.0 nm as measured by TEM (pg 178, col 2, para 1, lines 1-7). In such cases, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.
Li does not expressly teach a single embodiment comprising all the features of the claimed product. However, it would be prima facie obvious prior to the effective filing date of the claimed invention to combine the embodiments of diameters taught by Li as a skilled artisan recognizes that these claim elements are known in the art could have combined the elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately. Therefore, a person of ordinary skill in the art would have recognized that the results of the combination were predictable.
As to claim 20, Li teaches the fluorescent nanoparticles are provided to the patient at a dose (pg 184, col 2, para 4, lines 1-5; pg 182, col 2, para 1, lines 17-23). With respect to the 5x or more less than the unspecified concentration of the unspecified fluorophore, generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. It would have been routine optimization to have a concentration of the fluorescent nanoparticle 5x or more below the concentration of a free fluorophore since the fluorescent nanoparticle has a strong signal. As evidenced by Li-SI, the signal from the fluorescent nanoparticles is approximately 100x stronger than free fluorophore administered at the same dose (pg 9, Figure S9). Therefore, a person of ordinary skill in the art would have had a reasonable expectation of success in reducing the concentration of the fluorescent nanoparticle by 5-fold and still achieve a higher average fluorescence than free fluorophore.
Claim(s) 5 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li as applied to claims 1-4, 6-11, and 16-20 above, and further in view of Xu, X.; et al., Delivery of plasmid IGF-1 to chondrocytes via cationized gelatin nanoparticles, Journal of Biomedical Materials Research Part A, 2007, 84A, 1, 73-83. The teachings of Li as applied in the previous rejection are incorporated in this rejection.
As to claim 5, Li teaches the fluorescent nanoparticle of claim 1 (abstract, lines 14-21; pg 182, col 1, para 1, lines 1-8; pg 182, Figure 5).
Li does not teach a diamine molecule covalently conjugated to the gelatin matrix via peptide bond formation.
Xu, X.; et al. (hereafter referred to as Xu) is drawn to cationized gelatin nanoparticles for improved cell uptake (title; abstract). Xu teaches that incorporating gene vectors into 3D scaffolds has been a way to prolong overexpression of growth factors in cells but that there is an alternative approach of encapsulating plasmid DNA which can be injected in a nanoparticle (pg 73, col 1, lines 1-10; pg 73, col 2, lines 1-15). Xu teaches collagen-based scaffolds such as gelatin nanoparticles for this 9pg 73, col 2, lines 16-19). Xu teaches that gelatin nanoparticles are useful as carriers for small molecular weight drugs, peptides, and DNA (pg 74, col 1, para 2, lines 1-5) and that plasmid DNA and gelatin can undergo complex coacervation caused by oppositely charged colloids interacting and condensing the plasmid DNA (pg 74, col 1, para 2, lines 12-19). Xu teaches gelatin is ideal for nanoparticle formation due to its versatility to be chemically modified and cross-linked to meet specific controlled release needs (pg 74, col 1, para 3, lines 1-3) and particularly interest is the modification of the charge of the gelatin nanoparticles to increase the positive charge which interacts favorably with negatively charged cell membrane facilitating endocytosis (pg 74, col 1 para 3, lines 18-26). Xu teaches modifying gelatin with ethylene diamine to obtain cationized gelatin (pg 74, col 2, para 3, lines 1-12). Xu teaches that cationized gelatin showed superior fluorescence in cells compared to uncationized gelatin (pg 78, Figure 4; pg 75, Figure 5b).
As to a diamine molecule covalently conjugated to the gelatin matrix via peptide bond formation, Xu teaches ethylene diamine covalently conjugated to the gelatin matrix via a peptide bond (pg 74, col 2, para 3, lines 1-12) to increase an effective positive charge of the gelatin matrix (pg 78, Figure 3; pg 78, col 2, para 1, lines 1-4) and to increase cellular uptake (pg 78, Figure 4; pg 78, col 2 para 2, lines 1-8).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the gelatin nanoparticles of Li to include diamine molecules as taught by Xu because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of diamine molecules covalently conjugated to gelatin fluorescent nanoparticles.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the fluorescent nanoparticles of Li with the diamine molecules of Xu because the prior art of Li disclosed fluorescent nanoparticles known to be Type A and useful for imaing tumors (abstract, lines 14-21; pg 182, col 1, para 1, lines 1-8; pg 182, Figure 5). Additional prior art of Xu suggested adding diamine molecules to gelatin nanoparticles to have similar effect of imaging cells (Xu, Figure 4) and to have the added benefit of improving cellular uptake and imaging of cells (Xu, pg 78, Figure 4; pg 79, Figure 5) because of the overlap of gelatin matrix between them involves known chemistry.
The skilled artisan would have been motivated to modify the fluorescent nanoparticles of Li with the diamine molecules of Xu because increasing the positive charge of nanoparticles improves cellular uptake and can enhance the ability to image tumor cells. Therefore, it would have been prima facie obvious to combine the teachings of Li with Xu.
Claim(s) 12-13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li as applied to claims 1-4, 6-11, and 16-20 above, and further in view of Liu, G. L.; et al., WO 2014/145242 A1. The teachings of Li as applied in the previous rejection are incorporated in this rejection.
As to claim 12, Li teaches a fluorescent nanoparticle of claim 1 (abstract, lines 14-21; pg 182, col 1, para 1, lines 1-8; pg 182, Figure 5).
Li does not teach a peptide conjugated to a surface of the fluorescent for cancer cell delivery.
Liu, G. L.; et al. (hereafter referred to as Liu) is drawn to gelatin particles comprising peptides conjugated to the surface, fluorophore, and drugs internal to the gelatin nanoparticles (title; abstract). Liu teaches the most important aspect of cancer chemotherapy is delivering high doses of drug molecules to tumor sites for maximum treatment efficacy while minimizing systemic delivery to normal organs (pg 1, lines 14-15) and off-target drug release from particle drug carriers occurs due to fast nonspecific drug release from nanoparticles during circulation (pg 1, lines 29-30). Liu teaches gelatin nanocarriers are biodegradable and easily prepared in desired diameters in a cost-effective manner and that by conjugating peptides to the surface of the particles, off-target drug release can be reduced (pg 2, lines 9-12) and that the nanoparticles are suitable for fluorescence imaging with the peptides on the surface (pg 2, lines 12-14). Liu teaches a gelatin particle with a layer of peptides conjugated to the surface and teaches various lengths of the peptides can be 1 (pg 3, lines 6-17) or up to 50 (pg 2, lines 28-30). Liu teaches various specific embodiments of the cancer targeting peptides including dipeptides (pg 3, line 13). Liu teaches the fluorescent nanoparticles can monitor the progress of a therapeutic method after administration (pg 4, lines 8-13) and the killing or inhibiting the growth of cancer cells (pg 4, lines 20-23).
Regarding a peptide conjugated to a surface of the fluorescent for cancer cell delivery, Liu teaches peptides conjugated to a surface of the fluorescent nanoparticle (abstract; Fig 1; pg 2, lines 12-18) wherein the peptide is selected for specific degradation by a cancer cell secreted protease (abstract, Figure 1; pg 2, lines 17-18) to enhance a tumor selective degradation of the fluorescent nanoparticle (pg 2, lines 28-29; pg 3, lines 6-13) to release the encapsulated fluorophore from the gelatin matrix (pg 2, lines 28-39; pg 3, lines 6-13; pg 3, lines 34-36).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the fluorescent nanoparticle of Li to include targeting peptides as taught by Liu because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of cancer-secreted protease cleavable targeting peptides on the surface of the fluorescent nanoparticle.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the fluorescent nanoparticles of Li with peptides because the prior art of Li disclosed gelatin-based fluorescent nanoparticles known to accumulate in tumors (Li, pg 182, Figure 5). Additional prior art of Liu suggested adding targeting peptides to the surface of gelatin-based fluorescent nanoparticles to have similar ability to target tumors (pg 3, lines 6-13) and because of the overlap of the gelatin structure between them involves known chemistry, the conjugation of peptides would involve known chemistry.
The skilled artisan would have been motivated to modify the surface of the fluorescent nanoparticles with targeting peptides because targeting peptides are a well-known method of improving cell-specific or organ-specific uptake in a delivery system. Therefore, it would have been prima facie obvious to combine the teachings of Li with Liu.
As to claim 13, Liu teaches Phe-Lys (pg 3, lines 13).
Claim(s) 14-15 is/are rejected under 35 U.S.C. 103 as being unpatentable over Li as applied to claims 1-4, 6-11, and 16-20 above, and further in view of Dixit, N.; et al., Improved cisplatin delivery in cervical cancer cells by utilizing folate-grafted non-aggregated gelatin nanoparticles, Biomedicine and Pharmacotherapy, 2015, 69, 1-10. The teachings of Li as applied in the previous rejection are incorporated in this rejection.
As to claim 14, Li teaches the fluorescent nanoparticle (abstract, lines 14-21; pg 182, col 1, para 1, lines 1-8; pg 182, Figure 5).
Li does not teach a receptor-specific ligand connected to a surface of the gelatin nanoparticle.
Dixit, N.; et al. (hereafter referred to as Dixit) is drawn to improving fluorescent gelatin nanoparticle delivery to cisplatin through conjugating folic acid (title; abstract). Dixit teaches cisplatin can be useful for cervical cancer patients (pg 1, col 1, para 1, lines 1-2) and specific drug delivery to cancer cells can be achieved by adding a ligand on the surface of drug delivery systems (pg 1, col 2, para 1, line 16; pg 2, col 1, para 1, lines 1-2). Dixit teaches gelatin nanoparticles loaded with cisplatin (pg 2, col 2, para 3, lines 1-2) and grafting folic acid onto the nanoparticles (pg 2, col 2, para 4, lines 1-7) and conjugating a fluorescent molecule to the gelatin nanoparticle (pg 3, col 1, para 2, lines 1-5). Dixit teaches the fluorescent gelatin nanoparticles with folic acid have higher cellular accumulation compared to gelatin nanoparticles without folic acid (pg 8, Figure 6A).
Regarding a receptor-specific ligand connected to a surface of the gelatin nanoparticle, Dixit teaches receptor-specific ligand connected to a surface of the fluorescent nanoparticle (abstract; pg 2, col 2, para 3; pg 3, col 1, para 2) wherein the receptor-specific ligand is selected for a target cell, including a surface-expressed receptor on a cancer cell (pg 7, Figure 5; pg 5, col 1, para 2, lines 1-13; pg 5, col 2, para 1, lines 1-10).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to modify the fluorescent nanoparticle of Li to include folic acid receptor-specific ligand as taught by Dixit because these claim elements were known in the art and one of skill in the art could have combined these elements by known methods with no change in their respective functions, and the combination would have yielded the predictable outcome of modifying the fluorescent nanoparticle of Li with the receptor-specific ligand of the fluorescent nanoparticle of Dixit.
A person of ordinary skill in the art would have had a reasonable expectation of success in modifying the surface of the fluorescent nanoparticle of Li with a receptor-specific ligand because the prior art of Li disclosed a fluorescent gelatin nanoparticle known to accumulate in tumors (Li, pg 182, Figure 5). Additional prior art of Dixit suggested a gelatin nanoparticle to have similar tumor accumulating behavior because of the overlap of gelatin nanostructure and the presence of the receptor-specific ligand, folic acid, on the surface and the chemistry of attaching folic acid to gelatin involves known chemistry.
The skilled artisan would have been motivated to add a receptor-specific ligand to the surface of the fluorescent nanoparticle because these, especially folic acid, are well-studied methods of getting nanoparticle drug delivery system to target specific cells and tumors. Therefore, it would have been prima facie obvious to combine the teachings of Li with Dixit.
As to claim 15, Dixit teaches folic acid (pg 7, Figure 5; pg 5, col 1, para 2, lines 1-13; pg 5, col 2, para 1, lines 1-10).
Conclusion
No claims allowed.
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/EVAN M LEWOCZKO/Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
