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 .
Acknowledgement of Receipt
Applicant’s Response, filed 12/24/2025, in reply to the Office Action mailed 9/29/2025, is acknowledged and has been entered. Claims 1, 11 and 17 have been amended. Claims 1, 4-8 and 11-20 are pending, of which claim 20 is withdrawn from consideration at this time as being drawn to a non-elected invention. Claims 1, 4-8 and 11-19 encompass the elected invention and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. The Examiner’s response to Applicant’s arguments is incorporated below.
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.
Claim(s) 1, 4-7, 10, 11 and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (J. Mater. Chem. B, 2017, 5, 7538-7546) in view of Savariar et al. (Cancer Res., 2013, 73(2), p. 855-864), for reasons set forth in the previous Office Action.
Response to arguments
Applicant argues that the claimed subject matter, as now amended into claim 1, would not have been obvious to one of ordinary skill in the art in view of the cited references. The Examiner has asserted that the substitution of Cy5 and Cy7 into the conjugate system described by Liu, based on the ratiometric imaging approach of Savariar, would have been a straightforward modification. However, this position does not account for the fundamental differences in photophysical mechanism, chemical structure, and functional intent of the present invention compared to the combined teachings of the cited art. Applicant argues that the ratiometric system disclosed in Savariar is based on a Fluorescence Resonance Energy Transfer (FRET) mechanism, in which a donor and acceptor fluorophore, such as Cy5 and Cy7, operate through proximity-dependent energy transfer; and that in contrast, the system claimed herein employs switchable dyes, which are chemically activatable and exhibit a direct and substantial change in their fluorescence emission profile upon cleavage of a tether or linker. These switchable dyes are not FRET-dependent and do not require specific spatial configurations. Applicant asserts that in the claimed invention, the switchable dyes are carefully selected and engineered to exhibit tunable emission characteristics. Applicant notes that the push-pull configuration gives rise to NIR absorption and emission, enhanced solvatochromism, and high sensitivity to polarity and viscosity and that such features are leveraged in the present invention to achieve selective activation and reliable quantitative readout of cleavage events.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that at least ZW800, as set forth on page 11 of the previous Office Action, has a chemical structure corresponding to the second instantly claimed structure. With regard arguments directed to the photophysical mechanism, functional intent, and emission characteristics see MPEP 2112.01. "Products of identical chemical composition cannot have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (Applicant argued that the claimed composition was a pressure sensitive adhesive containing a tacky polymer while the product of the reference was hard and abrasion resistant. "The Board correctly found that the virtual identity of monomers and procedures sufficed to support a prima facie case of unpatentability of Spada’s polymer latexes for lack of novelty.").
Applicant argues that a person of ordinary skill in the art reviewing the teachings of Liu and Savariar would not be motivated to consider alternative mechanisms such as switchable dyes for ratiometric imaging because both references focus exclusively on well-established FRET-based systems, which were widely adopted and optimized at the time for dual- emission sensing. Savariar in particular emphasizes the use of Cy5/Cy7 donor-acceptor pairs and highlights the spatial proximity-driven nature of their emission modulation. Applicant asserts that neither Liu nor Savariar suggests or hints at employing dyes that change their intrinsic fluorescence in response to chemical cleavage, nor do they discuss the design principles or advantages associated with chemically switchable dyes.
Applicant’s arguments have been fully considered but are not found to be persuasive. As set forth above, at least ZW800 meets the structure of the instantly claimed switchable fluorophore. With regard to the assertion that the references do not discuss the principles or advantages associated with chemically switchable dyes, see MPEP 2145. “The fact that appellant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious.” Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985) (The prior art taught combustion fluid analyzers which used labyrinth heaters to maintain the samples at a uniform temperature. Although appellant showed that an unexpectedly shorter response time was obtained when a labyrinth heater was employed, the Board held this advantage would flow naturally from following the suggestion of the prior art.). See also Lantech Inc.v. Kaufman Co. of Ohio Inc., 878 F.2d 1446, 12 USPQ2d 1076, 1077 (Fed. Cir. 1989), cert. denied, 493 U.S. 1058 (1990) (unpublished — not citable as precedent) (“The recitation of an additional advantage associated with doing what the prior art suggests does not lend patentability to an otherwise unpatentable invention.”).
Claim(s) 1, 4-7, 10, 11 and 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Bokan et al. (Dyes and Pigments, December 2018, 159, p. 18-27) in view of Shami et al. (WO 2017/019559).
Bokan teaches switchable phenolo-cyanine reporters containing reactive alkylcarboxylic groups for fluorescence-based targeted drug delivery monitoring.
Figure 1 shows the drug—reporter—carrier conjugate for TDD enabling the drug release monitoring.
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Newly synthesized, acetylated phenolo-cyanine 3a-Ac are taught. The acetyl trigger group at the phenolic oxygen in these dyes is utilized to simulate a cleavable drug moiety.
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We synthesized and evaluated several switchable phenolo-cyanine dyes potentially suitable for fluorescence-based TDD monitoring and compared their spectral properties. These dyes contain substituted terminal indolenine moieties and triggering group in the polymethine chain.
O-acetyl group in this dye can be replaced with a drug and the carboxylic groups can be utilized for binding to a targeting carrier such as a peptide or antibody. This dye therefore can be suggested as a switchable reporter for fluorescence-based monitoring of targeted drug delivery (page 26).
Bokan does not specifically teach a second (reference) fluorophore.
Shami teaches that optical imaging techniques, including fluorescence imaging and bioluminescence imaging, play an important role in preclinical research as advances in photonic technology and reporter strategies have led to widespread exploration of biological processes in vivo. One of the most recent technological evolutions has been the development of fluorescence tomography for visualization at the whole animal or tissue level. For example, fluorescence molecular tomography (FMT) technology not only can provide non-invasive, whole-body, deep-tissue imaging in small animal models, but also enable 3D quantitative determination of fluorochrome distribution in tissues of live animals. In this study, multiple imaging modalities can be integrated to explore the optimal schedule/dose of the combination targeting system, to monitor the therapeutic efficacy, and to develop high sensitivity Gaussia-lucierease (Gluc)-based bioluminescence imaging for MRD detection (paragraph 0154).
HPMA copolymer-drug conjugates are taught, including dual fluorophore labeling with AF647 for polymer backbone and Cy3B for side-chain drug (paragraph 0045).
Internalization and subcellular fate of the conjugates is taught. A dual-fluorophore labeled model conjugate FITC-P-Cy5 (FITC labeled HPMA copolymer containing Cy5 as a drug model) and super-resolution fluorescence imaging were used to evaluate internalization and drug release at the single cell level. A2780 cells were visualized under a 3D super-resolution Vutara SR-200 fluorescence microscope equipped with a FITC filter (wavelength 495/519 nm), a Cy5 filter (wavelength 650/670 nm), and a Red DND- 99 filter (wavelength 557/590 nm). Images were analyzed using the SRX software. The model conjugate was internalized by A2780 cancer cells via endocytosis, and most of the FITC signal (related to polymer) co-localized with lysosomes and late endosomes (Fig. 16). At 4 h, most of the FITC and Cy5 molecules were located at the margins of the cytoplasm and FITC-labeled HPMA copolymer molecules were surrounded by clusters of Cy5. This indicates that the conjugate was intact and localized in endosomes/lysosomes. At longer time intervals, an increasing amount of Cy5 molecules was found inside the cell, and the majority was located at a distance from the FITC-labeled HPMA copolymer. At 12 h, Cy5 molecules diffused all over the cell (Fig. 16). This shows that the side chains GFLG-Cy5 are cleaved by enzymes (cathepsin B) in the lysosomes, and the functional payload (i.e. Cy5 as drug model) is released and translocates into the cytoplasm (paragraph 00163).
To synthesize dual-fluorophore labeled polymer conjugates, APMA can be used as comonomer to introduce pendant amino group for backbone labeling. For drug fate monitoring, the cleavable GFLG spacer can be extended by azidohomoalanine (Fig. 19). This permits attachment of imaging probes. In the lysosomes, cathepsin B can cleave the bond between glycine and azidohomoalanine, releasing a stable labeled drug (paragraph 00166).
It would have been obvious to one of ordinary skill in the art at the time of the invention to incorporate a second fluorophore in conjugates comprising a drug, cleavage site, targeting ligand, and switchable fluorophore when the teaching of Bokan is taken in view of Shami. One would have been motivated to do so, with a reasonable expectation of success, because Shami teaches that dual fluorophore conjugates are suitable for use in fluorescence imaging of drug delivery, and provide the advantage of allowing for visualization of both cellular uptake / localization of the conjugate, as well as drug cleavage.
Conclusion
No claims are allowed at this time.
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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/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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