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 .
Response to Amendment
The amendment filed 04/27/2026 has been fully considered. Regarding the Office action mailed 01/28/2026, the rejection of claims 1-3, 8, 13, 16-18, 21, 26, 27, 37, 72 and 88 over Dudani is maintained and reiterated below. Applicant’s arguments will be addressed following the rejection.
The rejection is newly applied to claims 31 and 32 as necessitated by the amendment to those claims.
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 1, 2, 3, 8, 13, 16, 17, 18, 21, 26, 27, 37, 72 and 88 are rejected under 35 U.S.C. 103 as being unpatentable over Dudani (WO 2019/075292 A1, previously cited).
Dudani disclosed a nanosensor library comprised of peptide substrates, each peptide conjugated to FRET pair (FAM and CPQ2; claims 3, 8, 13) for detecting protease activity. See page 35, last paragraph and page 36, Table 6, first row, indicating the 58 peptide substrates and the general structure. See figure 3, illustrating how, when the peptide (which is 11 amino acids in this case; see also peptide substrates disclosed on page 3; claims 17 and 18) binds to a protease (which is a protein; claim 16), the peptide is cleaved and fluorescence of FAM is unquenched (i.e., FRET from the donor (FAM) to the acceptor (CPQ2) decreases or stops; claims 1 and 2). At page 37, Dudani notes: “For use in vivo, the peptides maybe conjugated to a nanoparticle having robust accumulation in the prostate abilities.” To that end, Dudani tested three such particles: a multivalent PEG and two iron oxide carriers, noting that “a multivalent PEG polymer accumulated more in the prostate, and less in spleen and liver. Thus, the peptide substrates were conjugated to a PEG core and their cleavage profile was tested.” As shown in Table 7 (pages 37-38), each peptide substrate was conjugated to its own PEG carrier (see also page 2, lines 3-6). Thus, for a given sensor, all of the TBMs of the sensor system bind to the same target (claim 21). The purpose of the library of sensors was for diagnosis and classification of prostate cancer (page 35). Thus, the protease targets of the peptides represent gene products indicative or predictive of cancer (claims 26 and 27).
Dudani disclosed the substrate could be attached to the scaffold (such as PEG) directly (e.g. via a peptide bond, which is a covalent bond; claim 37), though Dudani also contemplated non-covalent linkage (page 20, lines 25-32).
Figure 5 illustrates the in vivo study with the 40 kDa “Multiam [sic, Multi-arm] PEG” and the two differently-sized iron oxide particles. See also page 6, lines 6-9.
Dudani disclosed the multi-arm PEG could comprise from 2-20 arms (page 2, lines 23-29; paragraph spanning pages 11-12), and a particular example of 8 arms (figure 6).
Dudani disclosed administering the nanosensors to a subject, and obtaining a sample from the subject containing the detectable markers released by the prostate protease nanosensors (page 3, last paragraph). See also figure 1A, where nanosensors are injected into a subject (thus, “implanted”; claim 72). See also page 39, where an in vivo protease activity imaging study was performed using a red-shifted FRET pair, and see page 4, line 23 where Dudani disclosed the detection could be performed by “optical imaging” (which means the signal was detectable by an optical camera; claim 88).
The only reason this rejection is not being made under 35 USC 102(a)(1) is because, in the particular example discussed on page 37, or the in vivo study with the red-shifted FRET pair on page 39, Dudani did not explicitly state that the peptide substrates were conjugated to a three-arm, four-arm or 8-arm PEG.
However, it would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to use three-arm, four-arm or 8-arm PEG for conjugating the peptides, since these were within the range taught by Dudani. MPEP 2144.05: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.”
Claim(s) 31 and 32 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dudani (WO 2019/075292 A1, previously cited) as applied to claims 1, 2, 3, 8, 13, 16, 17, 18, 21, 26, 27, 37, 72 and 88 above, and further in view of Reineck (Adv. Optical Mater. 5:1600446 (2017)).
Regarding claims 31 and 32, Dudani disclosed a sensor specifically for use in vivo, with a fluorescent readout; see Table 6, T7-QF. It, too, is labeled with a donor (Cy5) and an acceptor (QSY21). This is a red-shifted FRET pair (see Table notes). The only way that a fluorescent readout could be used in vivo is where FRET was used to quench the signal from Cy5 until the protease, in vivo, cleaved the substrate. Dudani tested this in vivo use; see Figure 18 which shows this peptide substrate attached to the 8 termini of an 8-arm PEG, and see page 32, lines 4-5, and page 39, lines 9-11: “An in vivo protease activity imaging study was also performed using a red-shifted FRET paired T7 substrate, which showed greater fluorescence signal in the tumor compared with the liver (Table 6).”
Dudani did not elaborate on the imaging equipment, or the conversion of RET signal into an electrical signal using a photodetector.
Reineck discussed bioimaging in the near infrared (NIR) ranges, specifically NIR1 from 650-950 nm, and NIR2 from 1000-1350 nm, stating: “In these spectral regions light can penetrate significantly deeper into biological matter” (page 2, first full paragraph). Cy5 (used in Dudani’s in vivo sensor peptide) absorbs and emits in the NIR1 range. Reineck taught that in this spectral region, “light is usually detected using photomultiplier tubes (PMTs), silicon-based photo detectors such as charge-coupled device (CCD) or an avalanche photodiode (APD) or complementary metal-oxide-semiconductor (CMOS) detectors” (page 15, section 5.1). All of these are “photodetectors” that convert light into an electrical signal.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the application to use one of these types of detectors when performing the in vivo imaging using Dudani’s T7-QF peptide coupled to an 8-arm PEG, as these types of detectors were known in the art for bioimaging applications involving NIR fluorophores. This represents nothing more than selecting an art-recognized material based on its suitability for its intended purpose (MPEP 2144.07).
Response to Arguments
Applicant's arguments filed 04/27/2026 have been fully considered but they are not persuasive.
Applicant argues:
“Dudani discloses a prostate protease nanosensor comprising a scaffold linked to a prostate-specific substrate including a detectable marker. Dudani emphasizes a mechanism wherein the detectable marker is cleaved and released from the nanosensor when exposed to a protease in the prostate, and is excreted into urine for subsequent detection. Detection of the released detectable marker in the urine noninvasively indicates the presence of the protease in the prostate…Therefore, Dudani does not disclose or suggest a system wherein a detectable signal is produced from a scaffold-substrate conjugate. Rather, a signal is produced from the detectable marker that has been cleaved and released from the scaffold. This cleavage-based nanosensor of Dudani is clearly distinct from the sensor system recited in claim 1, which produces a detectable signal from the labeled TMB -PEG conjugate.”
This argument is not persuasive for the following reasons. The claims are directed to a biomaterial, that is, to a composition of matter or article of manufacture. The limitation “wherein when the TBM linked to the donor and the TBM linked to the acceptor molecule binds to a target, a resonance energy transfer (RET) from the donor to the acceptor molecule (i) occurs or (ii) decreases or stops occurring and a detectable signal is produced from the labeled TBM-PEG conjugate” is a capability that the biomaterial must possess. In the case of Dudani’s suggested peptide substrate conjugates1, this capability is present. That is, if one were to incubate Dudani’s conjugate in the presence of a protease target while monitoring FRET between the donor (FAM) and the acceptor (CPQ2) (see, e.g., figure 3), one could monitor the elimination or reduction in FRET (RET) upon binding of the protease to the peptide substrate, which is cleaved by the protease, thereby allowing the donor (FAM) to move away from the acceptor (CPQ2) (or in the case of the probe T7-QF, allowing the separation of QSY21 and Cy5). The fact that Dudani, instead, collected the cleaved donor in the urine and measured fluorescence of the donor (in the absence of the acceptor/PEG conjugate) in the experiment described on page 37 is irrelevant. All that matters is whether one could use the claimed biomaterial in the way recited in the claim, which, as discussed above, one could do.
Applicant argues:
“Moreover, Dudani does not provide any guidance or motivation for the skilled artisan to use a FRET pair as a detectable marker, as used in the sensor system of claim 1. At best, Dudani vaguely discloses that the detectable marker may be a FRET pair amongst a list of other potential detectable markers including a peptide, nucleic acid, small molecule, fluorophore, carbohydrate, particle, radiolabel, MRI-active compound, ligand encoded reporter, or isotope coded reporter molecule (iCORE). See page 3, lines 23-26. However, Dudani does not motivate the skilled artisan to use a FRET pair in lieu of the other potential detectable markers described.”
The Examiner agrees that Dudani discloses FRET as a means of detection. And, more importantly, discloses FRET-pair labeled peptide substrates (i.e., those described in the first line of Table 6, as well as T7-QF in line 4 of the table, and the examples on pages 37 and 39).
Applicant argues:
“Indeed, Dudani does not describe how a FRET pair would even function in the nanosensor to enable detection of a prostate protease. Rather, such a FRET pair appears to be incompatible with the nanosensor mechanism described in Dudani. The nanosensor of Dudani depends on enzymatic cleavage to physically separate the detectable marker from the scaffold, allowing the detectable marker to be excreted in urine for subsequent remote detection, whereas FRET depends on molecular proximity, e.g. the donor must be in sufficient proximity to the acceptor for FRET to occur.”
This argument is not persuasive for the reasons already discussed. That is, the peptide substrate/PEG conjugate of Dudani is capable of being monitored for FRET, which FRET would be eliminated or reduced if incubated with the appropriate protease. This could be done in a cuvette in a standard spectrophotometer, where a sample containing the protease is added. The fact that Dudani did not do this is irrelevant. It could be done using the peptide/PEG conjugates Dudani disclosed. That these conjugates are capable of FRET is clearly shown in Figure 3.
Applicant argues:
“Furthermore, Dudani does not generate any nanosensor comprising a PEG scaffold conjugated to a donor linked to a target binding moiety and an acceptor molecule linked to a target binding moiety. Rather, Dudani employs FRET as a preliminary screening approach to identify peptide substates that are cleaved by select proteases and are thus suitable for inclusion in the nanosensor. Phrased alternatively, Dudani uses FRET as a screening tool and does not employ a FRET pair as a detectable marker in the subsequently developed nanosensor. Indeed, Dudani was clearly aware of FRET and was developing a nanosensor for noninvasive target detection and failed to produce any nanosensor comprising a PEG scaffold conjugated to a FRET pair.”
Dudani disclosed a sensor specifically for use in vivo, with a fluorescent readout; see Table 6, T7-QF. It, too, is labeled with a donor (Cy5) and an acceptor (QSY21). This is a red-shifted FRET pair (see Table notes). The only way that a fluorescent readout could be used in vivo is where FRET was used to quench the signal from Cy5 until the protease, in vivo, cleaved the peptide substrate. Dudani also indicated that “[f]or use in vivo, the peptides may be conjugated to a nanoparticle having robust accumulation in the prostate abilities” (page 37, first sentence). This led Dudani to test different carriers, and he found that “a multivalent PEG polymer accumulated more in the prostate, and less in spleen and liver” (page 37, first paragraph). Applicant’s contention that Dudani only considered FRET in the context of a “screening tool” is not persuasive, given these details. Dudani noted that “40 kDa PEG had significantly greater accumulation in the prostate”, referring to Figure 5, which refers to this as a “multiam” (sic, “multi-arm”) PEG (see also page 6, lines 6-9). Figure 6 shows a 40 kDa PEG in the form of an 8-arm, maleimide-terminated PEG. It would therefore have been obvious to use that 8-arm PEG for conjugating the FRET-pair labeled substrates for use in vivo. See also Figure 18, which illustrates an in vivo FRET detection.
Therefore, Applicant’s arguments are not found persuasive.
Conclusion
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMUEL C WOOLWINE whose telephone number is (571)272-1144. The examiner can normally be reached 9am-5:30pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, GARY BENZION can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SAMUEL C WOOLWINE/Primary Examiner, Art Unit 1681
1 That is, the peptide substrates discussed in the example on page 37, page 39 and shown in Table 6, conjugated to an 8-arm PEG.
Prosecution Insights