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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/09/2026 has been entered.
Remarks
The prior art rejections of claims 1-6, 8, 10, 12-13, 16-17 and 19-20 are withdrawn and claims 1-6, 8, 10, 12-13, 16-17, 19-20, 34, and 35 are allowed in view of the Hales Declaration and applicant’s arguments filed 07/09/2026.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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.
1. Claims 21, 22, 24, 30 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Lo et al. in view of Kelleher et al.
Lo et al. discloses devices and methods for differentiating proteins by frequency domain fluorescence lifetime spectroscopy that provides for quantifying the concentration of a protein of interest or the concentration of a conformational state of the protein of interest, in a mixture ([0012], [0054]), wherein the protein of interest or conformational state has an intrinsic fluorescence decay signature ([0042])
The apparatus of Lo et al. includes a modulated light source, a focusing optical fiber, a detecting optical fiber, and a detector. (Abstract). Lo et al. discloses a laser light source. [0006]
The method of Lo et al. includes directing light from a modulated laser light source onto a mixture of proteins, wherein the light has a wavelength of about 300 nm ([0048]), and taking a series of measurements of the fluorescence intensity of the mixture at a series of time points; wherein the phase shift between the modulated light source and the modulated fluorescent light is recorded and wherein decay times which differ from each other by less than a nanosecond up to 10 ns are deducible from the phase shift measurements ([0062], [0065]-[0073], [0084], [0086]), and quantifying the concentration of the protein of interest or of the conformational state of the protein of interest in the sample by reference to the fluorescence decay model (curve fit) ([0066]).
Lo et al. teaches photodetector temporal response (trigger system), as well as signal digitization and recording speed.
Lo et al. teaches excitation light in a wavelength of 300 nm and above, but does not teach using excitation light in a wavelength of 240-295 nm.
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to conduct routine engineering optimization experimentation to determine excitation wavelengths to use for different proteins including wavelengths of 240 to 290 nm.
In paragraph [0042] Lo et al. also discusses how the time domain method provides significant information over shorter pulses.
As for the mixture being introduced into a flow cell wherein the mixture is exposed to one or more pulses of light, Kelleher et al. using fluorescent excitation pulses that are less than a nanosecond (480 picoseconds) to excite particles to be analyzed using decay times of the emission. (page 18, second paragraph and Figs. 15(a) and 15 (b)).
Kelleher et al. further teaches that detection can be accomplished using flow cytometry which renders it obvious to use a flow cell to differentiate proteins in a mixture that is passed through a flow cell and irritated with fluorescent radiation.
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to modify Lo et al. in view of Kelleher et al. to differentiate proteins in mixtures via a flow cells, based on Kelleher et al. teaching flow cytometry for such analysis.
I.) As noted above, Lo et al. in view of Kelleher et al. renders obvious all of the element of claim 21.
Therefore, Lo et al. in view of Kelleher et al. renders claim 21 obvious.
II.) Regarding applicant’s claim 22, as noted above Lo et al. in view of Kelleher et al. renders claim 21 obvious from which claim 22 depends.
Claim 22 recites that the light source is a single light emitting diode, an array of light emitting diodes, and/or a laser; optionally wherein the laser is a diode pumped Q-switched solid state laser.
As noted above, Lo et al. teaches a laser light source.
Therefore, Lo et al. in view of Kelleher et al. renders claim 22 obvious.
III.) Regarding applicant’s claim 24, as noted above Lo et al. in view of Kelleher et al. renders claim 21 obvious from which claim 24 depends.
Claim 24 recites that the fluorescent emission is reflected towards the one or more detectors by an optionally ellipsoidal reflector or a lens; optionally wherein the fluorescent emission is reflected towards the one or more detectors via a filter assembly optionally comprising a long-pass optical filter.
Lo et al. teaches lens 160 that focuses fluorescent emission toward detector 130.
Therefore, Lo et al. in view of Kelleher et al. renders claim 24 obvious.
IV) Regarding applicant’s claim 30, as noted above Lo et al. in view of Kelleher et al. renders claim 21 obvious from which claim 30 depends.
Claim 30 recites that the one or more detectors are one or more photodiodes with a sub-nanosecond rise time; optionally wherein the one or more ultra-fast photodiodes is connected to a high bandwidth transimpedance amplifier.
Lo et al. teaches photodiode components. [0041]
Therefore, Lo et al. in view of Kelleher et al. renders claim 30 obvious.
V.) Regarding applicant’s claim 36, as noted above Lo et al. in view of Kelleher et al. renders claim 21 obvious from which claim 36 depends.
Claim 36 recites that the light source is capable of addressing the mixture with pulses of light at a wavelength in the range 250-280 nm, optionally at a wavelength of 266 nm.
Lo et al, in view of Kelleher et al. does not teach that the light source is capable of addressing the mixture with pulses of light at a wavelength in the range 250-280 nm, optionally at a wavelength of 266 nm.
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to conduct routine engineering optimization experimentation to determine excitation wavelengths to use for different proteins including wavelengths in the range 250-280 nm, optionally at a wavelength of 266 nm.
Therefore, Lo et al. in view of Kelleher et al. renders claim 36 obvious.
2. Claim 28 is rejected under 35 U.S.C. 103 as being unpatentable over Lo et al. as applied to claim 21 above, and further in view of U.S. Patent Application Publication No. 2017/0290515 to Butte et al.
I.) Regarding applicant’s claim 28, as noted above Lo et al. renders claim 21 obvious from which claim 28 depends.
Claim 28 recites a beam splitter configured to split the emitted pulses of laser light into first and second portions, where the first portion is directed to a photodiode and the second portion is directed towards the protein of interest in the mixture of proteins, optionally wherein the trigger system is triggered by a signal from the photodiode.
Lo et al. does not teach a beam splitter configured to split the emitted pulses of laser light into first and second portions, where the first portion is directed to a photodiode and the second portion is directed towards the protein of interest in the mixture of proteins, optionally wherein the trigger system is triggered by a signal from the photodiode.
Butte et al. teaches a beam splitter that directs a portion of excitation light pulses to a photodiode that may be used to time delayed fluorescence signals. [0131]
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to modify Lo et al. to include a beam splitter configured to split the emitted pulses of laser light into first and second portions, where the first portion is directed to a photodiode as taught by Butte et al. and the second portion is directed towards the protein of interest in the mixture of proteins for purposes of using the photodiode to detect time-delayed fluorescence signals as taught by Butte et al.
3. Claim 32 is rejected under 35 U.S.C. 103 as being unpatentable over Lo et al. as applied to claim 21 above, and further in view of Applicant’s Admitted Prior Art.
I.) Regarding applicant’s claim 32, as noted above Lo et al. renders claim 21 obvious from which claim 32 depends.
Claim 32 recites a chromatography assembly, wherein said apparatus is assembled such that the mixture that is addressed by the light is eluate in an elution capillary of the chromatography assembly, optionally wherein the elution capillary is a straight capillary.
Lo et al. does not teach a chromatography column.
As noted above, in the Background section of the disclosure applicant notes that chromatography is commonly used is protein separation for bioprocessing. On page 2, lines 1-2 applicant nots that “In a typical industrial bioprocess, chromatography is the key step for purifying the product from other proteins, cellular debris and components of the media.”
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to modify Lo et al. in view of Kelleher et al. to receive and quantify proteins from the eluate of a chromatography column as taught by Applicant’s Admitted Prior Art for purposes of bioprocessing and perform the quantifying of the proteins in the elute leaving the chromatography column. Providing an elution capillary from the chromatography would have been an obvious matter of size since such a size would be capable of the desired function.
Response to Arguments
Applicant's arguments filed 07/09/2026 have been fully considered but they are not persuasive.
Applicant argues that: “modification of Lo et al. from a frequency domain fluorescence intensity detection to a time-domain fluorescence intensity detection simply would not be considered practical. It would further increase costs and could even damage Lo's detection apparatus. (See Declaration of John Hales, paragraphs 22, 26.)”
Lo et al. notes that laser fluorescence and microscopy instrumentation is prohibitively costly and complicated for widespread biomedical application.
This teaching of Lo et al. suggests that laser fluorescence and microscopy instrumentation is possible, so that one not concerned with costs could practice laser fluorescence and microscopy instrumentation as taught by Lo.
Applicant argues that “modifying the Lo et al. reference from a frequency domain fluorescence intensity detection to a time-domain fluorescence intensity detection would both render Lo et al. unsatisfactory for its intended purpose and change the principal operation of the Lo et al. reference.”
As noted above, in paragraph [0042] Lo et al. also discusses how the time domain method provides significant information over shorter pulses.
The Hales Declaration notes that:
“Based on my understanding, Lo et al. is directed to frequency-domain fluorescence lifetime spectroscopy, rather than the pulsed time-domain scheme recited in the claims of this application, as a cost-effective alternative for monitoring solid biological tissues.”
In paragraph [0042] Lo et al. teaches:
“This time domain method has been demonstrated with sub-nanosecond pulsed lasers and fast photomultiplier tube (PMT) detectors to reconstruct collagen fluorescence impulse response decays, with associated lifetime constants. While the time domain method provides significant information over shorter pulses, the cost of the pulsed lasers, triggering electronics, and PMT detectors, in addition to the complexity of the system, prevent its wider use in biomedical applications.”
Thus Lo et al. teaches a pulsed time-domain scheme, howbeit at a cost that one could accept. The cost does not prohibit a pulsed time-domain scheme.
The Hales Declaration notes that: The excitation and emission wavelengths used by Lo do not match those required for measuring intrinsic fluorescence of proteins in the method of the invention.
Lo et al. teaches that the LED can emit light with a wavelength from about 300 nm to about 750 nm, which is near 290 nm recited in claim 21.
Lo et al. teaches detecting proteins. [0054].
It would have been obvious to one of ordinary skill in the art before applicant’s effective filing date to conduct routine engineering optimization experimentation to determine excitation wavelengths to use for different proteins including wavelengths of 240 to 290 nm.
The Hales Declaration notes that:
“Lo et al. states that the limit of detection of their method to be 25 µg collagen (Lo et al., paragraph [0084]). Even if it were possible to translate the Lo et al. method to the same application of the present invention, this limit would pose significant issues.”
Claims 21, 22, 24, 28, 30, 32 and 36 are apparatus claims that are not limited by the type or amount of protein to be detected.
Applicant’s arguments regarding Kelleher et al. are not persuasive since Kelleher et al. has been relied upon as using fluorescent excitation pulses that are less than a nanosecond (480 picoseconds) to excite particles to be analyzed using decay times of the emission and the use of flow cytometry which renders it obvious, in modifying Lo et al. to use a flow cell to differentiate proteins in a mixture that is passed through a flow cell and irritated with fluorescent radiation.
Allowable Subject Matter
Claims 1-6, 8, 10, 12-13, 16-17, 19-20, 34, and 35 are allowed.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
U.S. Patent Application Publication No. 2014/0039156 to Lasmezas et al. teaches fluorescent assaying using a cuvette, multiwell plate, tube, flask, disk, beads, vial, cassette, flow cell, cartridge, microfluidic chip or combinations thereof. [0104]
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/MICHAEL STANLEY GZYBOWSKI/Examiner, Art Unit 1798
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