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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 22 December 2025 has been entered.
Claim Interpretation
MPEP § 2111.01 states that “… Under a broadest reasonable interpretation (BRI), words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. The plain meaning of a term means the ordinary and customary meaning given to the term by those of ordinary skill in the art at the relevant time. The ordinary and customary meaning of a term may be evidenced by a variety of sources, including the words of the claims themselves, the specification, drawings, and prior art. However, the best source for determining the meaning of a claim term is the specification - the greatest clarity is obtained when the specification serves as a glossary for the claim terms …”. Thus under a broadest reasonable interpretation, the greatest clarity is obtained when the specification (e.g., see “… single microscope system and/or plurality of microscope systems may be matched (e.g., balanced) … balancing refers to adjusting operational settings of a fluorescence microscope, such as emission source intensity, in order to achieve reproducible fluorescence assays on a single microscope system over time and/or between a plurality of microscope systems …” in paragraphs 2 and 17) serves as a glossary (MPEP § 2111.01) for the claim term “balancing”.
Claim Objections
Claim(s) 9 is/are objected to because of the following informalities: “the first pixel area” on line 22 in claim 9 should probably be --the pixel area--. Appropriate correction is required.
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 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 of this title, 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.
Claim(s) 1-8 is/are rejected under 35 U.S.C. 103 as being unpatentable over Earney et al. (US 2021/0055224) in view of Haberstroh et al. (US 2011/0076687), Engelhardt (US 2012/0322267), and Boese (US 2014/0134711).
In regard to claim 1, Earney et al. disclose a photostable fluorescence balancing target, comprising:
(a) a holder (e.g., “… body 102 … central pocket 114 is configured to receive the optical target 120. The optical target 120 may be secured within the pocket 114 in various manners, such as with an adhesive … channels 116 receive an adhesive that bonds to the glass layer and the body 102, thereby covering and hermetically sealing the optical target 120 from the external environment … adhesive may be silicone which is highly stable in alcohol, whereas UV cure adhesive tend to break down in alcohol. The silicone is injected until the channels 116 arc filled …” in paragraphs 59 and 66);
(b) an inorganic crystalline fluorophore affixed to the holder, wherein the inorganic crystalline fluorophore affixed to the holder via a silicone adhesive (e.g., “… optical target 120 represents a solid body structure that includes a solid host material and a fluorescing material embedded within the solid host material … solid host material may include at least one of … crystalline materials … fluorescing material may be a rare-earth element such as rare earth ions: Tm3+ (455 nm), Ho3+ (550 nm), Tb3+ (540 nm), Eu3+ (611 nm), Sm3+ (550 nm), Pr3+ (488, 590 nm), Dy3+ (480 nm & 575 nm), or Er3+ (550 nm & 660 nm); an element from the Actinide series: U; transition metal ions: Ti3+, Cr2+/3+ etc. … fluorescing material emits in one or more emission channels of interest …” in paragraphs 52-54); and
(c) a fiducial marker positioned on the inorganic crystalline fluorophore (e.g., “… may be combined … grating layer 122 may have different regions to be used in connection with different types of alignment operations and/or calibration tests. For example, as discussed below in connection with FIG. 2D, grating layer 122 may include one or more … fiducials … grating structure may be patterned directly on the solid fluorescing substrate (e.g., see FIG. 2E) to form a monolithic structure …” in paragraphs 25 and 75),
wherein the fiducial marker is patterned directly on the inorganic crystalline fluorophore (e.g., “… instrument moves the objective to the auto centering fiducial and performs an XY stage position repeatability test. The instrument moves the X and Y stage multiple times from each direction to the auto centering fiducial and after each move it takes an image of the auto centering fiducial. Ideally, the auto centering fiducial would show up at exactly the same position in the image after every move … inspection apparatus can control the measured fluorescence to a desired tolerance (e.g., +/-0.6% in red and +/-0.1% in green). Measuring intensity of the inspection apparatus at a certain scan speed and laser power on one instrument will provide measurement information indicative of an intensity to expect on substantially all similar instruments. The fluorescent intensity measurement from the inspection apparatus can be utilized to indicate whether the instrument is behaving properly (e.g., providing proper laser power delivered to the flow cell, proper amount of fluorescent light collected and delivered to the camera, etc.). Given that the emission characteristics of the inspection apparatus will not change over time, any change in measured fluorescent intensity over the life of the instrument will indicate that either the proper laser power is not being delivered to the flow cell or not all the fluorescent light is being delivered to the camera …” in paragraphs 159 and 161).
The target of Earney et al. lacks an explicit description of details of the “… solid host material …” such as the inorganic crystalline fluorophore comprising a natural or synthetic gemstone, an explicit description of details of the “… patterned directly on the solid fluorescing substrate …” such as etched, and an explicit description of details of the “… adhesive may be silicone …” such as non-fluorescent transparent properties. However, “… solid host material …” details are known to one of ordinary skill in the art (e.g., see “… commercially available: diamond, silicon carbide (moissanite), ruby, sapphire, zircon, beryl, emerald, opal, quartz, jade, topaz, turquoise, lapis lazuli, chrysoberyl, amber, spine!, tourmaline, tanzanite, zincblende, wurtzite, and others …” in paragraph 36 of Haberstroh et al., “… patterned directly …” details are known to one of ordinary skill in the art (e.g., see “… methods for patterning wide band gap material substrates such as silicon carbide (SiC) substrates, aluminum oxide (Al2O3) substrates (e.g. sapphire substrates or ruby substrates), diamond substrates, wide band gap III-V semiconductor substrates, wide band gap II-VI semiconductor substrates, etc., by means of plasma etching may be provided. Patterning the substrate may, for example, include forming structures such as e.g. trenches, grooves, holes, vias, etc. in the substrate …” in paragraph 176 of Engelhardt), and “… adhesive …” details are known to one of ordinary skill in the art (e.g., see “… a non-fluorescent, transparent adhesive, preferably a silicone adhesive, particularly Sylguard 184 …” in paragraph 77 of Boese). It should be noted that “when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable results”. KSR International Co. v. Teleflex Inc., 550 U.S. 398 at 416, 82 USPQ2d 1385 (2007) at 1395 (citing United States v. Adams, 383 U.S. 39, 40 [148 USPQ 479] (1966)). See MPEP § 2143. In this case, one of ordinary skill in the art could have substituted a known conventional solid host material (e.g., comprising details such as “commercially available” “ruby”) for the unspecified solid host material of Earney et al., substituted a known conventional commercially available silicone adhesive (e.g., comprising details such as a “Sylguard 184” having “non-fluorescent, transparent adhesive” properties) for the unspecified silicone adhesive of Earney et al., and substituted a known conventional patterning technique (e.g., comprising details such as “plasma etching” in order to achieve “structures such as e.g. trenches, grooves, holes, vias, etc. in” “aluminum oxide (Al2O3) substrates (e.g. sapphire substrates or ruby substrates), diamond substrates”) for the unspecified patterning technique of Earney et al., and the results of the substitutions would have been predictable. Therefore it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention that silicone adhesive have properties (e.g., non-fluorescent and transparent) and to provide a known conventional patterned solid host material (e.g., comprising details such as the inorganic crystalline fluorophore comprising a natural or synthetic gemstone affixed to the holder via a non-fluorescent transparent adhesive, wherein the fiducial marker is etched on the inorganic crystalline fluorophore) as the unspecified patterned solid host material of Earney et al.
In regard to claim 2 which is dependent on claim 1, Earney et al. also disclose that the photostable fluorescence balancing target is usable to balance each wavelength channel of a multi-detector microscopy system (e.g., “… inspection apparatus 100 may be utilized in connection with calibration of standard consumer optical tools such as fluorescence microscopes … fluorescing material emits in one or more emission channels of interest …” in paragraphs 48 and 54).
In regard to claim 3 which is dependent on claim 1, Earney et al. also disclose that a length, a width, and a depth of the holder are based on a sample holder of a microscope system (e.g., “… inspection apparatus 100 may be utilized in connection with calibration of standard consumer optical tools such as fluorescence microscopes …” in paragraph 48).
In regard to claim 4 which is dependent on claim 1, Earney et al. also disclose that the inorganic crystalline fluorophore includes a transition metal dopant (e.g., “… optical target 120 represents a solid body structure that includes a solid host material and a fluorescing material embedded within the solid host material … solid host material may include at least one of … crystalline materials … fluorescing material may be a rare-earth element such as rare earth ions: Tm3+ (455 nm), Ho3+ (550 nm), Tb3+ (540 nm), Eu3+ (611 nm), Sm3+ (550 nm), Pr3+ (488, 590 nm), Dy3+ (480 nm & 575 nm), or Er3+ (550 nm & 660 nm); an element from the Actinide series: U; transition metal ions: Ti3+, Cr2+/3+ etc. … fluorescing material emits in one or more emission channels of interest …” in paragraphs 52-54).
In regard to claim 5 which is dependent on claim 1, Earney et al. also disclose that the inorganic crystalline fluorophore is doped with chromium (e.g., “… optical target 120 represents a solid body structure that includes a solid host material and a fluorescing material embedded within the solid host material … solid host material may include at least one of … crystalline materials … fluorescing material may be a rare-earth element such as rare earth ions: Tm3+ (455 nm), Ho3+ (550 nm), Tb3+ (540 nm), Eu3+ (611 nm), Sm3+ (550 nm), Pr3+ (488, 590 nm), Dy3+ (480 nm & 575 nm), or Er3+ (550 nm & 660 nm); an element from the Actinide series: U; transition metal ions: Ti3+, Cr2+/3+ etc. … fluorescing material emits in one or more emission channels of interest …” in paragraphs 52-54).
In regard to claim 6 which is dependent on claim 1, the target of Earney et al. lacks an explicit description of details of the “… solid host material …” such as the inorganic crystalline fluorophore is ruby. However, “… solid host material …” details are known to one of ordinary skill in the art (e.g., see “… commercially available: diamond, silicon carbide (moissanite), ruby, sapphire, zircon, beryl, emerald, opal, quartz, jade, topaz, turquoise, lapis lazuli, chrysoberyl, amber, spine!, tourmaline, tanzanite, zincblende, wurtzite, and others …” in paragraph 36 of Haberstroh et al.). It should be noted that “when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable results”. KSR International Co. v. Teleflex Inc., 550 U.S. 398 at 416, 82 USPQ2d 1385 (2007) at 1395 (citing United States v. Adams, 383 U.S. 39, 40 [148 USPQ 479] (1966)). See MPEP § 2143. In this case, one of ordinary skill in the art could have substituted a known conventional solid host material (e.g., comprising details such as “commercially available” “ruby”) for the unspecified solid host material of Earney et al. and the results of the substitution would have been predictable. Therefore it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to provide a known conventional solid host material (e.g., comprising details such as the inorganic crystalline fluorophore is ruby) as the unspecified solid host material of Earney et al.
In regard to claim 7 which is dependent on claim 1, Earney et al. also disclose that the inorganic crystalline fluorophore absorbs and emits multiple wavelengths of visible light (e.g., “… optical target 120 represents a solid body structure that includes a solid host material and a fluorescing material embedded within the solid host material … solid host material may include at least one of … crystalline materials … fluorescing material may be a rare-earth element such as rare earth ions: Tm3+ (455 nm), Ho3+ (550 nm), Tb3+ (540 nm), Eu3+ (611 nm), Sm3+ (550 nm), Pr3+ (488, 590 nm), Dy3+ (480 nm & 575 nm), or Er3+ (550 nm & 660 nm); an element from the Actinide series: U; transition metal ions: Ti3+, Cr2+/3+ etc. … fluorescing material emits in one or more emission channels of interest …” in paragraphs 52-54).
In regard to claim 8 which is dependent on claim 1, Earney et al. also disclose that the fiducial marker is one of a plurality of fiducial markers positioned on the inorganic crystalline fluorophore for redundancy (e.g., “… instrument moves the objective to the auto centering fiducial and performs an XY stage position repeatability test. The instrument moves the X and Y stage multiple times from each direction to the auto centering fiducial and after each move it takes an image of the auto centering fiducial. Ideally, the auto centering fiducial would show up at exactly the same position in the image after every move …” in paragraph 159), and the plurality of fiducial markers are labeled (e.g., see 280 and 282 in Fig. 2D). Alternatively it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention that one of the pictorial labels 280 and 282 in Fig. 2D of Earney et al. is selected to be “the auto centering fiducial”.
Claim(s) 9, 12, and 13 is/are rejected under 35 U.S.C. 103 as being unpatentable over Misener et al. (US 2006/0109475) in view of Thorburn (US 2012/0013726) and Earney et al. (US 2021/0055224).
In regard to claims 9 and 13, Misener et al. disclose a method comprising:
(a) positioning a fluorescence balancing target on a sample holder of a microscope system having a plurality of wavelength channels (e.g., “… In accordance with one form of the present invention … LEDs that emit light of different wavelengths … In this invention, when applied to a source for … microscopy … Calibration Method It is desirable to calibrate the LED or other source intensities in a way that is either non-iterative or rapidly converging, and fully automatic … parameters such as detected radiant intensity, source wavelength and bandwidth, etc., the preferred calibration method includes … 1. Placing a standard or reference material …” in paragraphs 45, 49, 109, 110, 114, and 115);
(b) imaging the fluorescence balancing target in the first wavelength channel of the plurality of wavelength channels of the microscope system, the imaging in the first wavelength channel including acquiring a first image’s pixel signals collected using a first time (e.g., “… digital camera … 2. Turning on a single source … signal from a single pixel. the average of signals from a number of adjacent pixels, etc.). and comparing these values lo the modeled intensities from the same areas …” in paragraphs 113 and 120 and the first time can also be labeled a first exposure time);
(c) defining a pixel area of the first image relative to area positioned on the fluorescence balancing target (e.g., “… 2. Turning on a single source … signal from a single pixel. the average of signals from a number of adjacent pixels, etc.). and comparing these values lo the modeled intensities from the same areas …” in paragraph 120);
(d) in response to a pixel average of the pixel area not being within an allowable range of a pixel average threshold, adjusting an excitation intensity of the first wavelength channel and re-imaging the fluorescence balancing target in the first wavelength channel (e.g., “… 3. Adjusting the source's intensity and again measuring the … fluoresced intensity from each physical area of the object repeatedly until the scaled intensities best match … Stated another way … comparing the measured first signal with a first predetermined signal target value; adjusting the intensity of the first light source to be substantially equal to the first predetermined signal target value …” in paragraphs 123 and 130); and
(e) in response to the pixel average of the pixel area being within the allowable range of the pixel average threshold, imaging the fluorescence balancing target in the second wavelength channel to acquire a second image’s pixel signals collected using a second time (e.g., “… 3. Adjusting the source's intensity and again measuring the … fluoresced intensity from each physical area of the object repeatedly until the scaled intensities best match … 4. Turning off the source, and repeating Steps 2 and 3 for all sources … Stated another way … comparing the measured first signal with a first predetermined signal target value; adjusting the intensity of the first light source to be substantially equal to the first predetermined signal target value … In many cases, it will be advantageous to illuminate a slide or flow matrix sequentially, with more than one wavelength per slide …” in paragraphs 123, 124, 130, and 142 and the second time can also be labeled a second exposure time);
(f) imaging the fluorescence balancing target in a third wavelength channel to acquire a third image’s pixel signals collected using a third time (e.g., “… 3. Adjusting the source's intensity and again measuring the … fluoresced intensity from each physical area of the object repeatedly until the scaled intensities best match … 4. Turning off the source, and repeating Steps 2 and 3 for all sources … Stated another way … comparing the measured first signal with a first predetermined signal target value; adjusting the intensity of the first light source to be substantially equal to the first predetermined signal target value … In many cases, it will be advantageous to illuminate a slide or flow matrix sequentially, with more than one wavelength per slide …” in paragraphs 123, 124, 130, and 142 and the third time can also be labeled a third exposure time); and
(g) imaging the fluorescence balancing target in a fourth wavelength channel to acquire a fourth image’s pixel signals collected using a fourth time (e.g., “… 3. Adjusting the source's intensity and again measuring the … fluoresced intensity from each physical area of the object repeatedly until the scaled intensities best match … 4. Turning off the source, and repeating Steps 2 and 3 for all sources … Stated another way … comparing the measured first signal with a first predetermined signal target value; adjusting the intensity of the first light source to be substantially equal to the first predetermined signal target value … In many cases, it will be advantageous to illuminate a slide or flow matrix sequentially, with more than one wavelength per slide …” in paragraphs 123, 124, 130, and 142 and the fourth time can also be labeled a fourth exposure time).
The method of Misener et al. lacks an explicit description of details of the “… calibrate the LED or other source intensities …” (paragraph 110) such as the first, second, third, and fourth exposure times are set based on an inorganic crystalline fluorophore identity included in the fluorescence balancing target and details of the “… same areas …” such as a fiducial marker positioned on the fluorescence balancing target. However, “… calibrate the LED …” details are known to one of ordinary skill in the art (e.g., see “… microscope illumination system 100 … calibrated pure white color temperature where the proportion of red to green to blue light is the same … acquisition software instructs illumination system 100 to output light using the red LED, then the green LED, and last the blue LED. With each output, the software calculates and stores the exposure time for the particular channel … acquisition software instructs illumination system 100 to output light using the red LED, then the green LED, and last the blue LED. With each output, the software uses the stored exposure time for the particular color to acquire, "pseudo color" and store the image …” in paragraphs 12, 19, 26, and 27 of Thorburn) and “… same areas …” details are known to one of ordinary skill in the art (e.g., see “… may be combined … grating layer 122 may have different regions to be used in connection with different types of alignment operations and/or calibration tests. For example, as discussed below in connection with FIG. 2D, grating layer 122 may include one or more … fiducials … grating structure may be patterned directly on the solid fluorescing substrate (e.g., see FIG. 2E) to form a monolithic structure …” in paragraphs 25 and 75 of Earney et al.). It should be noted that “when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable results”. KSR International Co. v. Teleflex Inc., 550 U.S. 398 at 416, 82 USPQ2d 1385 (2007) at 1395 (citing United States v. Adams, 383 U.S. 39, 40 [148 USPQ 479] (1966)). See MPEP § 2143. In this case, one of ordinary skill in the art could have substituted a known conventional pixel acquisition for calibration on same area (e.g., comprising details such as a “monolithic” “solid fluorescing substrate” including “fiducials” for calibration with “acquisition software instructs illumination system 100 to output light using the red LED, then the green LED, and last the blue LED. With each output, the software calculates and stores the exposure time for the particular channel”, in order to achieve “calibrated pure white color temperature where the proportion of red to green to blue light is the same”) for the same area calibration and the results of the substitution would have been predictable. Therefore it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to provide a known conventional calibration (e.g., comprising details such as the fluorescence balancing target including an inorganic crystalline fluorophore, setting a respective exposure time for each wavelength channel of the plurality of wavelength channels of the microscope system based on an identity of the inorganic crystalline fluorophore, including setting a first exposure time for a first wavelength channel of the plurality of wavelength channels and setting a second exposure time for a second wavelength channel of the plurality of wavelength channels, imaging the fluorescence balancing target in the first wavelength channel of the plurality of wavelength channels of the microscope system, the imaging in the first wavelength channel including acquiring a first image using the first exposure time, defining a pixel area of the first image relative to a fiducial marker positioned on the inorganic crystalline fluorophore, in response to a pixel average of the pixel area not being within an allowable range of a pixel average threshold, adjusting an excitation intensity of the first wavelength channel and re-imaging the inorganic crystalline fluorophore in the first wavelength channel, in response to the pixel average of the first pixel area being within the allowable range of the pixel average threshold, imaging the inorganic crystalline fluorophore in the second wavelength channel to acquire a second image using the second exposure time, and imaging the inorganic crystalline fluorophore in a third wavelength channel to acquire a third image using a third exposure time and imaging the inorganic crystalline fluorophore in a fourth wavelength channel to acquire a fourth image using a fourth exposure time) as the calibration of Misener et al.
In regard to claim 12 which is dependent on claim 11, the method of Misener et al. lacks an explicit description of details of the “… calibrate …” such as the first wavelength channel is blue and the second wavelength channel is green, and wherein the first exposure time is 0.5 seconds and the second exposure time is 2 seconds. However, “… calibrate the LED …” details are known to one of ordinary skill in the art (e.g., see “… microscope illumination system 100 … calibrated pure white color temperature where the proportion of red to green to blue light is the same … acquisition software instructs illumination system 100 to output light using the red LED, then the green LED, and last the blue LED. With each output, the software calculates and stores the exposure time for the particular channel … acquisition software instructs illumination system 100 to output light using the red LED, then the green LED, and last the blue LED. With each output, the software uses the stored exposure time for the particular color to acquire, "pseudo color" and store the image …” in paragraphs 12, 19, 26, and 27 of Thorburn). It should be noted that “when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable results”. KSR International Co. v. Teleflex Inc., 550 U.S. 398 at 416, 82 USPQ2d 1385 (2007) at 1395 (citing United States v. Adams, 383 U.S. 39, 40 [148 USPQ 479] (1966)). See MPEP § 2143. In this case, one of ordinary skill in the art could have substituted a known conventional pixel acquisition for calibration on same area (e.g., comprising details such as “acquisition software instructs illumination system 100 to output light using the red LED, then the green LED, and last the blue LED. With each output, the software calculates and stores the exposure time for the particular channel”, in order to achieve “calibrated pure white color temperature where the proportion of red to green to blue light is the same”) for the same area calibration and the results of the substitution would have been predictable. Therefore it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to provide a known conventional calibration (e.g., comprising details such as the first wavelength channel is blue and the second wavelength channel is green, and wherein the first exposure time is 0.5 seconds and the second exposure time is 2 seconds) as the calibration of Misener et al.
Claim(s) 10 is/are rejected under 35 U.S.C. 103 as being unpatentable over Misener et al. in view of Thorburn and Earney et al. as applied to claim(s) 9 above, and further in view of Hing et al. (US 2009/0310213) and Jaffe et al. (US 2016/0123886).
In regard to claim 10 which is dependent on claim 9, the method of Misener et al. lacks an explicit description of details of the “… microscopy …” such as a multi-detector system. However, “… microscopy …” details are known to one of ordinary skill in the art (e.g., see “… For the calibration of the microscope 2, a known standard sample 54 (see FIG. 5) is introduced into the sample region 10. Said standard sample 54 contains structures which are identified by the image processing … each illumination field 56 can be varied in terms of its brightness … sample is simultaneously irradiated by means of illumination sources 44a, 44b with the differing wavelength ranges, in order to detect the total number of marked cells …” in paragraphs 54, 56, and 62 of Hing et al. and “… Automated calibration of scanners provides for inter and intra instrument consistency of scanning/imaging results … high-throughput fluorescence scanning system which includes a plurality of integrated fluorescence scanners, wherein each integrated fluorescence scanner includes a solid state light engine, an epifluorescence microscope, a motion stage, an embedded computer which controls the solid state light engine, microscope and motion stage, and a network interface which allows for remote operation of the integrated fluorescence scanner as a network appliance …” in paragraphs 34 and 60 of Jaffe et al.). It should be noted that “when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable results”. KSR International Co. v. Teleflex Inc., 550 U.S. 398 at 416, 82 USPQ2d 1385 (2007) at 1395 (citing United States v. Adams, 383 U.S. 39, 40 [148 USPQ 479] (1966)). See MPEP § 2143. In this case, one of ordinary skill in the art could have substituted a known conventional microscopy (e.g., comprising details such as “high-throughput fluorescence scanning system which includes a plurality of integrated fluorescence scanners”, in order to achieve “inter and intra instrument consistency of scanning/imaging results”) for the unspecified microscopy of Misener et al. and the results of the substitution would have been predictable. Therefore it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to provide a known conventional microscopy (e.g., comprising details such as a multi-detector system) as the unspecified microscopy of Misener et al.
Claim(s) 11 is/are rejected under 35 U.S.C. 103 as being unpatentable over Misener et al. in view of Thorburn and Earney et al. as applied to claim(s) 9 above, and further in view of Haberstroh et al. (US 2011/0076687).
In regard to claim 11 which is dependent on claim 9, the method of Misener et al. lacks an explicit description of details of the “… standard or reference material …” such as ruby. However, “… standard or reference material …” details are known to one of ordinary skill in the art (e.g., see “… commercially available: diamond, silicon carbide (moissanite), ruby, sapphire, zircon, beryl, emerald, opal, quartz, jade, topaz, turquoise, lapis lazuli, chrysoberyl, amber, spine!, tourmaline, tanzanite, zincblende, wurtzite, and others …” in paragraph 36 of Haberstroh et al.) It should be noted that “when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable results”. KSR International Co. v. Teleflex Inc., 550 U.S. 398 at 416, 82 USPQ2d 1385 (2007) at 1395 (citing United States v. Adams, 383 U.S. 39, 40 [148 USPQ 479] (1966)). See MPEP § 2143. In this case, one of ordinary skill in the art could have substituted a known conventional reference material (e.g., comprising details such as “commercially available” “ruby”) for the unspecified reference material of Misener et al. and the results of the substitution would have been predictable. Therefore it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to provide a known conventional reference material (e.g., comprising details such as the inorganic crystalline fluorophore comprises ruby) as the unspecified reference material of Misener et al.
Claim(s) 15 and 17-20 is/are rejected under 35 U.S.C. 103 as being unpatentable over Earney et al. (US 2021/0055224) in view of Thorburn (US 2012/0013726).
In regard to claim 15, Earney et al. disclose a method of using a photostable fluorescence balancing target, comprising:
(a) positioning the photostable fluorescence balancing target on a sample holder of a first microscope system (e.g., “… inspection apparatus 100 may be utilized in connection with calibration of standard consumer optical tools such as fluorescence microscopes … In accordance with the examples herein, the method of FIG. 10 aligns an objective of an instrument with an optical target that includes a solid body that encloses a fluorescing material …” in paragraphs 48 and 146);
(b) imaging an inorganic crystalline fluorophore of the photostable fluorescence balancing target with a first wavelength channel of n wavelength channels of the first microscope system and defining a pixel area positioned with respect to a fiducial marker on the inorganic crystalline fluorophore (e.g., “… fluorescing material emits in one or more emission channels of interest … method of FIG. 10 directs excitation light onto the optical target, detects fluorescence emission from the optical target as reference information and utilizes the reference information in connection with at least one of optical alignment or calibration of the instrument … During the auto centering operation, the instrument records the XY stage position of fiducial(s) on the inspection apparatus. The positions of the fiducials are used to monitor drift in the XY stage of the instrument and/or the flow cell deck position when a flow cell is inserted into the instrument … lasers on at multiple laser powers to get images at different counts of intensity (e.g., about 500, about 1000, about 1500, about 2000, about 2500, about 3000, and about 3500 counts of intensity) in the images … impact of dust, fingerprints, etc. can be averaged out by averaging all pixels in the scanning (Y) dimension …” in paragraphs 54, 146, 147, and 157); and
(c) balancing the first wavelength channel and each remaining wavelength channel of the n wavelength channels of the first microscope system based on a respective pixel average in the pixel area, wherein a position of the pixel area with respect to the fiducial marker is substantially the same when balancing the first wavelength channel and balancing each remaining wavelength channel of the n wavelength channels of the first microscope system, and wherein the balancing includes adjusting an intensity of an emission source of one or more wavelength channels of the n wavelength channels such that each wavelength channel of the n wavelength channels generates images having intensities expected on substantially all similar instruments (e.g., “… images are utilized to identify where the camera fields of view for each emission band of interest … lasers on at multiple laser powers to get images at different counts of intensity (e.g., about 500, about 1000, about 1500, about 2000, about 2500, about 3000, and about 3500 counts of intensity) in the images … impact of dust, fingerprints, etc. can be averaged out by averaging all pixels in the scanning (Y) dimension … to characterize the response of that pixel (combination of how much light it is exposed to combined with the photo response of that pixel of the camera) … Ideally, the auto centering fiducial would show up at exactly the same position in the image after every move … By collecting and analyzing images of the inspection apparatus periodically (e.g., at the start of every sequencing run), the instrument may monitor the performance of the imaging system over time … to characterize the response of that pixel (combination of how much light it is exposed to combined with the photo response of that pixel of the camera) … fluorescent intensity is proportional to dopant concentration. By controlling the dopant concentration (e.g., about 1.1 %+/-0.01 %) … inspection apparatus can control the measured fluorescence to a desired tolerance (e.g., +/-0.6% in red and +/-0.1% in green). Measuring intensity of the inspection apparatus at a certain scan speed and laser power on one instrument will provide measurement information indicative of an intensity to expect on substantially all similar instruments. The fluorescent intensity measurement from the inspection apparatus can be utilized to indicate whether the instrument is behaving properly (e.g., providing proper laser power delivered to the flow cell, proper amount of fluorescent light collected and delivered to the camera, etc.). Given that the emission characteristics of the inspection apparatus will not change over time, any change in measured fluorescent intensity over the life of the instrument will indicate that either the proper laser power is not being delivered to the flow cell or not all the fluorescent light is being delivered to the camera …” in paragraphs 155, 157, and 159-161).
The method of Earney et al. lacks an explicit description of details of the “… intensity to expect on substantially all similar instruments …” such as similar channel intensities. However, “… intensity to expect on substantially all similar instruments …” details are known to one of ordinary skill in the art (e.g., see “… microscope illumination system 100 … calibrated pure white color temperature where the proportion of red to green to blue light is the same … acquisition software instructs illumination system 100 to output light using the red LED, then the green LED, and last the blue LED. With each output, the software calculates and stores the exposure time for the particular channel … acquisition software instructs illumination system 100 to output light using the red LED, then the green LED, and last the blue LED. With each output, the software uses the stored exposure time for the particular color to acquire, "pseudo color" and store the image …” in paragraphs 12, 19, 26, and 27 of Thorburn). It should be noted that “when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable results”. KSR International Co. v. Teleflex Inc., 550 U.S. 398 at 416, 82 USPQ2d 1385 (2007) at 1395 (citing United States v. Adams, 383 U.S. 39, 40 [148 USPQ 479] (1966)). See MPEP § 2143. In this case, one of ordinary skill in the art could have substituted known conventional expected intensities (e.g., comprising details such as “calibrated pure white color temperature where the proportion of red to green to blue light is the same” achieved by “acquisition software instructs illumination system 100 to output light using the red LED, then the green LED, and last the blue LED. With each output, the software uses the stored exposure time for the particular color”) for the unspecified expected intensities of Earney et al. and the results of the substitution would have been predictable. Therefore it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to provide known conventional expected intensities (e.g., comprising details such as each wavelength channel of the n wavelength channels generates images having similar intensities) as the unspecified expected intensities of Earney et al.
In regard to claim 17 which is dependent on claim 15, Earney et al. also disclose that the method is executed automatically by the first microscope system (e.g., “… processors 730 that execute program instructions stored in memory 732 to perform the operations described … objective 701 may be moved to the inspection apparatus before, during and/or after a sequencing session, in connection with various types of tests …” in paragraphs 135 and 137).
In regard to claim 18 which is dependent on claim 15, Earney et al. also disclose that after balancing the first wavelength channel and each remaining wavelength channel of the n wavelength channels, proceeding with a fluorescence assay (e.g., “… By collecting and analyzing images of the inspection apparatus periodically (e.g., at the start of every sequencing run), the instrument may monitor the performance of the imaging system over time …” in paragraph 160), wherein proceeding with the fluorescence assay includes imaging with each of the n wavelength channels simultaneously (e.g., “… an image of numerous clusters is taken in four channels (i.e., one for each fluorescent label) … inspection apparatus may be utilized at various points before and/or during the sequencing session …” in paragraph 132).
In regard to claim 19 which is dependent on claim 15, Earney et al. also disclose that balancing the first wavelength channel and each remaining wavelength channel of the n wavelength channels includes controlling the intensity of the first wavelength channel’s emission source to achieve an expected intensity within a desired tolerance such as ±0.6% (e.g., “… inspection apparatus can control the measured fluorescence to a desired tolerance (e.g., +/-0.6% in red and +/-0.1% in green). Measuring intensity of the inspection apparatus at a certain scan speed and laser power on one instrument will provide measurement information indicative of an intensity to expect on substantially all similar instruments. The fluorescent intensity measurement from the inspection apparatus can be utilized to indicate whether the instrument is behaving properly (e.g., providing proper laser power delivered to the flow cell, proper amount of fluorescent light collected and delivered to the camera, etc.). Given that the emission characteristics of the inspection apparatus will not change over time, any change in measured fluorescent intensity over the life of the instrument will indicate that either the proper laser power is not being delivered to the flow cell or not all the fluorescent light is being delivered to the camera …” in paragraph 161), and wherein the intensity is calculated from an average of at least two pixels (e.g., “… impact of dust, fingerprints, etc. can be averaged out by averaging all pixels in the scanning (Y) dimension … instrument uses the measured polynomial response of each pixel and adjusts the intensity of that pixel in the cluster image to make the whole image equivalent to what would be obtained with perfectly uniform illumination and perfectly uniform pixel gain and offsets …” in paragraph 157). The method of Earney et al. lacks an explicit description of details of the “… intensity to expect on substantially all similar instruments …” such as setting a threshold. However, “… intensity to expect on substantially all similar instruments …” details are known to one of ordinary skill in the art (e.g., see “… microscope illumination system 100 … calibrated pure white color temperature where the proportion of red to green to blue light is the same … acquisition software instructs illumination system 100 to output light using the red LED, then the green LED, and last the blue LED. With each output, the software calculates and stores the exposure time for the particular channel … acquisition software instructs illumination system 100 to output light using the red LED, then the green LED, and last the blue LED. With each output, the software uses the stored exposure time for the particular color to acquire, "pseudo color" and store the image …” in paragraphs 12, 19, 26, and 27 of Thorburn). It should be noted that “when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable results”. KSR International Co. v. Teleflex Inc., 550 U.S. 398 at 416, 82 USPQ2d 1385 (2007) at 1395 (citing United States v. Adams, 383 U.S. 39, 40 [148 USPQ 479] (1966)). See MPEP § 2143. In this case, one of ordinary skill in the art could have substituted known conventional expected intensities (e.g., comprising details such as “calibrated pure white color temperature where the proportion of red to green to blue light is the same” achieved by “acquisition software instructs illumination system 100 to output light using the red LED, then the green LED, and last the blue LED. With each output, the software uses the stored exposure time for the particular color”) for the unspecified expected intensities of Earney et al. and the results of the substitution would have been predictable. Therefore it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to provide known conventional expected intensities (e.g., comprising details such as setting a pixel average threshold and an allowable range of the pixel average threshold, wherein balancing the first wavelength channel and each remaining wavelength channel of the n wavelength channels includes determining that the pixel area of a first image acquired with the first wavelength channel has a pixel average that is not within the allowable range of the pixel average threshold, and adjusting the intensity of the emission source of the first wavelength channel) as the unspecified expected intensities of Earney et al.
In regard to claim 20 which is dependent on claim 15, Earney et al. also disclose that the first wavelength channel and each remaining wavelength channel of the n wavelength channels span a wavelength range between blue and far red (e.g., “… inspection apparatus can control the measured fluorescence to a desired tolerance (e.g., +/-0.6% in red and +/-0.1% in green) …” in paragraph 161).
Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Earney et al. in view of Thorburn as applied to claim(s) 15 above, and further in view of Hing et al. (US 2009/0310213) and Jaffe et al. (US 2016/0123886).
In regard to claim 16 which is dependent on claim 15, the method of Earney et al. lacks an explicit description of details of the “… calibrate …” such as the pixel area’s position is substantially the same when balancing the first microscope system and at least one additional microscope system. However, “… calibrate …” details are known to one of ordinary skill in the art (e.g., see “… For the calibration of the microscope 2, a known standard sample 54 (see FIG. 5) is introduced into the sample region 10. Said standard sample 54 contains structures which are identified by the image processing … each illumination field 56 can be varied in terms of its brightness … sample is simultaneously irradiated by means of illumination sources 44a, 44b with the differing wavelength ranges, in order to detect the total number of marked cells …” in paragraphs 54, 56, and 62 of Hing et al. and “… Automated calibration of scanners provides for inter and intra instrument consistency of scanning/imaging results … high-throughput fluorescence scanning system which includes a plurality of integrated fluorescence scanners, wherein each integrated fluorescence scanner includes a solid state light engine, an epifluorescence microscope, a motion stage, an embedded computer which controls the solid state light engine, microscope and motion stage, and a network interface which allows for remote operation of the integrated fluorescence scanner as a network appliance …” in paragraphs 34 and 60 of Jaffe et al.). It should be noted that “when a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable results”. KSR International Co. v. Teleflex Inc., 550 U.S. 398 at 416, 82 USPQ2d 1385 (2007) at 1395 (citing United States v. Adams, 383 U.S. 39, 40 [148 USPQ 479] (1966)). See MPEP § 2143. In this case, one of ordinary skill in the art could have substituted a known conventional calibrating (e.g., comprising details such as “standard sample 54 contains structures which are identified by the image processing”, in order to achieve “inter and intra instrument consistency of scanning/imaging results”) for the unspecified calibrating of Earney et al. and the results of the substitution would have been predictable. Therefore it would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to provide a known conventional calibrating (e.g., comprising details such as the first microscope system is one of a plurality of microscope systems and the method further includes balancing each microscope system of the plurality of microscope systems, and wherein the position of the pixel area is substantially the same when balancing each of the plurality of microscope systems) as the unspecified calibrating of Earney et al.
Response to Arguments
Applicant’s arguments with respect to the amended claims have been fully considered but some are moot in view of the new ground(s) of rejection. Applicant's remaining arguments filed 22 December 2025 have been fully considered but they are not persuasive.
Applicant argues that one having ordinary skill in the art would not be motivated to replace the solid host material of Earney et al. with ruby because Earney et al. disclose that the optical target must satisfy an energy level ratio criterion in paragraphs 52-59 and the energy level ratio of ruby is less than 3. Examiner respectfully disagrees. Initially, applicant's arguments that the energy level ratio of ruby is less than 3 are not persuasive because applicant fails to provide any evidence or even any explanation. Further, Earney et al. state (paragraph 57) that “… solid host material and the dopant may be chosen such that the combination exhibits a desired energy level ratio. For example, the combination may exhibit an energy level ratio of HOSTPE/FMET, where the HOSTPE represents the maximum phonon energy of the solid host material and FMET represents the energy transition between a target emission energy level and a nearest neighbor energy level of the fluorescing material …”. The phrase “may be chosen” of Earney et al. expressly motivate one having ordinary skill in the art to choose a solid host material and a dopant. Thus applicant's arguments that “desired” is interpreted as “must satisfy” are not persuasive. Even if it an energy level ratio is “desired” as taught by Earney et al., it is important to recognize that one having ordinary skill in the art knows (e.g., see Figs. 5A and 6A in Malíčková et al., Laser effect in the optical luminescence of oxides containing Cr, Acta Geologica Slovaca, Vol. 10, no. 1, 2018, pp. 27-34) that Ruby has ~413 cm-1 phonon energy and ~698 nm photon energy (or 1/698 nm = ~14327 cm-1) with an energy level ratio of 14327 cm-1/413 cm-1 = ~35. Therefore, the combination of the cited prior art teaches or suggests all limitations as arranged in the claims.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Malíčková et al. (Laser effect in the optical luminescence of oxides containing Cr, Acta Geologica Slovaca, Vol. 10, no. 1, 2018, pp. 27-34) teaches Ruby properties.
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/SL/
Examiner, Art Unit 2884
/UZMA ALAM/Supervisory Patent Examiner, Art Unit 2884