DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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 Arguments
2. Applicant’s arguments with respect to claims 1-8 and 10-22 have been considered, but are moot because of the new grounds of rejection.
Claim Rejections - 35 USC § 103
3. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
4. Claims 1-3, 5-6, and 10-13 are rejected under 35 USC 103 as being unpatentable over Sroda et al. (“SOFISM: Super-resolution optical fluctuation image scanning microscopy.” ARXIV.ORG (Feb 2020)—of record) in view of Segal et al. (“High-throughput smFRET analysis of freely diffusing nucleic acid molecules and associated proteins.” Methods, vol. 169, pp. 21-45 (Jul 2019)—of record), and further in view of Asai (US 20120273656 A1).
Regarding claim 1, Sroda discloses a method for operating a light microscope (Abstract) comprising
emitting and guiding illumination light (Fig. 1(a), blue line) as a plurality of illumination light beams from one or more light sources (Discussion on page 11, “multiple laser beams … are used”) towards a specimen positioning location (Fig. 1(a)), and forming a plurality of separated illumination light spots at the specimen positioning location (Fig. 5); and
guiding detection light beams (Fig. 1(a)) coming from the illumination light spots at the specimen positioning location to a detector (Discussion on page 11, “multiple laser beams and a large detector array are used”) comprising a plurality of sensor arrays (Fig. 1(a), 14 detectors detect each spot), wherein each sensor array comprises photon-counting detector elements (Fig. 1(a), SPADs), and the detection light beams form a plurality of light spots on the sensor arrays (Fig. 1(a)), wherein detection light beams from different illumination light spots at the specimen positioning location are guided to different sensor arrays (Discussion on page 11, “SPAD arrays”),
for adjusting where the light spots hit the sensor arrays during fabrication of the detector,
movably placing optical elements in front of the sensor arrays, wherein the optical elements affect a position of the respective light spot on the respective sensor array (Fig. 1(a)),
emitting illumination light to form light spots on the sensor arrays (Fig. 1(a)), and
interpreting measured signals of the sensor arrays through a controller to generate positioning commands (Data acquisition and analysis, “a time-correlated single-photon counting (TCSPC) board is used in the absolute timing mode (DPC-230, Becker & Hickl GmbH). An excitation pulse trigger is synchronized and recorded at every 40th pulse (0.5 MHz)”).
Sroda fails to disclose analyzing measured signals from the sensor arrays to determine positional information about the light spots on the sensor arrays; adjusting where the light spots hit the sensor arrays based on the positional information; and moving the optical elements according to the positioning commands.
However, Segal teaches a similar method for operating a light microscope, and discloses wherein sensor array signals are analyzed to determine positional information about light spots on the arrays; adjusting where the light spots hit the arrays based on the positional information (2.3. Detection path & Appendix B. Setup description and parts information sections); and moving optical elements according to positioning commands (2.3. Detection paths & Appendix B. Setup description and parts information).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine Sroda and Segal such that the locations where the spots hit the arrays were adjusted, motivated by optimizing imaging quality.
Modified Sroda fails to disclose fixating the optical elements with glue after the optical elements are moved or tilted according to the positioning commands.
However, Asai teaches an optical system (Figs. 1A-B), and discloses fixating optical elements with glue after they are moved or tilted ([0044] and [0060]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine modified Sroda and Asai such that optical elements were fixated with glue after being moved or tilted, motivated by securing components of the device in place.
Regarding claim 2, modified Sroda discloses wherein in the adjusting step, the sensor arrays are jointly moved transverse to an optical axis of the detection light beams (Segal - 2.3. Detection path, “Adjustments in the transversal directions are performed”).
Regarding claim 3, modified Sroda discloses wherein in the adjusting step, a common optical element is adjusted, wherein all illumination or detection light beams are guided via the common optical element, and wherein adjustment of the common optical element affects a position of the light spots perpendicular to an optical axis of the detection light beams (Segal - 2.2. Phase modulation by LCOS-SLMs on page 25, “During alignment the pitch is optimized to account for the actual excitation path demagnification, by adjusting the pattern by fractions of LCOS-SLM pixels”).
Regarding claim 5, modified Sroda discloses wherein in the adjusting step, the sensor arrays are jointly rotated about an optical axis of the detection light beams (Segal - 2.3. Detection path, “SPAD array is mounted on a rotation stage”).
Regarding claim 6, modified Sroda discloses wherein in the adjusting step, at least one optical zoom element provided in a beam path of the illumination or detection light beams is adjusted to change a pitch between the light spots on the sensor arrays such that the pitch matches a pitch of the sensor arrays (Segal - 2.2. Phase modulation by LCOS-SLMs on page 25, “spot pitch in the sample plane (5.4 μm) is defined by the pitch between adjacent SPADs (500 μm)”).
Regarding claim 13, Sroda discloses a light microscope (Abstract) comprising
at least one light source and optical elements for illuminating a specimen at a specimen positioning location (Fig. 1(a)) with a plurality of illumination light beams which form a plurality of separated illumination light spots at the specimen positioning location (Discussion on pg. 11, “multiple laser beams … are used”);
a detector (Discussion on pg. 11, “a large detector array [is] used”) with a plurality of sensor arrays (Fig. 1(a), 14 detectors detect each spot), each comprising photon-counting detector elements for measuring light spots formed on the sensor arrays by detection light beams coming from the specimen (Fig. 1(a), SPADs), wherein detection light beams from different illumination light spots at the specimen positioning location are guided to different sensor arrays (Discussion on pg. 11, “SPAD arrays”);
a controller configured to control the at least one light source and the detector (Data acquisition and analysis, “a time-correlated single-photon counting (TCSPC) board is used in the absolute timing mode (DPC-230, Becker & Hickl GmbH). An excitation pulse trigger is synchronized and recorded at every 40th pulse (0.5 MHz)”);
for adjusting where the light spots hit the sensor arrays during fabrication of the detector,
optical elements are movably placed in front of the sensor arrays wherein the optical elements affect a position of the respective light spot on the respective sensor array (Sroda - Fig. 1(a)),
illumination light is emitted to form light spots on the sensor arrays (Sroda - Fig. 1(a)), and
a controller interprets measured signals of the sensor arrays to generate positioning commands (Sroda - Data acquisition and analysis, “a time-correlated single-photon counting (TCSPC) board is used in the absolute timing mode (DPC-230, Becker & Hickl GmbH). An excitation pulse trigger is synchronized and recorded at every 40th pulse (0.5 MHz)”),
Sroda fails to disclose wherein the controller is configured to analyze measured signals from the sensor arrays to determine positional information about the light spots on the sensor arrays, and instruct an adjustment device of the light microscope to adjust where the light spots hit the sensor arrays based on the positional information, and wherein the optical elements are moved according to the positioning commands.
However, Segal teaches a similar light microscope, and discloses wherein sensor array signals are analyzed to determine positional information about light spots on the arrays, and adjustment where the light spots hit the arrays based on the positional information (2.3. Detection path & Appendix B. Setup description and parts information sections), and wherein optical elements are moved according to positioning commands (Segal - 2.3. Detection paths & Appendix B. Setup description and parts information).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine Sroda and Segal such that the locations where the spots hit the arrays were adjusted, motivated by optimizing imaging quality.
Modified Sroda fails to disclose fixating the optical elements with glue after the optical elements are moved or tilted according to the positioning commands.
However, Asai teaches an optical system (Figs. 1A-B), and discloses fixating optical elements with glue after they are moved or tilted ([0044] and [0060]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine modified Sroda and Asai such that optical elements were fixated with glue after being moved or tilted, motivated by securing components of the device in place.
5. Claim 4 is rejected under 35 USC 103 as being unpatentable over Sroda in view of Segal and Asai, and further in view of Tyndall et al. (“Automatic laser alignment for multifocal microscopy using a LCOS SLM and a 32x32 pixel CMOS SPAD array.” Advanced Microscopy Techniques II, SPIE, vol. 8086, no. 1 (Jun 2011)—of record).
Regarding claim 4, modified Sroda fails to disclose wherein in the adjusting step, the sensors arrays are jointly tilted relative to an optical axis of the detecting light beams depending on differences between the detection light beams.
However, Tyndall teaches a similar method for operating a light microscope, and discloses wherein sensor arrays are jointly tilted relative to an optical axis of a light beam (Abstract, “roll, pitch, and yaw”; 3.3 Multiple Point Alignment, “rotation of the entire array”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine modified Sroda and Tyndall such that the sensor arrays were tilted, motivated by optimizing imaging quality.
6. Claim 7 is rejected under 35 USC 103 as being unpatentable over Sroda in view of Segal and Asai, and further in view of York et al. (“Resolution Doubling in Live, Multicellular Organisms via Multifocal Structured Illumination Microscopy.” Nature Methods, vol. 9, no. 7, pp. 749-754 (Jul 2012)—of record).
Regarding claim 7, modified Sroda fails to disclose wherein at least some of the illumination light beams are scanned over common specimen points, photon-count values measured with different illumination light beams for the same specimen points are combined, and a number of used illumination light beams is set according to an averaging factor which is set depending on a specimen under observation.
However, York teaches a similar method for operating a light microscope, and discloses wherein at least some of the illumination light beams are scanned over common specimen points (Results, “parallelization of ISM by using a sparse lattice of excitation foci (similar to swept-field or spinning disk confocal microscopy)”), photon-count values measured with different illumination light beams for the same specimen points are combined (Figs. 2(a-b)).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine modified Sroda and York such that different beams were scanned over common points, motivated by increasing speed (York - Results).
7. Claim 8 is rejected under 35 USC 103 as being unpatentable over Sroda in view of Segal and Asai, and further in view of Ingargiola et al. (“48-spot single-molecule FRET setup with periodic acceptor excitation.” The Journal of Chemical Physics, vol. 148, no. 12 (Mar 2018)—of record).
Regarding claim 8, modified Sroda discloses wherein for adjusting where the light spots hit the sensor arrays during fabrication of the detector,
the illumination light is emitted to form the plurality of light spots on the sensor arrays (Sroda - Fig. 1(a)),
a controller interprets measured signals of the sensor arrays to generate positioning commands (Sroda - Data acquisition and analysis, “a time-correlated single-photon counting (TCSPC) board is used in the absolute timing mode (DPC-230, Becker & Hickl GmbH). An excitation pulse trigger is synchronized and recorded at every 40th pulse (0.5 MHz)”),
and the sensor arrays are moved according to the positioning commands (Segal - 2.3. Detection paths & Appendix B. Setup description and parts information).
Modified Sroda fails to disclose wherein the plurality of sensor arrays are movably placed on a common printed circuit board and operatively connected.
However, Ingargiola teaches a similar method for operating a light microscope, and discloses wherein sensor arrays are movably (Appendix C: SPAD Arrays Alignment, “SPADs are manually positioned in X and Y”) placed on a common printed circuit board and operatively connected (II. Setup Description on page 148, PXI-7813R).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine modified Sroda and Ingargiola such that sensors were placed on a common printed circuit board and connected, motivated by promoting compact design.
8. Claim 10 is rejected under 35 USC 103 as being unpatentable over Sroda in view of Segal and Asai, and further in view of Engelhardt (US 20020008904 A1—of record).
Regarding claim 10, modified Sroda discloses wherein as optical elements, tiltable transparent plates are arranged in front of the sensor arrays (Fig. 1(a), DM).
Modified Sroda fails to explicitly disclose wherein after the tiltable transparent plates are tilted according to the positioning commands, the tiltable transparent plates are fixated with glue.
However, Engelhardt teaches a similar microscope, and discloses wherein tiltable plates are fixated with glue ([0014]-[0019]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine modified Sroda such that Engelhardt, motivated by securing the components of the device.
9. Claim 11 is rejected under 35 USC 103 as being unpatentable over Sroda in view of Segal and Asai, and further in view of Bahlman et al. (US 20070057211 A1—of record).
Regarding claim 11, modified Sroda fails to explicitly disclose setting a binning pattern with a plurality of superpixels, wherein each superpixel is formed by jointly reading out several of the photon-counting detector elements to produce a common photon count value; and wherein the binning pattern is set in dependence of the positional information.
However, Bahlman teaches a similar microscope, and discloses setting a binning pattern with a plurality of superpixels, wherein each superpixel is formed by jointly reading out several of photon-counting detector elements to produce a common photon count value; and wherein the binning pattern is set in dependence of positional information (claim 72).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine modified Sroda and Bahlman such that a binning pattern was established, motivated by improving signal-to-noise ratio.
Regarding claim 12, modified Sroda discloses determining a center position of each light spot on the sensor arrays (Bahlman - [0069]-[0073]), and wherein the superpixels are aligned with regard to the center positions (Bahlman - [0069]-[0073]).
10. Claims 14-22 are rejected under 35 USC 103 as being unpatentable over Sroda in view of Segal and Asai, and further in view of Bruschini et al. (“Single-photon avalanche diode imagers in biophotonics: review and outlook.” Light: Science & Applications, vol. 8, no. 1 (Sep 2019)—of record).
Regarding claim 14, modified Sroda fails to disclose wherein the sensor arrays are arranged on a common printed circuit board, and/or the sensor arrays are formed as different regions of one chip.
However, Bruschini teaches a similar light microscope, and discloses wherein sensor arrays are formed as different regions of one chip (Fig. 2(f), 32x32 pixels).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine modified Sroda and Bruschini such that the sensor arrays were formed as different regions of one chip, motivated by optimizing space efficiency.
Regarding claim 15, modified Sroda fails to disclose wherein the sensor arrays are arranged directly next to each other to form a common array within one chip or on one printed circuit board.
However, Bruschini teaches a similar light microscope, and discloses wherein the sensor arrays are arranged directly next to each other to form a common array within one chip (Fig. 2(f), 32x32 pixels).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine modified Sroda and Bruschini such that the sensor arrays were arranged to form a common array within one chip, motivated by optimizing space efficiency.
Regarding claim 16, modified Sroda fails to disclose wherein a plurality of bonding pads per sensor array is provided, and at least some of the sensor arrays are arranged directly next to each other without any bonding pads in between.
However, Bruschini teaches a similar light microscope, and discloses wherein a plurality of bonding pads per sensor array is provided (Fig. 2(f), LVDS banks 0-3), and at least some of the sensor arrays are arranged directly next to each other without any bonding pads in between (Fig. 2(f), 32x32 pixels).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine modified Sroda and Bruschini such that the sensor arrays were arranged directly next to each other, motivated by optimizing space efficiency.
Regarding claim 17, modified Sroda fails to disclose wherein a total number of bonding pads for outputting measured photon-count signals is smaller than a total number of photon-counting detector elements, and measured photon-count signals of several photon-counting detector elements are output through the same bonding pad.
However, Bruschini teaches a similar light microscope, and discloses wherein a total number of bonding pads for outputting measured photon-count signals is smaller than a total number of photon-counting detector elements (Fig. 2(f), 4096 SPADs vs. about 400 bonding pads), and measured photon-count signals of several photon-counting detector elements are output through the same bonding pad (Fig. 2(f)).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine modified Sroda and Bruschini that a total number of bonding pads for outputting measured photon-count signals is small than a total number of photon-counting detector elements, motivated by optimizing space efficiency.
Regarding claim 18, modified Sroda fails to disclose wherein each photon-counting detector element comprises at least a first memory element and second memory element to allow read-out of a measured signal from the second memory element during an exposure time in which a photon detection event can be registered in the first memory element of this photon-counting detector element.
However, Bruschini teaches a similar light microscope, and discloses wherein each photon-counting detector element comprises at least a first memory element and second memory element to allow read-out of a measured signal from the second memory element during an exposure time in which a photon detection event can be registered in the first memory element of this photon-counting detector element (page 8, left column, lines 8-20 & 43-47).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine modified Sroda and Bruschini such that each photon-counting detector element was to comprise memories, motivated by storing data.
Regarding claim 19, modified Sroda discloses wherein each photon-counting detector element is formed by a single-photon avalanche detector comprising a SPAD anode which forms the first memory element (Bruschini - page 8, left column, lines 5-20 & 43-47), and the second memory element is configured to receive a measured signal from the first memory element (Bruschini - page 8, left column, lines 5-20 & 43-47).
Regarding claim 20, modified Sroda discloses wherein the photon-counting detector elements of the same sensor array are arranged in columns and rows, a common read-out line connects the photon-counting detector elements of the same column to one of the bonding pads (Bruschini - page 8, left column, lines 8-20 & 43-47), and row addresses for the photon-counting detector elements are used to distinguish between measured signals from the photon-counting detector elements of the same column (Bruschini - page 8, left column, lines 8-20 & 43-47).
Regarding claim 21, modified Sroda discloses wherein for reducing the number of required bonding pads, multi-bit counters are provided which count several photon detection events of the same or different photon-counting detector elements (Bruschini - page 6, right column, lines 26-38).
Regarding claim 22, modified Sroda fails to disclose wherein a plurality of through-silicon vias is provided for each sensor array, and several of the photon-counting detector elements share one of the through-silicon vias.
However, Bruschini teaches a similar light microscope, and discloses wherein a plurality of through-silicon vias is provided for each sensor array (page 22, left column, lines 16-23), and several of the photon-counting detector elements share one of the through-silicon vias (page 22, left column, lines 16-23).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to combine modified Sroda and Bruschini such that through-silicon vias were provided, motivated by promoting efficient 3D integration.
Conclusion
11. 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.
12. Any inquiry concerning this communication or earlier communications from the examiner should be directed to Daniel Jeffery Jordan whose telephone number is 571-270-7641. The examiner can normally be reached 9:30a-6:00p.
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/D. J. J./Examiner, Art Unit 2872
/STEPHONE B ALLEN/Supervisory Patent Examiner, Art Unit 2872