DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Response to Amendment
The amendment filed 11/07/2025 has been entered. Claims 1 - 4 and 6 - 24 are pending. Claim 5 has been cancelled. Applicant’s amendments to the claims have overcome each and every objection in the claims. The objections to claims 9 & 22 have been withdrawn.
Claim Objections
Claim 15 is objected to because of the following informalities:
Claim 15 recites, “further comprising positioning a second lens between the first light filter and the first sensor”. However, claim 14 from which claim 15 depends uses the phrase “installing” for similar claim limitations. Consistent language should be used to improve the clarity of the claims.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1 - 13, 17, & 24 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
In regard to claim 1, line 2 recites, “a plurality of light sources emitting different wavelengths of light…” which implies a method step. However, claim 1 is drawn to a system. Line 2 should be amended to -- a plurality of light sources configured to emit Claims 2 - 13 are rejected by virtue of dependence on claim 1.
In regard to claim 7, the “generation” of “activation maps” and “intensity maps” are directed towards an implied method step despite being a part of a system claim. Claim 7 should be amended to, -- the system is configured to generate…--.
In regard to claim 8, the line, ”the system simultaneously measures…” implies a method step despite being a part of a system claim. Claim 8 should be amended to, -- the system is configured to simultaneously measure…--.
In regard to claim 10, the line “parametric mapping is used to indicate drug effects…” implies a method step despite being a part of a system claim. Claim 10 should be amended to, -- parametric mapping is configured to indicate drug effects…--.
In regard to claims 4 & 17, line 2 recites, “the mapping…” However, “the mapping,” lacks antecedent basis.
In regard to claim 24, line 2 recites, “a plurality of light sources emitting different wavelengths of light…” which implies a method step. However, claim 24 is drawn to a system. Line 2 should be amended to -- a plurality of light sources configured to emit third indicator of cardiac physiology are mapped simultaneously,” which implies a method step of “mapping” the “indicators”, making the metes and bounds of the claim unclear.
Further, lines 18 - 19 recite, “a third sensor… generating a third indicator of cardiac physiology, wherein the third indicator comprises voltage…” However, it is unclear if “voltage” refers to transmembrane voltage potential.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 1 - 13 and 24 are rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101).
In regard to claims 1 and 24, line 1 recites, “a plurality of light sources emitting different wavelengths of light to a cardiac tissue,” which positively claims “a cardiac tissue”. However, claiming a human tissue as a part of a system is improper under 35 U.S.C. 101. Appropriate correction is required. Claims 2 - 13 are rejected by virtue of dependence on claim 1.
Claim Rejections - 35 USC § 102
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 (i.e., changing from AIA to pre-AIA ) 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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 14, 21, & 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ntziachristos (US 20130041267 A1 - Previously Cited).
In regard to claim 14, Ntziachristos discloses an optical mapping method (FIG. 1) comprising:
Emitting different wavelengths of light from a plurality of light sources to a cardiac tissue (FIG. 1, components 11.1 & 11.2; see annotated FIG. 1 below);
Installing a first lens situated in a path of the light. Ntziachristos discloses that the imaging optic (FIG. 1, component 31) includes a zoom lens (paragraph [0065]) that is situated in the light path (FIG. 1, components 31; see annotated FIG. 1 below);
Installing a first filter in the path of the light, wherein the first light filter outputs first filtered light (FIG. 1, component 35; see annotated FIG. 1 below) to a first sensor receiving the first filtered light and generating a first indicator of cardiac physiology (FIG. 1, component 22; see annotated FIG. 1 below);
Installing a second filter in the path of the light, wherein the second light filter outputs second filtered light (FIG. 1, component 22 & FIG. 2, component 27; see annotated FIGs. 1 & 2 below) to a second sensor receiving the second filtered light and generating a second indicator of cardiac physiology (FIG. 1, component 22 & FIG. 2, component 23; see annotated FIGs. 1 & 2 below);
and installing a third light filter in the path of the light, wherein the third light filter outputs third filtered light (FIG. 1, component 22 & FIG. 2, component 27; see annotated FIGs. 1 & 2 below) to a third sensor receiving the third filtered light and generating a third indicator of cardiac physiology (FIG. 1, component 22 & FIG. 2, component 24; see annotated FIGs. 1 & 2 below);
wherein the first indicator of cardiac physiology, the second indicator of cardiac physiology, and the third indicator of cardiac physiology are mapped simultaneously. Ntziachristos discloses that light going to each light sensor (FIG. 1, components 22; FIG. 2, components 23 & 24) is collected simultaneously by using a light splitting imaging optic (FIG. 1, component 33) that is configured for directing light from the sample onto each sensor (paragraph [0025]). Cameras (FIG. 1, components 22) are made up of two camera fields that act as optical sensors (FIG. 2, components 23 & 24) each with a separate CCD chip and filter (FIG. 2, components 27) that allows the two camera fields to generate a complete image of the sample (paragraphs [0057] – [0058]). Light is collected by each sensor simultaneously, thus allowing for real time processing of the multiple different images of the sample. A diagnostic image, such as a map of the sample highlighting various sample conditions, is produced (paragraph [0033], lines 16 - 18; paragraphs [0075] - [0077]). Additionally, Ntziachristos discloses that the system can be utilized to identify tissue alterations associated with cardiac disease by measuring the signal of probes designed to highlight said tissue alterations, such as changes in metabolism (paragraph [0035]).
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In regard to claim 21, Ntziachristos discloses the claimed invention substantially as set forth in claim 14, wherein the system simultaneously measures up to ten physiological parameters during simultaneous mapping. Based on the claim language, examiner is interpreting the phrase “up to ten physiological parameters,” to mean anywhere from 1 - 10 physiological parameters. Ntziachristos is able to measure the concentration of the fluorescent markers (paragraph [0090]) by measuring the signal of probes such as those designed to highlight said tissue alterations, such as changes in metabolism (paragraph [0035]).
In regard to claim 23, Ntziachristos discloses the claimed invention substantially as set forth in claim 14, wherein parametric mapping is used to indicate drugs effects or sequence of modulation of cardiac physiology in a disease of the cardiac tissue. Ntziachristos specifically discloses that their optical mapping system utilizes multiple targeted probes or marker substances that alter the optical properties of the tissue (e.g. fluorescence or absorbance) in such a way that the detected optical signals reveal the progress of a disease (paragraph [0034] and further that the system can be utilized to assess cardiac disease (paragraph [0035]).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 6 - 10, 12, 13, 18, & 24 are rejected under 35 U.S.C. 103 as being unpatentable over Ntziachristos (US 20130041267 A1 - Previously Cited) and further in view of Laurita (Laurita K., et al., Mapping action potentials and calcium transients simultaneously from the intact heart; American Journal of Physiology-Heart and Circulatory Phys. 2001 280:5, H2053-H2060 - Previously Cited) in view of Salama (Salama G. et al., Maps of optical action potentials and NADH fluorescence in intact working hearts. Am J Physiol. 1987 Feb;252(2 Pt 2):H384-94. doi: 10.1152/ajpheart.1987.252.2.H384. PMID: 3812752. – Previously Cited)
In regard to claim 1, Ntziachristos discloses an optical mapping method (FIG. 1) comprising:
A plurality of light sources emitting different wavelengths of light to a cardiac tissue (FIG. 1, components 11.1 & 11.2; see annotated FIG. 1 below);
A first lens situated in a path of light reflected from the cardiac tissue. Ntziachristos discloses that the imaging optic (FIG. 1, component 31) includes a zoom lens (paragraph [0065]) that is situated in the light path (FIG. 1, components 31; see annotated FIG. 1 below) that captures light from a biological sample (See annotated FIG. 1 below), including a biological tissue or part thereof (paragraph [0029]) which one of ordinary skill in the art would recognize includes cardiac tissue;
A first light filter in the path of the light from the first lens, wherein the first light filter outputs first filtered light (FIG. 1, component 35; see annotated FIG. 1 below)
A first sensor receiving the first filtered light and generating a first indicator of cardiac physiology (FIG. 1, component 22; see annotated FIG. 1 below);
A second light filter in the path of the light, wherein the second light filter outputs second filtered light (FIG. 1, component 22 & FIG. 2, component 27; see annotated FIGs. 1 & 2 below)
A second sensor receiving the second filtered light and generating a second indicator of cardiac physiology (FIG. 1, component 22 & FIG. 2, component 23; see annotated FIGs. 1 & 2 below);
a third light filter in the path of the light from the first lens, wherein the third light filter outputs third filtered light (FIG. 1, component 22 & FIG. 2, component 27; see annotated FIGs. 1 & 2 below)
A third sensor receiving the third filtered light and generating a third indicator of cardiac physiology (FIG. 1, component 22 & FIG. 2, component 24; see annotated FIGs. 1 & 2 below);
wherein the first indicator of cardiac physiology, the second indicator of cardiac physiology, and the third indicator of cardiac physiology are mapped simultaneously. Ntziachristos discloses that light going to each light sensor (FIG. 1, components 22; FIG. 2, components 23 & 24) is collected simultaneously by using a light splitting imaging optic (FIG. 1, component 33) that is configured for directing light from the sample onto each sensor (paragraph [0025]). Cameras (FIG. 1, components 22) are made up of two camera fields that act as optical sensors (FIG. 2, components 23 & 24) each with a separate CCD chip and filter (FIG. 2, components 27) that allows the two camera fields to generate a complete image of the sample (paragraphs [0057] – [0058]). Light is collected by each sensor simultaneously, thus allowing for real time processing of the multiple different images of the sample. A diagnostic image, such as a map of the sample highlighting various sample conditions, is produced (paragraph [0033], lines 16 - 18; paragraphs [0075] - [0077]). Additionally, Ntziachristos discloses that the system can be utilized to identify tissue alterations associated with cardiac disease by measuring the signal of probes designed to highlight said tissue alterations, such as changes in metabolism (paragraph [0035]).
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While Ntziachristos specifically discloses that multiple probes can be utilized to reveal molecular, structural, functional, or compositional features of the tissue (paragraph [0034]), giving the example of detecting alterations in tissue such as metabolic activity (paragraph [0035]), they do not specifically disclose that the first, second, and third indicators of cardiac physiology are NADH, calcium, and voltage.
However, Laurita teaches that voltage-sensitive and calcium-sensitive dyes can be applied to the heart (Page H2053, column 1, paragraph 1, lines 9 - 13) to measure indicators of cardiac physiology including calcium and voltage.
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have modified the optical mapping system disclosed by Ntziachristos with the teaching of Laurita that measurements indicating levels of calcium and voltage in the heart can be taken using calcium-sensitive and voltage-sensitive dyes because Ntziachristos discloses that multispectral fluorescent probes representing a can be utilized to determine molecular, structural, functional or compositional features of the tissue of interest and using the calcium-sensitive and voltage-sensitive dyes taught by Laurita would be considered combining prior art elements according to known methods to yield the predictable result of determining a molecular or function feature of the heart.
Additionally, while Ntziachristos discloses the use of multiple probes that can be utilized to reveal molecular, structural, functional, or compositional features of the tissue (paragraph [0034]), and more specifically detecting alterations in tissue such as metabolic activity (paragraph [0035]), they do not disclose that one of the indicators of cardiac physiology measured is NADH.
However, Salama teaches that local metabolic state of the heart can be measured through intrinsic NADH fluorescence (Page H385, column 2, paragraph 3).
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have modified the optical mapping system disclosed by Ntziachristos with the teaching of Salama that measurements indicating levels of NADH in the heart can be determine from intrinsic NADH fluorescence because Ntziachristos discloses that multispectral fluorescent probes or naturally occurring marker substances in the tissue can be utilized to determine molecular, structural, functional or compositional features of the tissue of interest (Ntziachristos, paragraph [0033]) and the use of the intrinsic fluorescence of NADH taught by Salama would be considered combining prior art elements according to known methods to yield the predictable result of determining a molecular or function feature of the heart.
In regard to claim 6, Ntziachristos discloses the claimed invention substantially as set forth in claim 1, wherein the plurality of light sources comprise a first excitation light source and a second excitation light source, and the first excitation light source has a wavelength of approximately 520 nm and the second excitation source has a wavelength of approximately 365 nm. Ntziachristos discloses that the optical system includes two light sources (FIG. 1, components 11.1 & 11.2) that are configured to deliver light to the tissue of interest (FIG. 1, component 1). Ntziachristos additionally discloses that the imaging device is able to capture a combination of color images, multispectral fluorescence images, multispectral reflectance images, and opto-acoustic signals, all of which are captured and used to calculate diagnostic images (paragraphs [0066] - [0070]), which include mapping the tissue to identify healthy and diseased tissue (paragraph [0077]). One of ordinary skill in the art would recognize that the wavelength of the light source may be chosen based on what marker substance or probes of interest a user is measuring. Laurita further teaches an optical measurement system of the heart that uses voltage-sensitive and calcium-sensitive dyes to visualize action potentials and calcium transients in the heart. Laurita further teaches that a light source with a wavelength of 515 nm +/- 5 nm, which is substantially similar to approximately 520 nm, can be utilized to excite voltage-sensitive dye and a light source with a wavelength of 365 nm +/- 25 nm, which is substantially similar to 365 nm, can be used to excite calcium-sensitive dye in order to optically map the heart (Page H2053, column 1, paragraph 1, lines 9 - 13).
In regard to claim 7, Ntziachristos as modified discloses the claimed invention substantially as set forth in claim 1, wherein the system further generates one or more activation maps and further generates one or more intensity maps from the first, second, and third indicators of cardiac physiology. Ntziachristos discloses that the system generates maps of the tissue of interest highlighting various sample conditions (paragraph [0033]) or a diagnostic map of the tissue that identifies healthy and disease tissue based on the fluorescence and reflectance images which represent the spatial distribution of marker substances (paragraph [0075]) and Laurita further teaches that voltage-sensitive and calcium-sensitive dyes can be applied to the heart (Page H2053, column 1, paragraph 1, lines 9 - 13) and imaged in order to generate contour maps of activation and intensity in terms of depolarization time and calcium transient onset (FIG. 6).
In regard to claim 8, Ntziachristos discloses the claimed invention substantially as set forth in claims 1, wherein the system simultaneously measures up to ten physiological parameters during simultaneous mapping. Based on the claim language, examiner is interpreting the phrase “up to ten physiological parameters,” to mean anywhere from 1 - 10 physiological parameters. Ntziachristos is able to measure the concentration of the fluorescent markers (paragraph [0090]) by measuring the signal of probes such as those designed to highlight said tissue alterations, such as changes in metabolism (paragraph [0035]).
In regard to claims 9, Ntziachristos discloses the claimed invention substantially as set forth in claims 8, wherein the up to ten physiological parameters are related to repolarization and calcium reuptake. Laurita teaches that parameters such as action potentials and calcium transients (FIGs. 5 & 6) can be measured simultaneously using voltage-sensitive and calcium-sensitive dyes that are excited by a light source and measured using an optical sensor (FIG. 1)
In regard to claim 10, Ntziachristos discloses the claimed invention substantially as set forth in claims 1, wherein parametric mapping is used to indicate drugs effects or sequence of modulation of cardiac physiology in a disease of the cardiac tissue. Ntziachristos specifically discloses that their optical mapping system utilizes multiple targeted probes or marker substances that alter the optical properties of the tissue (e.g. fluorescence or absorbance) in such a way that the detected optical signals reveal the progress of a disease (paragraph [0034] and further that the system can be utilized to assess cardiac disease (paragraph [0035]).
In regard to claim 12, Ntziachristos discloses the claimed invention substantially as set forth in claim 1, wherein the first, second and third sensors each comprise a camera. Ntziachristos specifically discloses the light sensors (FIG. 1, components 21 & 22; see annotated FIG. 1 above) are cameras (paragraph [0053], line 1).
In regard to claim 13, Ntziachristos discloses the claimed invention substantially as set forth in claim 1, further comprising a processing device mapping the first, second, and third indicators of cardiac physiology. Ntziachristos specifically discloses that the imaging device includes a processor device adapted for processing light images in parallel (paragraph [0026], lines 1 - 2) and more specifically real-time collection and processing of multispectral data capable of molecular imaging to capture the specific and accurate visualization of administered marker substances with specificity to healthy and diseased tissue marker substances of interest (paragraph [0032]). The image produced by the processor includes generating a map of the sample highlighting various sample conditions (paragraph [0033], lines 16 - 18) of cardiac disease (paragraph [0035]).
In regard to claim 18, Ntziachristos discloses the claimed invention substantially as set forth in claims 14. While Ntziachristos specifically discloses that multiple probes can be utilized to reveal molecular, structural, functional, or compositional features of the tissue (paragraph [0034]), giving the example of detecting alterations in tissue such as metabolic activity (paragraph [0035]), they do not specifically disclose that the first, second, and third indicators of cardiac physiology are NADH, calcium, and voltage.
However, Laurita teaches that voltage-sensitive and calcium-sensitive dyes can be applied to the heart (Page H2053, column 1, paragraph 1, lines 9 - 13) to measure indicators of cardiac physiology including calcium and voltage.
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have modified the optical mapping system disclosed by Ntziachristos with the teaching of Laurita that measurements indicating levels of calcium and voltage in the heart can be taken using calcium-sensitive and voltage-sensitive dyes because Ntziachristos discloses that multispectral fluorescent probes representing a can be utilized to determine molecular, structural, functional or compositional features of the tissue of interest and using the calcium-sensitive and voltage-sensitive dyes taught by Laurita would be considered combining prior art elements according to known methods to yield the predictable result of determining a molecular or function feature of the heart.
Additionally, while Ntziachristos discloses the use of multiple probes that can be utilized to reveal molecular, structural, functional, or compositional features of the tissue (paragraph [0034]), and more specifically detecting alterations in tissue such as metabolic activity (paragraph [0035]), they do not disclose that one of the indicators of cardiac physiology measured is NADH.
However, Salama teaches that local metabolic state of the heart can be measured through intrinsic NADH fluorescence (Page H385, column 2, paragraph 3).
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have modified the optical mapping system disclosed by Ntziachristos with the teaching of Salama that measurements indicating levels of NADH in the heart can be determine from intrinsic NADH fluorescence because Ntziachristos discloses that multispectral fluorescent probes or naturally occurring marker substances in the tissue can be utilized to determine molecular, structural, functional or compositional features of the tissue of interest (Ntziachristos, paragraph [0033]) and the use of the intrinsic fluorescence of NADH taught by Salama would be considered combining prior art elements according to known methods to yield the predictable result of determining a molecular or function feature of the heart.
In regard to claim 24, Ntziachristos discloses an optical mapping system comprising:
a plurality of light sources emitting different wavelengths of light to a cardiac tissue (FIG. 1, components 11.1 & 11.2);
an optical lens situated in a path of the light and providing an optical lens light output (FIG. 1, components 13.1 & 13.2; paragraph [0051]);
a first light splitter receiving the optical lens light output, and providing a first light splitter first output and a second light splitter second output (FIG. 1, component 33);
a first light filter receiving the first light splitter first output, wherein the first light filter outputs first filtered light (FIG. 1, component 34);
a first sensor receiving the first filtered light (FIG. 1, component 21);
a second light splitter receiving the first light splitter second output, and providing a second light splitter first output and a second light splitter second output (FIG. 2, component 25);
a second light filter receiving the second light splitter first output, wherein the second light filter outputs second filtered light (FIGs. 1 & 2, component 22; FIG. 2, component 27);
a second sensor receiving the second filtered light (FIGs. 1 & 2, component 22; FIG. 2, component 23);
and a third light filter receiving the second light filter second output, wherein the third light filter outputs third filtered light (FIG. 2, component 27);
a third sensor receiving the third filtered light (FIG. 2, component 24);
wherein the first indicator of cardiac physiology, the second indicator of cardiac physiology, and the third indicator of cardiac physiology are mapped simultaneously. Ntziachristos discloses that light going to each light sensor (FIG. 1, components 22; FIG. 2, components 23 & 24) is collected simultaneously by using a light splitting imaging optic (FIG. 1, component 33) that is configured for directing light from the sample onto each sensor (paragraph [0025]). Cameras (FIG. 1, components 22) are made up of two camera fields that act as optical sensors (FIG. 2, components 23 & 24) each with a separate CCD chip and filter (FIG. 2, components 27) that allows the two camera fields to generate a complete image of the sample (paragraphs [0057] – [0058]). Light is collected by each sensor simultaneously, thus allowing for real time processing of the multiple different images of the sample. A diagnostic image, such as a map of the sample highlighting various sample conditions, is produced (paragraph [0033], lines 16 - 18; paragraphs [0075] - [0077]). Additionally, Ntziachristos discloses that the system can be utilized to identify tissue alterations associated with cardiac disease by measuring the signal of probes designed to highlight said tissue alterations, such as changes in metabolism (paragraph [0035]).
While Ntziachristos specifically discloses that multiple probes can be utilized to reveal molecular, structural, functional, or compositional features of the tissue (paragraph [0034]), giving the example of detecting alterations in tissue such as metabolic activity (paragraph [0035]), they do not specifically disclose that the first, second, and third indicators of cardiac physiology are NADH, calcium, and voltage.
However, Laurita teaches that voltage-sensitive and calcium-sensitive dyes can be applied to the heart (Page H2053, column 1, paragraph 1, lines 9 - 13) to measure indicators of cardiac physiology including calcium and voltage.
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have modified the optical mapping system disclosed by Ntziachristos with the teaching of Laurita that measurements indicating levels of calcium and voltage in the heart can be taken using calcium-sensitive and voltage-sensitive dyes because Ntziachristos discloses that multispectral fluorescent probes representing a can be utilized to determine molecular, structural, functional or compositional features of the tissue of interest and using the calcium-sensitive and voltage-sensitive dyes taught by Laurita would be considered combining prior art elements according to known methods to yield the predictable result of determining a molecular or function feature of the heart.
Additionally, while Ntziachristos discloses the use of multiple probes that can be utilized to reveal molecular, structural, functional, or compositional features of the tissue (paragraph [0034]), and more specifically detecting alterations in tissue such as metabolic activity (paragraph [0035]), they do not disclose that one of the indicators of cardiac physiology measured is NADH.
However, Salama teaches that local metabolic state of the heart can be measured through intrinsic NADH fluorescence (Page H385, column 2, paragraph 3).
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have modified the optical mapping system disclosed by Ntziachristos with the teaching of Salama that measurements indicating levels of NADH in the heart can be determine from intrinsic NADH fluorescence because Ntziachristos discloses that multispectral fluorescent probes or naturally occurring marker substances in the tissue can be utilized to determine molecular, structural, functional or compositional features of the tissue of interest (Ntziachristos, paragraph [0033]) and the use of the intrinsic fluorescence of NADH taught by Salama would be considered combining prior art elements according to known methods to yield the predictable result of determining a molecular or function feature of the heart.
Claims 2, 3, & 11 are rejected under 35 U.S.C. 103 as being unpatentable over Ntziachristos (US 20130041267 A1 - Previously Cited) and further in view of Laurita (Laurita K., et al., Mapping action potentials and calcium transients simultaneously from the intact heart; American Journal of Physiology-Heart and Circulatory Phys. 2001 280:5, H2053-H2060 - Previously Cited) in view of Salama (Salama G. et al., Maps of optical action potentials and NADH fluorescence in intact working hearts. Am J Physiol. 1987 Feb;252(2 Pt 2):H384-94. doi: 10.1152/ajpheart.1987.252.2.H384. PMID: 3812752. – Previously Cited) as applied to claim 1 above, and further in view of Cathey (Cathey B, et al., Open-Source Multiparametric Optocardiography. Sci Rep. 2019 Jan 24;9(1):721. - Previously Cited)
In regard to claims 2 – 3, Ntziachristos discloses the claimed invention substantially as set forth in claim 1. While Ntziachristos discloses that the light is relayed from the sample to the cameras using a light splitting imaging optic (FIG. 1, component 30) that directs the light through filters (FIG. 1, components 32, 34, & 35) to adjust spectral features from the light, and an image splitter (FIG. 1, component 33) that separates the light path towards each sensor (FIG. 1, components 21 & 22), but does not disclose a second lens positioned between the first light filter and the first sensor or a third lens between the second light filter and the second sensor.
However, Cathey teaches a multiparametric optocardiography system that includes the incorporation of a lens between a light filter and sensor (FIG. 1D) such that there are two lenses per light path in order to achieve an infinity-corrected light path between them and allow for the addition of multiple photodetectors to record several parameters simultaneously (Page 2, paragraph 1, lines 3 - 7).
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have modified the imaging system disclosed by Ntziachristos that includes a first light filter and first sensor and additionally a second light filter and second sensor with the teaching that a lens can be positioned in between a light filter and sensor because including two lenses per light path allows for an infinity-corrected light path to be formed and allows for the addition of multiple photodetectors that record several parameters simultaneously (Cathey, Page 2, paragraph 1, lines 3 - 7).
In regard to claim 11, Ntziachristos discloses the claimed invention substantially as set forth in claim 1, wherein the system includes a first, second, and third filter (see annotated FIG. 1 above). Ntziachristos does not disclose that the first, second, and third filter comprises a cube.
However, Cathey teaches that filter cubes can be utilized in optical mapping systems (page 4, “Optical Components,” paragraph 1, line 1).
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have modified the first, second, and third filters of the imaging system disclosed by Ntziachristos with the filter cubes taught by Cathey because it would be considered a simple substitution of one known element for another, in this case the different filters, to obtain the predictable result of filtering light before being measured by a first, second, or third optical sensor.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Ntziachristos (US 20130041267 A1 - Previously Cited) and further in view of Laurita (Laurita K., et al., Mapping action potentials and calcium transients simultaneously from the intact heart; American Journal of Physiology-Heart and Circulatory Phys. 2001 280:5, H2053-H2060 - Previously Cited) in view of Salama (Salama G. et al., Maps of optical action potentials and NADH fluorescence in intact working hearts. Am J Physiol. 1987 Feb;252(2 Pt 2):H384-94. doi: 10.1152/ajpheart.1987.252.2.H384. PMID: 3812752. – Previously Cited) as applied to claim 1 above and further in view of Zhang (Zhang H, et al., Optical Mapping of Membrane Potential and Epicardial Deformation in Beating Hearts. Biophysical Journal. 2016 July 26; Volume 111, Issue 2, 438 - 451).
In regard to claim 4, Ntziachristos discloses the claimed invention substantially as set forth in claim 1. Ntziachristos additionally discloses that their system is compatible for use with multiple probes or marker substances that bind to a specific target in the sample, such as a target tissue, target cells, or certain cell components, such as proteins, that exhibit an interaction with light resulting in a specific absorption and/or fluorescence (paragraph [0033] - [0034]) although probes can also be omitted if the target can be identified naturally without a probe or contrast agent (paragraph [0033]). In particular, the marker substance is selected so that it targets and reveals a molecular, structural, functional or compositional feature of the tissue which specifically changes in a gradual manner during the disease progress (paragraph [0034]). One example that Ntziachristos discloses is the monitoring of metabolic activity in the tissue of interest. While Ntziachristos discloses that multiple probes can be utilized to reveal molecular, structural, functional, or compositional features of the tissue (paragraph [0034]), they do not specifically disclose that the mapping comprises parametric mapping that analyzes metabolism-excitation-contraction coupling in cardiac tissue.
However, Zhang teaches an optical mapping system (FIG. 2) of the heart that includes the use of three different filters and sensor pairs (F1, GC1, F2, MC, F3, GC2) to map membrane potential and deformation in the heart to study excitation-contraction coupling in cardiac tissue.
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have modified the imaging system disclosed by Ntziachristos that specifically discloses that metabolic activity can be measured as well as other indicators of cardiac physiology that reveal molecular, structural, functional, or compositional features of the tissue with the teaching of Zhang that membrane potential and deformation of the heart can be measured using an optical mapping system in order to study excitation contraction coupling in the heart because Ntziachristos already discloses that multiple parameters can be measured using their system. Including the measurement of membrane potential and deformation of the heart as taught by Zhang would be considered combining prior art elements according to known methods to yield the predictable results of measuring several features that characterize cardiac disease (Ntziachristos, paragraph [0036]).
Claims 15, & 16 are rejected under 35 U.S.C. 103 as being unpatentable over Ntziachristos (US 20130041267 A1 - Previously Cited) as applied to claim 14 above, and further in view of Cathey (Cathey B, et al., Open-Source Multiparametric Optocardiography. Sci Rep. 2019 Jan 24;9(1):721. - Previously Cited).
In regard to claims 15 - 16, Ntziachristos discloses the claimed invention substantially as set forth in claim 14. While Ntziachristos discloses that the light is relayed from the sample to the cameras using a light splitting imaging optic (FIG. 1, component 30) that directs the light through filters (FIG. 1, components 32, 34, & 35) to adjust spectral features from the light, and an image splitter (FIG. 1, component 33) that separates the light path towards each sensor (FIG. 1, components 21 & 22), but does not disclose a second lens positioned between the first light filter and the first sensor or a third lens between the second light filter and the second sensor.
However, Cathey teaches a multiparametric optocardiography system that includes the incorporation of a lens between a light filter and sensor (FIG. 1D) such that there are two lenses per light path in order to achieve an infinity-corrected light path between them and allow for the addition of multiple photodetectors to record several parameters simultaneously (Page 2, paragraph 1, lines 3 - 7).
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have modified the imaging system disclosed by Ntziachristos that includes a first light filter and first sensor and additionally a second light filter and second sensor with the teaching that a lens can be positioned in between a light filter and sensor because including two lenses per light path allows for an infinity-corrected light path to be formed and allows for the addition of multiple photodetectors that record several parameters simultaneously (Cathey, Page 2, paragraph 1, lines 3 - 7).
Claim 17 is rejected under 35 U.S.C. 103 as being unpatentable over Ntziachristos (US 20130041267 A1 - Cited Previously) as applied to claim 14 above, and further in view of Zhang (Zhang H, et al., Optical Mapping of Membrane Potential and Epicardial Deformation in Beating Hearts. Biophysical Journal. 2016 July 26; Volume 111, Issue 2, 438 - 451 - Cited Previously).
In regard to claims 4 & 17, Ntziachristos discloses the claimed invention substantially as set forth in claims 1 & 14. Ntziachristos additionally discloses that their system is compatible for use with multiple probes or marker substances that bind to a specific target in the sample, such as a target tissue, target cells, or certain cell components, such as proteins, that exhibit an interaction with light resulting in a specific absorption and/or fluorescence (paragraph [0033] - [0034]) although probes can also be omitted if the target can be identified naturally without a probe or contrast agent (paragraph [0033]). In particular, the marker substance is selected so that it targets and reveals a molecular, structural, functional or compositional feature of the tissue which specifically changes in a gradual manner during the disease progress (paragraph [0034]). One example that Ntziachristos discloses is the monitoring of metabolic activity in the tissue of interest. While Ntziachristos discloses that multiple probes can be utilized to reveal molecular, structural, functional, or compositional features of the tissue (paragraph [0034]), they do not specifically disclose that the mapping comprises parametric mapping that analyzes metabolism-excitation-contraction coupling in cardiac tissue.
However, Zhang teaches an optical mapping system (FIG. 2) of the heart that includes the use of three different filters and sensor pairs (F1, GC1, F2, MC, F3, GC2) to map membrane potential and deformation in the heart to study excitation-contraction coupling in cardiac tissue.
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have modified the imaging system disclosed by Ntziachristos that specifically discloses that metabolic activity can be measured as well as other indicators of cardiac physiology that reveal molecular, structural, functional, or compositional features of the tissue with the teaching of Zhang that membrane potential and deformation of the heart can be measured using an optical mapping system in order to study excitation contraction coupling in the heart because Ntziachristos already discloses that multiple parameters can be measured using their system. Including the measurement of membrane potential and deformation of the heart as taught by Zhang would be considered combining prior art elements according to known methods to yield the predictable results of measuring several features that characterize cardiac disease (Ntziachristos, paragraph [0036]).
Claims 19, 20, & 22 are rejected under 35 U.S.C. 103 as being unpatentable over Ntziachristos (US 20130041267 A1 - Cited Previously) as applied to claims 14 & 21 above, and further in view of Laurita (Laurita K., et al., Mapping action potentials and calcium transients simultaneously from the intact heart; American Journal of Physiology-Heart and Circulatory Phys. 2001 280:5, H2053-H2060 - Cited Previously ).
In regard to claim 19, Ntziachristos discloses the claimed invention substantially as set forth in claim 14 wherein the optical system includes a plurality of light sources that comprise a first excitation light source and a second excitation light source (FIG. 1, components 11.1 & 11.2) that are configured to deliver light to the tissue of interest (FIG. 1, component 1). Ntziachristos additionally discloses that the imaging device is able to capture a combination of color images, multispectral fluorescence images, multispectral reflectance images, and opto-acoustic signals, all of which are captured and used to calculate diagnostic images (paragraphs [0066] - [0070]), which include mapping the tissue to identify healthy and diseased tissue (paragraph [0077]). One of ordinary skill in the art would recognize that the wavelength of the light source may be chosen based on what marker substance or probes of interest a user is measuring. While Ntziachristos discloses that the marker substances that the optical system evaluates can be within the UV, visible, or infrared ranges (paragraph [0034]), they do not specifically disclose that the first excitation light source has a wavelength of approximately 520 nm and the second excitation source has a wavelength of approximately 365 nm.
However, Laurita teaches an optical measurement system of the heart that uses voltage-sensitive and calcium-sensitive dyes to visualize action potentials and calcium transients in the heart. Laurita further teaches that a light source with a wavelength of 515 nm +/- 5 nm, which is substantially similar to approximately 520 nm, can be utilized to excite voltage-sensitive dye and a light source with a wavelength of 365 nm +/- 25 nm, which is substantially similar to 365 nm, can be used to excite calcium-sensitive dye in order to optically map the heart (Page H2053, column 1, paragraph 1, lines 9 - 13).
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have modified the first excitation light source of the imaging system disclosed by Ntziachristos with the first excitation light source that has a wavelength of approximately 520 nm and the second excitation light source that has a wavelength of approximately 365 nm because it would be considered simple substitution of one known element, in this case the light source of the optical mapping system, to yield the predictable result of exciting a marker substance and taking an optical measurement.
In regard to claim 20, Ntziachristos discloses the claimed invention substantially as set forth in claim 14, wherein the system generates maps of the tissue of interest highlighting various sample conditions (paragraph [0033]) or a diagnostic map of the tissue that identifies healthy and disease tissue based on the fluorescence and reflectance images which represent the spatial distribution of marker substances (paragraph [0075]). While the optical mapping system disclosed by Ntziachristos discloses a mapping capability, they do not specifically disclose that the system generates one or more activation maps and further generates one or more intensity maps from the first, second, and third indicators of cardiac physiology.
However, Laurita teaches that voltage-sensitive and calcium-sensitive dyes can be applied to the heart (Page H2053, column 1, paragraph 1, lines 9 - 13) and imaged in order to generate contour maps of activation and intensity in terms of depolarization time and calcium transient onset (FIG. 6).
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have modified the optical mapping system disclosed by Ntziachristos with the teaching of Laurita that measurements taken of multispectral fluorescent probes representing a molecular, structural, functional or compositional feature of the tissue can be mapped as activation and intensity maps from cardiac indicators because it would be considered combining prior art elements according to known methods to yield the predictable result of generating a map from imaging multispectral fluorescent probes that can be used for diagnostic purposes.
In regard to claim 22, Ntziachristos discloses the claimed invention substantially as set forth in claim 21. While Ntziachristos is able to measure physiological parameters, such as molecule concentrations by measuring fluorescent signals during multispectral fluorescent imaging and the simultaneous mapping of the heart, they do not specifically disclose that the up to ten physiological parameters are related to repolarization and calcium uptake.
However, Laurita teaches that parameters such as action potentials and calcium transients (FIGs. 5 & 6) can be measured simultaneously using voltage-sensitive and calcium-sensitive dyes that are excited by a light source and measured using an optical sensor (FIG. 1)
It would have been obvious to one of ordinary skill in the art before the filing date of the claimed invention to have modified the optical mapping system disclosed by Ntziachristos with the teaching of Laurita that measurements taken of multispectral fluorescent probes representing a molecular, structural, functional or compositional feature of the tissue can be used to measure up to ten parameters related to repolarization and calcium reuptake because it would be considered combining prior art elements according to known methods to yield the predictable result of measuring a physiological parameter based on measured fluorescent signals.
Response to Arguments
Applicant’s arguments, see Remarks, filed 11/07/2025, with respect to the rejections of claims 4, 6, 7, 10, 17, 19, 20, & 23 under 35 U.S.C. 112(b) have been fully considered and are persuasive. The rejections of claims 4, 6, 7, 10, 17, 19, 20, & 23 under 35 U.S.C. 112(b) have been withdrawn.
Applicant’s arguments, see Remarks, filed 11/07/2025, with respect to the rejections of claims 1, 8, 10, 12, and 13 under 35 U.S.C. 102(a)(1) and the rejections of claims 2 - 4, 6, 7, 9, & 11 have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, a new grounds of rejection of independent claim 1 is made in view of Ntziachristos (US 20130041267 A1 - Previously Cited) and further in view of Laurita (Laurita K., et al., Mapping action potentials and calcium transients simultaneously from the intact heart; American Journal of Physiology-Heart and Circulatory Phys. 2001 280:5, H2053-H2060 - previously cited) in view of Salama (Salama G. et al., Maps of optical action potentials and NADH fluorescence in intact working hearts. Am J Physiol. 1987 Feb;252(2 Pt 2):H384-94. doi: 10.1152/ajpheart.1987.252.2.H384. PMID: 3812752. – Previously Cited. Applicant argues that the combination of Ntziachristos as modified by Laurita does not teach the role of NADH, which is true. However, Applicant does not address that the role of NADH is taught by Salama as described previously in the non-final rejection mailed 05/13/2025 in regard to claim 5. Without rebutting the details that each reference was cited for, the arguments made by the Applicant are not persuasive. As applicant points out, Ntziachristos teaches that multiple fluorophores and spectra can be imaged simultaneously, but does not describe the specifics of imaging calcium, transmembrane potential, and NADH. However, Laurita and Salama do teach the specifics of imaging calcium, transmembrane potential, and NADH such that the combination of Ntziachristos as modified by Laurita and Salama meets the claim limitations.
Conclusion
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/ERIC F WINAKUR/Primary Examiner, Art Unit 3791
/S.C.P./Examiner, Art Unit 3791