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 .
Election/Restriction and Claim Status
This action is in response to the papers filed on December 12, 2025.
Applicant’s election without traverse of Group I (claims 1-2, 4, 6, 8-10, 30-31, 33, 36, 38-39, 44-46, and 151) in the reply filed on December 2, 2025 is acknowledged.
Claims 1-2, 4, 6, 8-10, 30-31, 33, 36, 38-39, 44-46, 58-59, and 104 and 151 are pending.
Claims 58-59 and 104 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1-2, 4, 6, 8-10, 30-31, 33, 36, 38-39, 44-46, and 151 are under examination.
Priority/Effective Filing Date
The present application, filed on April 25, 2023, is a 371 of PCT/US2021/056821, filed on October 27, 2021 and claims priority to U.S. Provisional Patent Application No 63/178864, filed on April 23, 2021 and U.S. Provisional Patent Application No 63/106292, filed on October 27, 2020.
Specification
The use of the terms Shipley, Matrigel, Seurat, MicroChem, Karl Suss, Microposit, Anatech, Sigma-Aldrich, Molex, Transene, Thermo Fisher, Bio-Logic, WiCell, Gibco, RPMI, CerePlex, BlackRock Microsystems, Mattek, Gel Slick, Superase, Leica, and MATLAB which are each a trade name or a mark used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The listing of references in the specification on pages 55-59 is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Drawings
The drawings filed on April 25, 2023 are acceptable.
Claim Rejections - 35 USC § 112(b)
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.
Claims 1-2, 4, 6, 8-10, 30-31, 33, 36, 38-39, 44-46, and 151 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999).
Claim 1 recites the terms “physiological process” and “biomolecular process” as different genera of processes that are correlated in cells in a tissue. There is no special definition in the specification for these terms. The specification provides only examples of the terms: “physiological process (e.g., electrophysiological activity)” (paragraph 0007 and throughout) and “In some embodiments, the biomolecular process is DNA replication, DNA translation, RNA transcription, gene expression, or protein expression” (paragraph 0056).
The ordinary meaning in the art of “physiological process” is “The functions… of living organisms, including both the physical and chemical factors and processes, supporting life in single- or multi-cell organisms from their origin through the progression of life (National Center for Biotechnology Information National Library of Medicine MeSH terminology definition; “Physiological Phenomena”, synonym “Physiological Process”). The ordinary meaning in the art of “biomolecule” is “an organic molecule and especially a macromolecule (such as a protein or nucleic acid) in living organisms.” Merriam-Webster, “Biomolecular”.
It is unclear what processes are intended to be encompassed by “biomolecular processes” in contrast to “physiological processes”, as “physiological processes” encompass “functions of living organisms including… chemical factors and processes supporting life…” (i.e. biomolecular processes; those processes pertaining to organic molecules in living organisms).
Claims 1 and 151 require “performing a continuous physiological measurement on the cells” (step b), but do not require that the measurement is performed using the one or more nanoelectronic devices recited by (step a). Therefore, it is unclear if applicant intends to claim any method comprising measurement of a continuous physiological process by any method, or if applicant intends to require that the continuous physiological measurement is carried out using the one or more nanoelectronic devices recited by (step a). Similarly, there is no positively recited method step in any of the claims involving the one or more nanoelectronic devices requiring anything more of the devices than “embedding” the devices in a tissue.
Claim 30 recites “wherein the nanoelectronic devices comprise an electrical device, an optical device, a mechanical sensor, a stimulator, or an actuator”. The specification defines “As used herein, a “nanoelectronic device” is a nanoscale wire or other device small enough as to be injectable or insertable into a biological tissue.” (paragraph 0039). From the specification, it appears that all “nanoelectronic devices” necessarily comprise an “electrical device”. Therefore, it is unclear what “nanoelectronic devices” are encompassed by the independent claim outside the ostensibly further limiting claim term “compris[ing] an electrical device” recited by claim 30.
Claim 45 recites the limitation “wherein the tissue is a tissue with electrical activity”. The specification defines “As used herein, “electrophysiological activity” refers to the electrical properties of a biological system” and “involves measurements of voltage changes or electric current, and in particular the flow of ions.” (paragraph 0036). It is well known in the art that eukaryotic cells in tissues maintain electrochemical gradients (i.e. restrict the flow of ions; generate electrical potential differences (i.e. voltage changes)) at least across their plasma membrane and across the outer and inner mitochondrial membranes. These electrical properties of a biological system are therefore present and measurable in all eukaryotic cells and it is consequently unclear what tissues are excluded from the ostensibly further limiting claim term “a tissue with electrical activity” recited by claim 45.
Claim 151 is indefinite in addition to the reasons discussed above because it is unclear how the preamble is intended to breathe life and meaning into the claim. The preamble of claim 151 is directed to “A method for discovering a target for treating a disease”. However, the claim only requires steps of: a) embedding nanoelectronic devices in a first tissue…; b) performing continuous electrophysiological recording; c) fixing the tissue; d) performing in situ single-cell transcriptome mapping; e) performing transcriptome mapping; f) identifying the position of the electronic barcode; g) performing cell segmentation to correlate the [two data types]; and h) performing steps a-g on a second tissue, wherein the second tissue is a disease model, and comparing the [two data types] between the first and second tissues. There is no positively recited step of discovering, determining, identifying, etc. any “target for treating a disease” in addition to the “comparing” step. Thus it is not clear if applicant intends to cover any method for determining any difference(s) in the recited data types between any control and any disease model tissues comprising the steps a-g, or if the method is intended to somehow require more to accomplish the goal set forth in the preamble. If the claim requires something more than a comparison between a disease model and a control to accomplish the goal “discovering a target for treating a disease”, it is unclear what active process step the method requires and it appears that the claims are incomplete. The claim fails to provide any active steps that clearly accomplish the goal set forth by the preamble of the claim.
Claims 2, 4, 6, 8-10, 30-31, 33, 36, 38-39, and 44-46 are additionally indefinite because they depend from, and thus include the indefinite limitations of the claims discussed above.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 30 and 45 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 30 recites “wherein the nanoelectronic devices comprise an electrical device, an optical device, a mechanical sensor, a stimulator, or an actuator”. The specification defines “As used herein, a “nanoelectronic device” is a nanoscale wire or other device small enough as to be injectable or insertable into a biological tissue.” (paragraph 0039). From the specification, it appears that all “nanoelectronic devices” necessarily comprise an “electrical device”. Therefore, it is unclear what “nanoelectronic devices” are encompassed by the independent claim outside the ostensibly further limiting claim term “compris[ing] an electrical device” recited by claim 30.
Claim 45 recites the limitation “wherein the tissue is a tissue with electrical activity”. The specification defines “As used herein, “electrophysiological activity” refers to the electrical properties of a biological system” and “involves measurements of voltage changes or electric current, and in particular the flow of ions.” (paragraph 0036). It is well known in the art that eukaryotic cells in tissues maintain electrochemical gradients (i.e. restrict the flow of ions; generate electrical potential differences (i.e. voltage changes)) at least across their plasma membrane and across the outer and inner mitochondrial membranes. These electrical properties of a biological system are therefore present and measurable in all eukaryotic cells and it is consequently unclear what tissues are excluded from the ostensibly further limiting claim term “a tissue with electrical activity” recited by claim 45.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-2, 4, 6, 8-10, 30-31, 33, 36, 38-39, 44-46 are rejected under 35 U.S.C. 103 as being unpatentable over Li et al., “Cyborg Organoids: Implantation of Nanoelectronics via Organogenesis for Tissue-Wide Electrophysiology” Nano Lett. 2019, 5781-5789 (published July 26, 2019) in view of Wang et al., “Three-dimensional intact-tissue sequencing of single-cell transcriptional states” Science 361, 380 (published July 27, 2018) and Disawal et al., US 2013/0292879 A1 (published November 7, 2013).
Regarding claim 1, Li et al. teach methods for measuring continuous electrophysiological activity (i.e. a continuous physical process) in cells in a tissue with single-cell and millisecond spatiotemporal resolution in a cardiac organoid (i.e. cells in a tissue) (Li et al., Abstract). Li et al. teach the method comprises: a) embedding nanoelectronic devices comprising multiple sensors in the tissue (Li et al., Figure 1A, reproduced below for clarity), wherein the device is labeled with the fluorescent dye rhodamine 6G (R6G)(Li et al., Figure 3),
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b) performing continuous tissue-wide electrophysical mapping (i.e. continuous physiological measurement), c) fixing the cyborg organoids (i.e. the nanoelectronics-tissue hybrid), d) performing in situ analysis of stage-specific marker expression (including protein markers TNT, alpha actinin and actin by immunostaining), and e) performing mapping of the protein expression on the cells (Li et al., figure 3).
Li et al. further teaches that each of the sensors in the device are individually addressable (Li et al., page 5781, column 1) and are fabricated in a photolithographic process (Li et al., page 5785, column 2, paragraph 2).
Li et al. do not teach that the multiple sensors in the nanoelectronic device (Li et al., figure 1) each comprise a unique electronic barcode.
However, Disawal et al. teach that individual sensors in microelectronic devices (Disawal et al., paragraph 0067) can be individually labeled with unique barcodes using photolithography (Disawal et al., paragraph 0182) and that there is no particular limit to how small the lateral dimension (of the barcode) can be as long as the feature can be detected (with a microscope) and that barcodes in particular can vary from nanoscopic to microscopic (Disawal et al., paragraph 0187-0188). Disawal et al. teach that unique micron and nanoscale identifier features (such as barcodes) are useful for labeling objects including individual sensors or medical devices for purposes such as the prevention of counterfeiting such components (Disawal et al., paragraph 0229).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have modified the lithographically-fabricated, fluorescently-labeled nanoelectronic devices, taught by Li et al. to comprise individually labeled (i.e. “electronic barcod[ed]”) sensor components, encoded using the same fluorescent molecule taught by Li et al., by the methods taught by Disawal et al. comprising lithographic fabrication of nanoscopic barcode features. The ordinary artisan would have been motivated to utilize individually barcoded sensor components, fabricated by the lithographic processes taught by Disawal et al. and Li et al., because of the teaching of Disawal et al. that individually barcoded components beneficially prevent counterfeiting of products such as medical devices and sensors in microelectronic devices.
Li et al. and Disawal et al. do not teach performing cell segmentation to correlate an in situ analysis (of the expression of various gene expression markers) with a continuous physiological measurement (spatiotemporally-resolved electrophysiology).
However, Wang et al. teach methods comprising three-dimensional in situ sequencing of individual RNA molecules in intact single cells in intact tissues (Wang et al., Figures 1-2). Wang et al. further teach attributing the in situ analysis of gene expression to individual cells in an intact tissue by cell segmentation analysis (Wang et al., page 8, column 3). Finally, Wang et al. explicitly suggest that this method can be integrated with cell-type information with single-cell morphology, projection anatomy, and in vivo neural activity imaging and electrophysiology (Wang et al., page 9, column 2, paragraph 2).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have substituted the immunofluorescence methods of measuring in situ gene expression in cells in a tissue, taught by Li et al. with the single-cell, in situ gene expression analysis comprising in situ, single-cell RNA sequencing and cell segmentation analysis taught by Wang et al.
The ordinary artisan would have been motivated to substitute the method of Wang et al. into the methods taught by Li et al. because of the express suggestion of Wang et al. that single cell, in situ RNA sequencing can integrate in vivo neural activity electrophysiology (i.e. a continuous physiological process) with single cell gene expression analysis (i.e. an in situ analysis of a biomolecular process) in intact tissues. Furthermore, Wang et al. explicitly provide the motivation that: in situ transcriptomics exemplified by STARmap (i.e. single cell in situ RNA sequencing) can effectively link this imaging-based molecular information with complementary cellular-resolution datastreams describing anatomy, natural activity, and causal importance (e.g., electrophysiology), thus promising to fundamentally deepen our understanding of brain function and dysfunction (Wang et al., page 9, column 2, paragraph 2).
Regarding claim 2, Li et al. teach that the continuous physiological process comprises electrophysiological activity, wherein the measuring step comprises continuous electrophysiological recording (Li et al., figure 4).
Regarding claims 4 and 6, Wang et al. teach the biomolecular process comprises gene expression, wherein the in situ analysis of gene expression comprises performing in situ single cell transcriptome sequencing (Wang et al., abstract) and mapping of the transcripts onto single cells (i.e. transcriptomic mapping) (Wang et al., abstract).
Regarding claim 8, Li in view of Disawal et al. teach that the “electronic barcode” is a fluorescent electronic barcode (see claim 1 above).
Regarding claim 9, Li et al. teach “The mesh nanoelectronics are highly scalable due to the photolithographic nature of the fabrication process” and “it is possible to further scale up to larger sensor arrays, 96, 128, or more without sacrificing the geometries and mechanics that are essential for integration via organogenesis (Li et al., page 5785, column 1-2 bridging paragraph). Even more, Li et al. teach the method “is scalable for integrating a larger number of sensors and stimulators” (Li et al., page 5787, column 2, paragraph 3).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have scaled up the number of sensors arrayed in the nanoelectronic device to comprise over 1000 sensors. The ordinary artisan would have been motivated to increase the number of sensors in the device to predictably increase the spatial resolution of signals detected by the sensor array. Furthermore, the ordinary artisan would have been reasonably confident that an increased number of sensors would have been easily integrated into the device, given the express teaching/suggestion of Li et al. that the device is scalable for integrating a larger number of sensors without any observed practical trade-off. Furthermore, the courts have previously held that duplication of parts taught by the prior art “has no patentable significance unless a new and unexpected result is produced” (see In re Harza, below). In this case, given the predictable benefit of increased spatial resolution provided by an increased number of sensors in a device comprising a sensor array and the teaching of Li et al. that the number of sensors in such a device may be scaled up without compromising the integration of the device, it is the position of the examiner that one of ordinary skill in the art would have been motivated to increase the number of sensors in the array with a reasonable expectation of success.
In re Harza, 274 F.2d 669, 124 USPQ 378 (CCPA 1960) (Claims at issue were directed to a water-tight masonry structure wherein a water seal of flexible material fills the joints which form between adjacent pours of concrete. The claimed water seal has a "web" which lies in the joint, and a plurality of "ribs" projecting outwardly from each side of the web into one of the adjacent concrete slabs. The prior art disclosed a flexible water stop for preventing passage of water between masses of concrete in the shape of a plus sign (+). Although the reference did not disclose a plurality of ribs, the court held that mere duplication of parts has no patentable significance unless a new and unexpected result is produced.).
Regarding claim 10, Li et al. teach the cells in the tissue comprise over 1,000,000 (i.e. 1x106 cells (Li et al., Materials and methods, page 6, section 2.4 “3D culture of cyborg organoids”).
Regarding claim 30, Li et al. teach the nanoelectronic device comprises electrical sensors (i.e. an electrical device) or stimulators (Li et al., page 5781, column 2, paragraph 2).
Regarding claim 31, Li et al. teach the step of embedding the device comprises transferring the device onto a 2D sheet of cells and allowing the cells to aggregate, proliferate, and migrate, leading to device compression and embedding within the tissue (Li et al., Figure 1).
Regarding claim 33, Wang et al. teach the step of performing in situ single cell transcriptome sequencing comprises: constructing cDNA amplicons in situ by probe hybridization, enzymatic amplification of the cDNA amplicons, and immobilization of the amplified cDNA in a hydrogel network (Wang et al., Figure 1, reproduced below for clarity and convenience).
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Regarding claim 36, Wang et al. teaches the step of performing in situ single cell transcriptome mapping comprises “STARmap” (Wang et al., page 1, column 3).
Regarding claim 38, Wang et al. teaches mapping over 1000 genes simultaneously (Wang et al., abstract).
Regarding claim 39, Wang et al. and Li et al. teach imaging the tissues using confocal microscopy (Wang et al., page 8, column 3; Li et al., materials and methods, page 36, figure S23). Li et al. further teach determining the structure and position of the stretchable mesh nanoelectronics using confocal microscopy (Li et al., materials and methods, page 36, figure S23) (i.e. in combination with Disawal et al., see claim 1 above, identifying the position of the electronic barcode).
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Regarding claim 44, Li et al. and Wang et al. teach that the tissue is three dimensional (Li et al., Figure 1; Wang et al., Figure 1).
Regarding claims 45 and 46, Li et al. teach the tissue is a cardiac organoid (i.e. a tissue with electrical activity; heart tissue; muscle tissue; developing tissue) (Li et al., abstract).
Claim 151 is rejected under 35 U.S.C. 103 as being unpatentable over Li et al., “Cyborg Organoids: Implantation of Nanoelectronics via Organogenesis for Tissue-Wide Electrophysiology” Nano Lett. 2019, 5781-5789 (published July 26, 2019) in view of Wang et al., “Three-dimensional intact-tissue sequencing of single-cell transcriptional states” Science 361, 380 (published July 27, 2018) and Disawal et al., US 2013/0292879 A1 (published November 7, 2013) as applied to claims 1-2, 4, 6, 8-10, 30-31, 33, 36, 38-39, 44-46 above, and further in view of Lee et al., “Engineered Cardiac Organoid Chambers: Toward a Functional Biological Model Ventricle” Tissue Engineering: Part A Volume 14, Number 2, 2008.
Regarding claim 151, as described for claim 1 above, the methods of Li et al. in view of Wang et al., and Disawal et al. teach the method steps (a) through (g) recited by claim 151. Li et al. further suggests that cardiac cyborg organoids may be applied to study cardiac development, diseases, and therapeutics (Li et al., page 5787 , column 2, paragraph 3). Li et al. in view of Wang et al., and Disawal et al. do not teach performing the method comprising steps (a) through (g) (i.e. the steps recited by claim 1) on a second tissue, wherein the second tissue is engineered as a disease model, and comparing the single cell transcriptome data and electrophysiological recording data from the first (i.e. control) tissue and the second (i.e. disease model) tissue.
However, Lee et al. teach engineered cardiac organoid chambers comprising an engineered cryoinjured organoid model of myocardial infarction (i.e. a disease model). Lee et al. teach comparing contractile function between the first (control) organoid and a second (injured/diseased) organoid (Lee et al., Figure 7). Lee et al. further teach that the contractile function is driven by electrophysiological activity, as measured by electrophysiology measurements (Lee et al., page 217, column 1 and page 221, column 1-2 bridging paragraph).
Therefore, it would have been prima facie obvious prior to the effective filing date of the claimed invention for one of ordinary skill in the art to have combined the methods for correlating single cell transcriptome data with electrophysiological activity in cyborg cardiac organoids, taught by Li et al. in view of Wang et al. and Disawal et al. with the engineered cardiac organoid model of myocardial infarction taught by Lee et al.
The ordinary artisan would have been motivated to combine the cyborg cardiac organoid system and method with the engineered cardiac organoid disease model taught by Lee et al. because of the suggestion of Li et al. that cardiac cyborg organoids may be applied to study cardiac development, diseases, and therapeutics (Li et al., page 5787 , column 2, paragraph 3) and the teaching of Lee et al. that experimental cryoinjury, previously established as a controllable model of myocardial infarction in rat animal models, was implemented in an organoid model (Lee et al., page 217, column 2, paragraph 2) and exhibited similar changes in physiology to those observed in the animal model (Lee et al., page 223, paragraph 1). Finally, Lee et al. suggests that engineered cardiac organoids can reduce the use of experimental animals for cardiac research. The ordinary artisan would have been reasonably confident that the relatively straightforward disease model applied by Lee et al. (i.e. cryoinjury of cardiac organoid tissue) would have been readily applied to the cardiac cyborg organoids and methods taught by Li et al. in view of Wang et al. and Disawal et al.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ZACHARY MARK TURPIN whose telephone number is (703)756-5917. The examiner can normally be reached Monday-Friday 8:00 am - 5:00 pm.
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/Z.M.T./Examiner, Art Unit 1682
/WU CHENG W SHEN/Supervisory Patent Examiner, Art Unit 1682