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 .
Claim Status
Claims 7-11, 13-14, 21-25, 27-28, 34-38, and 40-41 are canceled.
Claims 1-6, 12, 15-20, 26, 29-33, and 39 are pending and under examination herein.
Claims 1, 6, 12, 15, 17 and 30 are objected to.
Claims 1-6, 12, 15-20, 26, 29-33, and 39 are rejected.
Priority
The instant application is a National Stage entry of PCT/US2020/050643 , International Filing Date: 09/14/2020, which claims priority from US Provisional Application 62/899993 , filed 09/13/2019. As such, the effective filing date assigned to each of claims 1-6, 12, 15-20, 26, 29-33, and 39 is 09/13/2019.
Information Disclosure Statement
The Information Disclosure Statement filed 03/10/2022 is in compliance with the provisions of 37 CFR 1.97 and has therefore been considered. A signed copy of the IDS is included with this Office Action.
Drawings
The drawings are objected to as failing to comply with 37 CFR 1.84(p)(4) because:
Reference character “41” has been used to designate both Optical Modules and Brightfield in fig 2.
Reference character “42” has been used to designate both brightfield and phase-contrast module in the instant specification.
Reference character “44” is described as a hologram in the drawing and as diffraction module in the instant specification.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The use of the term “Bluetooth” ( (e.g. para 0051), which is 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.
Claim Objections
Claims 1, 6, 12, 15, 17 and 30 are objected to because of the following informalities:
In claim 1: “a brightfield data, a darkfield data, a phase contrast data, multichannel fluorescence data, or diffraction data” should be “a brightfield data, a darkfield data, a phase contrast data, a multichannel fluorescence data, or a diffraction data” for consistency.
In claim 6, the diseases/ disorders of the group should be separated by commas.
In claim 12, “an antibody, chromogen, microsphere, nanoparticle” should be “an antibody, a chromogen, a microsphere, a nanoparticle” for consistency.
In claim 15, 17 and 30, the elements of the list should be separated by commas.
Appropriate correction is required.
Claim Interpretation
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
This application includes one or more claim limitations that do not use the word “means,” but are nonetheless being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, because the claim limitation(s) uses a generic placeholder that is coupled with functional language without reciting sufficient structure to perform the recited function and the generic placeholder is not preceded by a structural modifier. Such claim limitation(s) is/are:
In claim 29:
a re-suspension unit configured to re-suspend a sample of a cellular specimen in perm lyse buffer in a vial.
a tagging unit configured to tag a sample of the cellular specimen with a reporter
an immobilization unit configured to immobilize the sample of the cellular specimen on an optically transparent substrate.
an imaging device configured to acquire images
Because this/these claim limitation(s) is/are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, it/they is/are being interpreted to cover the corresponding structure described in the specification as performing the claimed function, and equivalents thereof.
a re-suspension unit configured to re-suspend a sample of a cellular specimen in perm lyse buffer in a vial - It is not clear from the disclosure what structure is intended to be the re-suspension unit. MPEP 2181.11C sets forth that the structure disclosed in the written description of the specification must clearly link or associate that structure to the function recited in the means-plus-function limitation to qualify as the corresponding structure. Since there is no clear link with the recited function and a structure in the written description, there is no disclosed corresponding structure. For the purpose of examination, this unit is interpreted as any unit that can re-suspend a sample of a cellular specimen in perm lyse buffer in a vial.
a tagging unit configured to tag a sample of the cellular specimen with a reporter- It is not clear from the disclosure what structure is intended to be the tagging unit. MPEP 2181.11C sets forth that the structure disclosed in the written description of the specification must clearly link or associate that structure to the function recited in the means-plus-function limitation to qualify as the corresponding structure. Since there is no clear link with the recited function and a structure in the written description, there is no disclosed corresponding structure. For the purpose of examination, this unit is interpreted as any unit that can tag a sample of the cellular specimen with a reporter.
an immobilization unit configured to immobilize the sample of the cellular specimen on an optically transparent substrate- It is not clear from the disclosure what structure is intended to be the tagging unit. MPEP 2181.11C sets forth that the structure disclosed in the written description of the specification must clearly link or associate that structure to the function recited in the means-plus-function limitation to qualify as the corresponding structure. Since there is no clear link with the recited function and a structure in the written description, there is no disclosed corresponding structure. For the purpose of examination, this unit is interpreted as any unit that can immobilize the sample of the cellular specimen on an optically transparent substrate.
an imaging device configured to acquire images – The instant specification discloses in para 0059 that the imaging device may include at least one of a CCD, CMOS, NMOS, or Quanta image sensor.
If applicant does not intend to have this/these limitation(s) interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, applicant may: (1) amend the claim limitation(s) to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph (e.g., by reciting sufficient structure to perform the claimed function); or (2) present a sufficient showing that the claim limitation(s) recite(s) sufficient structure to perform the claimed function so as to avoid it/them being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 29-33 and 39 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 29, and those claims dependent thereon, recite limitations for a
a re-suspension unit that has been interpreted to invoke 35 U.S.C.112(f). However, as discussed in the Claim Interpretation section above, the instant specification does not recite any structure associated with a means to re-suspend a sample of a cellular specimen in perm lyse buffer in a vial. Therefore, in accordance with MPEP 2181.IV, the instant specification does not provide written description support for these limitations as there is not a corresponding structure disclosed in the specification.
a tagging unit that has been interpreted to invoke 35 U.S.C.112(f). However, as discussed in the Claim Interpretation section above, the instant specification does not recite any structure associated with a means to tag a sample of the cellular specimen with a reporter. Therefore, in accordance with MPEP 2181.IV, the instant specification does not provide written description support for these limitations as there is not a corresponding structure disclosed in the specification.
an immobilization unit that has been interpreted to invoke 35 U.S.C.112(f). However, as discussed in the Claim Interpretation section above, the instant specification does not recite any structure associated with a means to immobilize the sample of the cellular specimen on an optically transparent substrate. Therefore, in accordance with MPEP 2181.IV, the instant specification does not provide written description support for these limitations as there is not a corresponding structure disclosed in the specification.
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 1-6, 12, 15-20, 26, 29-33, and 39 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.
Claim 1, and all claims dependent thereon, recites the limitation "the image types" in line 4. There is insufficient antecedent basis for this limitation in the claim.
Claims 4, 18 and 31, and all claims dependent thereon, recites the limitation "the presence" in line 1. There is insufficient antecedent basis for this limitation in the claim.
Claims 5-6, 12, 19-20, 26, 32-33, and 39, and all claims dependent thereon, recites the limitation "the group". There is insufficient antecedent basis for this limitation in the claim.
The metes and bounds of claims 15, 17 and 30, and all claims dependent thereon, are rendered indefinite by the use of “and”, as a sample cannot be simultaneously obtained by all the methods listed. For the purposes of examination, this limitation is interpreted as “or”.
Claim 29, and all claims dependent thereon, recite a re-suspension unit configured to re-suspend a sample of a cellular specimen in perm lyse buffer in a vial, a tagging unit configured to tag a sample of the cellular specimen with a reporter, and an immobilization unit configured to immobilize the sample of the cellular specimen on an optically transparent substrate. However, the written description fails to disclose the corresponding structures, materials, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. The disclosure is devoid of any structures that performs the functions in the claim. Therefore, the claims are indefinite.
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.
Claims 1-6, 12, 15-20, 26, 29-33, and 39 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea/law of nature/natural phenomenon without significantly more. In accordance with MPEP § 2106, claims found to recite statutory subject matter (Step 1: YES) are then analyzed to determine if the claims recite any concepts that equate to an abstract idea, law of nature or natural phenomenon (Step 2A, Prong 1). In the instant application, the claims recite the following limitations that equate to an abstract idea:
Claim 1, 16 and 29 recite predicting cell features based on the captured image; predicting a segmentation based on the captured image; predicting a cellular phenotype; determining at least one of a molecular readout or diagnosis/prognosis based on the cellular phenotype.
Claims 2 recites wherein the method further includes: in a case where the captured image includes at least one of the brightfield data, the darkfield data, or the phase contrast data: the cell features include a cell identification; the method further includes determining a morphology of the identified cell; and the cell features include sub-cellular features, the sub cellular features including nuclei and mitochondria; in a case where the captured image includes multichannel fluorescence data: the predicting further includes a molecular phenotype; and in a case where the captured image includes the diffraction data: predicting phase information; and determining cell volume based on the generated 3D tomographic images.
These recitations equate to steps of collecting information, analyzing data and making observations, evaluations and judgements that can be carried out in the human mind. Specifically, predicting cell features/identification/morphology, segmentation, phase information and cellular phenotype based on an image, and determining a molecular readout or diagnosis/prognosis based on the cellular phenotype, as claimed, can be practically performing the human mind as claimed, since the mind can read data and make mathematical estimations/comparisons as claimed and are similar to the concepts of collecting and comparing known information in Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1067, 100 USPQ2d 1492, 1500 (Fed. Cir. 2011) and collecting information, analyzing it, and reporting certain results of the collection and analysis in Electric Power Group v. Alstom, S.A., 830 F.3d 1350, 1353-54, 119 USPQ2d 1739, 1741-42 (Fed. Cir. 2016) that the courts have identified as concepts that can be practically performed in the human mind. Therefore, each of the above recited limitations fall under the “Mental Processes” grouping of abstract ideas. Claim 6, 20, and 33 further qualify the recited judicial exception. As such, claims 1-6, 12, 15-20, 26, 29-33, and 39 recite an abstract idea (Step 2A, Prong 1: YES).
Claims found to recite a judicial exception under Step 2A, Prong 1 are then further analyzed to determine if the claims as a whole integrate the recited judicial exception into a practical application or not (Step 2A, Prong 2). This judicial exception is not integrated into a practical application because the claims do not recite an additional element that reflects an improvement to technology, applies or uses the recited judicial exception to affect a particular treatment for a condition, implements a judicial exception with, or uses a judicial exception in conjunction with, a particular machine or manufacture that is integral to the claim, effects a transformation or reduction of a particular article to a different state or thing or applies or uses the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception. Rather, the instant claims recite additional elements that amount to mere data gathering and outputting and mere instructions to implement the abstract idea in a generic computing environment. Specifically, the claims recite the following additional elements:
Claims 1, 16 and 29 recite capturing multi-modal images, by an imaging device, the images including a subject sample tagged with reporters, the image types including at least one of a brightfield data, a darkfield data, a phase contrast data, multichannel fluorescence data, or diffraction data; communicating the captured image to an image processing unit, the image processing unit including a first neural network; displaying, on a display, at least one of the readout or the diagnosis/prognosis.
Claim 3 recites wherein the subject sample is a cellular sample.
Claim 4 recites wherein the reporter detects the presence of one or more biomarkers associated with a disease or disorder within the sample.
Claims 5, 19, and 32 recite wherein the biomarker is selected from the group consisting of EpCAM, HER2, ER, PR, Ki67, EGFR, CD24, Lin8a, GPA22, CD133, MET, ALK, MUC1, MUC5ac, TTF-1, CYFRA 21-1, WNT2, CYFRA 21-1 Trop2, CD44, p16, GPA33, EpCA, BRAFF, EGFR, MET, k (kappa), X (lambda), CD 19/20, p40, p63, tsMHCl, tsMHC2, CD133, GPC3, HepPar-1, CEA, AFP, Arg-1, CD45, CD1a CD3, CD4, CD8, CD11B, CD11C, CD20, CD45, CD45RA, CD45RO, CD49a, CD66B, CD68, CD103, CD161, CD163, FoxP3, PD-L1, PD1, TCF1, GZMB, IFNg, MHCI, MHCII,IL12b, the TAM (Tyro3, Axl, and Mer) family of receptors and TAN.
Claim 12, 26 and 39 recites wherein the reporter is selected from the group consisting of an antibody, chromogen, microsphere, nanoparticle, a molecule affinity ligand er a nucleic acid, a reporter directly tagged with a detectable label, and a reporter indirectly tagged with a detectable label.
Claims 15, 17 and 30 recite wherein the subject sample is obtained by endoscopy, bronchoscopy, aspiration of a palpable mass; aspiration of a visually detectable mass; image guided aspiration by, for example, ultrasound or CT scan; endoscopic biopsy; surgical (i.e. incisional) fine needle aspiration (FNA); biopsy washes; thoracentesis, paracentesis, urine collection and mucosal brushing (e.g. cervical, buccal).
Claims 16 and 29 further recites receiving a sample of a cellular specimen, re-suspending the sample of the cellular specimen in perm lyse buffer in a vial; tagging the sample of the cellular specimen with a reporter; immobilizing the sample of the cellular specimen on an optically transparent substrate.
Claim 29 further recites a re-suspension unit configured to re-suspend a sample of a cellular specimen in perm lyse buffer in a vial; a tagging unit configured to tag a sample of the cellular specimen with a reporter; an immobilization unit configured to immobilize the sample of the cellular specimen on an optically transparent substrate; an imaging device configured to acquire images; a display device; a processor; and a memory.
The additional elements of the claims recite limitations for gather data, as well as limitations for the type of data gathered. These limitations equate to mere data gathering activity to obtain the data necessary for the mental evaluations and judgements (see MPEP 2106.05(g)). Claims 1, 16 and 29 also recite limitations for outputting data that the courts consider to be an insignificant extra-solution activity (see MPEP 2106.05(d)). There is no indication that any of these additional elements provide a practical application of the recited judicial exception outside of the judicial exception itself.
The neural network is used to generally apply the abstract idea without placing any limits on how the neural network functions. The claims also recite using a generic computing systems and computer program products to carry out instructions to implement an abstract idea on a computer. recites using a generic computing systems and computer program products to carry out instructions to implement an abstract idea on a computer. The computer system and computer program product as claimed fails to recite details of how a solution to a problem is accomplished and only recites the idea of a solution or outcome. There are no limitations that indicate that the claimed steps require anything other than generic computing systems. As such, these limitations equate to mere instructions to implement the abstract idea on a generic computer that the courts have stated does not render an abstract idea eligible in Alice Corp., 573 U.S. at 223, 110 USPQ2d at 1983. See also 573 U.S. at 224, 110 USPQ2d at 1984. Furthermore, the use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not integrate a judicial exception into a practical application. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit). As such, claims 1-6, 12, 15-20, 26, 29-33, and 39 are directed to an abstract idea (Step 2A, Prong 2: NO).
Claims found to be directed to a judicial exception are then further evaluated to determine if the claims recite an inventive concept that provides significantly more than the judicial exception itself (Step 2B). Further analyzing the additional elements under step 2B, the additional elements as described above do not rise to the level of significantly more than the judicial exception. As set forth in the MPEP, determinations of whether or not additional elements (or a combination of additional elements) may provide significantly more and/or an inventive concept rests in whether or not the additional elements (or combination of elements) represents well-understood, routine, conventional activity. Said assessment is made by a factual determination stemming from a conclusion that an element (or combination of elements) is widely prevalent or in common use in the relevant industry, which is determined by either a citation to an express statement in the specification or to a statement made by an applicant during prosecution that demonstrates a well-understood, routine or conventional nature of the additional element(s); a citation to one or more of the court decisions as discussed in MPEP 2106(d)(II) as noting the well-understood, routine, conventional nature of the additional element(s); a citation to a publication that demonstrates the well-understood, routine, conventional nature of the additional element(s); and/or a statement that the examiner is taking official notice with respect to the well-understood, routine, conventional nature of the additional element(s).
With respect to the instant claims under the 2B analysis, Gupta et al. (Cytometry Part A 2019, 95(4), pp.366-380; hereafter referred to as Gupta) reviews deep learning in image cytometry and discloses automation of microscopy, including sample handling and microscope control to enable rapid collection of digital image data from cell samples, tissue slides, and cell cultures grown in multi-well plates using artificial intelligence, deep convolutional neural networks, and deep learning is well-known, routine and conventional in the art (abstract; p 366, para 1). Gupta further there are numerous published articles on deep learning for image cytometry including performing image processing, classification, detection, and segmentation for brightfield, electron and fluorescence for tissue, cellular and sub-cellular cell types, including in cancer samples, using reporters (fig 6; p 371, col 1, para 1-col 2, para 2; p 372, col 1, para 4-p 373, col 2, para 2). Furthermore, the prior art to Abraham et al. (Methods in enzymology 2019, 628, pp.191-221)discloses automated cytometry and discloses automated capillary electrophoresis-based instruments with hardware to lyse, load, and separate cells in an automated fashion, along with xy-stage, capillary and fluorescence-detection system mount, xyz-micromanipulators, white LED, custom fluidic cassette, CE optical path mount, capillary outlet holder & buffer vial, optical post, microscope revolving turret w/objective, Nd:YAG laser entry port, coarse/fine focus knobs, xy-stage mounts, microscope filter-sets, and CCD camera coupled to a computer for analysis is also well-known, routine and conventional in the art (abstract; fig 1-2; table 1-5; fig 5-7; p 215, para 3). The prior art to Penault-Llorca et al. (American journal of clinical pathology 2009, 132(4), pp.539-548) and Powell et al. (Hum Pathol. 2007;38:1145–1159) disclose that a fully automated technique to detect chromogenic signals has recently been introduced by Ventana Medical Systems, Tucson, AZ, using INFORM HER2 SISH technology with automated sample preparation, pretreatment, hybridization, detection and counterstaining steps, using receptors that bind to HER2for gene determination in breast cancer and other biopsy specimens using automated image analysis (Penault-Llorca et al.: p 542, col 1, para 2-4; Powell et al.: abstract; table 1; p 1151, col 2, para 2-p 1154, col 1, para 2). Furthermore, use of a computer or other machinery in its ordinary capacity for economic or other tasks (e.g., to receive, store, or transmit data) or simply adding a general purpose computer or computer components after the fact to an abstract idea (e.g., a fundamental economic practice or mathematical equation) does not provide significantly more. See Affinity Labs v. DirecTV, 838 F.3d 1253, 1262, 120 USPQ2d 1201, 1207 (Fed. Cir. 2016) (cellular telephone); TLI Communications LLC v. AV Auto, LLC, 823 F.3d 607, 613, 118 USPQ2d 1744, 1748 (Fed. Cir. 2016) (computer server and telephone unit). Therefore, the additional elements do not comprise an inventive concept when considered individually or as an ordered combination that transforms the claimed judicial exception into a patent-eligible application of the judicial exception, and the claims do not amount to significantly more than the judicial exception itself (Step 2B: NO). As such, claims 1-6, 12, 15-20, 26, 29-33, and 39 are not patent eligible under 35 U.S.C. 101.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim 1, 3, 4-5, 12 and 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu et al. (IEEE transactions on medical imaging 2018, 38(2), 617-628; hereafter referred to as Liu), as evidenced by Rakha et al. (Br J Cancer 2014, 110, 1688–1697; hereafter referred to as Rakha), Abd El-Rehim et al. (Int J Cancer 2005, 116: 340-350;hereafter referred to as Abd El-Rehim) and Kononen et al. (Nature medicine 1998, 4(7), 844-847;hereafter referred to as Kononen).
With respect to claims 1, 3, and 15, Liu discloses a CNN based CAD framework for biomarker assessment of TMA images (p 619, col 2, para 3).
Liu further discloses using TMA images of breast adenocarcinomas from the NPI+ set, as disclosed by Rakha (p 622, col 1, para 2). Rakha discloses immunohistochemical reactivity for 10 proteins, with known relevance in BC including those used in routine clinical practice, was previously determined using standard immunocytochemical techniques on tumour samples prepared as tissue microarrays (TMAs) and these markers were chosen from a comprehensive panel of 25 markers used in their previously study, and that levels of immunohistochemical reactivity were determined by microscopic analysis and equivocal cases were confirmed by CISH (i.e. brightfield data) (p 1689, col 2, para 3-p1690, col 1, para 1). Their previous study, Abd El-Rehim, discloses breast cancer TMA were prepared as described previously, such as by Kononen, and cores of 0.6 mm thickness were obtained from the most representative areas of the tumors then re-embedded in microarray blocks (p 341, col 1, para 4). Kononen discloses obtaining tissue biopsies from individual tumors, including small tissue core biopsies (abstract; fig 1).
Liu further discloses an end-to-end system that takes a TMA image as the input and directly outputs a clinical score, by using one fully convolutional network (FCN) to extract all nuclei region (tumor and non-tumor), a second FCN to extract tumor nuclei region, and a multi-column convolutional neural network, which takes the outputs of the first two FCNs and the stain intensity description image as an input and acts as the high-level decision making mechanism to directly output the H-Score of the input TMA image (abstract).
Liu further discloses it consists of three stages: 1) general nuclei and tumor regions segmentation; 2) stain intensity description; 3) constructing the SINI and SITI, and predicting the final histochemical score (H-Score) by the Region Attention Multi-column Convolutional Neural Network (RAM-CNN) (p 619, col 2, para 3-p620, col 1, para 1). Liu discloses using use two separate FCNs, one for segmenting the foreground region which contains all nucleus and the other for segmenting the region of tumor nucleus only (p 621, col 1, para 2).
Liu discloses the H-scores is one of the most important pieces of information for molecular tumor classification and are combined together to determine the biological class of a case using semi-qualitative information of the total number of cells, the number of tumor cells and the stain intensity distributions within the tumor cells (p 617, col 2, para 2-p 618, col 1, para 1).
Liu discloses a CNN based Computer Aided Diagnosis (CAD) framework, and further discloses outputting the H-score, indicating the H-score is displayed on a display (fig 3; abstract; p 619, col 2, para 3).
With respect to claim 4, 5, and 12, Liu discloses using TMA images of breast adenocarcinomas from the NPI+ set, as disclosed by Rakha (p 622, col 1, para 2). Rakha discloses determining immunohistochemical reactivity biomarkers used for classification were ER, progesterone receptor (PgR), cytokeratin (CK) 5/6, CK7/8, epidermal growth factor receptor (EGFR; HER1), c-erbB2 (HER2), c-erbB3 (HER3), c-erbB4 (HER4), p53 and Mucin 1, associated with breast cancer, and that levels of immunohistochemical reactivity were determined by microscopic analysis using the modified Histochemical score (H-score), giving a semiquantitative assessment of both the intensity of staining and the percentage of positive cells (p 1689, col 2, para 3-p1690, col 1, para 1). Rakha’s previous study, Abd El-Rehim, discloses, immunohistochemical staining for the sections was performed using the streptavidin-Biotin Complex method (p 341, col 1, para 4).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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 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.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (IEEE transactions on medical imaging 2018, 38(2), 617-628; hereafter referred to as Liu), as evidenced by Rakha et al. (Br J Cancer 2014, 110, 1688–1697; hereafter referred to as Rakha), Abd El-Rehim et al. (Int J Cancer 2005, 116: 340-350;hereafter referred to as Abd El-Rehim) and Kononen et al. (Nature medicine 1998, 4(7), 844-847;hereafter referred to as Kononen), as applied to claim 1 above, and in further view of (Nat Rev Clin Oncol 2004, 1, 104–111; hereafter referred to as Giltnane).
With respect to claim 2, Liu, as evidenced by Rakha, Abd El-Rehim and Kononen discloses the methods of claim 1, as applied above.
Liu further discloses determining nuclei morphology and providing a tumor identification, which is able to identify tumor region from normal tissue (i.e. cell identification) (p 623, col 1, para 2).
However, Liu does not disclose the that the sub-cellular features include mitochondria.
However, Giltnane discloses most subcellular organelles are not identifiable by eye and optimized automated TMA analysis should measure target expression within subcellular compartments, and fluorescence-based systems allow co-localization with markers of specific subcellular compartments, such as the Golgi, mitochondria, or endoplasmic reticulum, or even virtual compartments such as tyrosine kinases or second messengers, and that automated analysis should enable high-throughput processing (p 108, col 2, para 1-2).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods of Liu for use with the images produced by TMA and fluorescence-based systems, as disclosed by Giltnane, because automated TMA analysis should measure target expression within subcellular compartments not identifiable by eye, and fluorescence-based systems allow co-localization with markers of specific subcellular compartments, such as the Golgi, mitochondria, or endoplasmic reticulum, or even virtual compartments such as tyrosine kinases or second messengers, as disclosed by Giltnane. There would be a reasonable expectation of success, as the images produced by Giltnane can be used for automated analysis and would not impede the method of Liu. Therefore, the invention is prima facie obvious.
Claims 16-20, 26, 29-33, and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Liu et al. (IEEE transactions on medical imaging 2018, 38(2), 617-628; hereafter referred to as Liu), as evidenced by Rakha et al. (Br J Cancer 2014, 110, 1688–1697; hereafter referred to as Rakha), Abd El-Rehim et al. (Int J Cancer 2005, 116: 340-350;hereafter referred to as Abd El-Rehim) and Kononen et al. (Nature medicine 1998, 4(7), 844-847;hereafter referred to as Kononen), in further view of Gupta et al. (Cytometry Part A 2019, 95(4), pp.366-380; hereafter referred to as Gupta), Abraham et al. (Methods in enzymology 2019, 628, pp.191-221), Penault-Llorca et al. (American journal of clinical pathology 2009, 132(4), pp.539-548) and Powell et al. (Hum Pathol. 2007;38:1145–1159).
With respect to claims 16-17 and 29-30, Liu discloses a CNN based CAD framework for biomarker assessment of TMA images (p 619, col 2, para 3).
Liu further discloses using TMA images of breast adenocarcinomas from the NPI+ set, as disclosed by Rakha (p 622, col 1, para 2). Rakha discloses immunohistochemical reactivity for 10 proteins, with known relevance in BC including those used in routine clinical practice, was previously determined using standard immunocytochemical techniques on tumour samples prepared as tissue microarrays (TMAs) and these markers were chosen from a comprehensive panel of 25 markers used in their previously study, and that levels of immunohistochemical reactivity were determined by microscopic analysis and equivocal cases were confirmed by CISH (i.e. brightfield data) (p 1689, col 2, para 3-p1690, col 1, para 1). Their previous study, Abd El-Rehim, discloses breast cancer TMA were prepared as described previously, such as by Kononen, and cores of 0.6 mm thickness were obtained from the most representative areas of the tumours then re-embedded in microarray blocks (p 341, col 1, para 4). Kononen discloses obtaining tissue biopsies from individual tumors, including small tissue core biopsies (abstract; fig 1).
Liu further discloses an end-to-end system that takes a TMA image as the input and directly outputs a clinical score, by using one fully convolutional network (FCN) to extract all nuclei region (tumor and non-tumor), a second FCN to extract tumor nuclei region, and a multi-column convolutional neural network, which takes the outputs of the first two FCNs and the stain intensity description image as an input and acts as the high-level decision making mechanism to directly output the H-Score of the input TMA image (abstract).
Liu further discloses it consists of three stages: 1) general nuclei and tumor regions segmentation; 2) stain intensity description; 3) constructing the SINI and SITI, and predicting the final histochemical score (H-Score) by the Region Attention Multi-column Convolutional Neural Network (RAM-CNN) (p 619, col 2, para 3-p620, col 1, para 1). Liu discloses using use two separate FCNs, one for segmenting the foreground region which contains all nucleus and the other for segmenting the region of tumor nucleus only (p 621, col 1, para 2).
Liu discloses the H-scores is one of the most important pieces of information for molecular tumor classification and are combined together to determine the biological class of a case using semi-qualitative information of the total number of cells, the number of tumor cells and the stain intensity distributions within the tumor cells (p 617, col 2, para 2-p 618, col 1, para 1).
Liu discloses a CNN based Computer Aided Diagnosis (CAD) framework, and further discloses outputting the H-score, indicating the H-score is displayed on a display (fig 3; abstract; p 619, col 2, para 3).
However, Liu does not appear to disclose the steps for resuspending a sample in perm lyse buffer in a vial or using a system with a re-suspension, tagging and immobilization units.
However, the prior art to Gupta et al. (Cytometry Part A 2019, 95(4), pp.366-380; hereafter referred to as Gupta) reviews deep learning in image cytometry and discloses automation of microscopy, including sample handling and microscope control to enable rapid collection of digital image data from cell samples, tissue slides, and cell cultures grown in multi-well plates using artificial intelligence, deep convolutional neural networks, and deep learning is well-known in the art (abstract; p 366, para 1). Gupta further there are numerous published articles on deep learning for image cytometry including performing image processing, classification, detection, and segmentation for brightfield, electron and fluorescence for tissue, cellular and sub-cellular cell types, including in cancer samples, using reporters (fig 6; p 371, col 1, para 1-col 2, para 2; p 372, col 1, para 4-p 373, col 2, para 2). Furthermore, the prior art to Abraham et al. discloses automated cytometry and discloses automated capillary electrophoresis-based instruments with hardware to lyse, load, and separate cells in an automated fashion, along with xy-stage, capillary and fluorescence-detection system mount, xyz-micromanipulators, white LED, custom fluidic cassette, CE optical path mount, capillary outlet holder & buffer vial, optical post, microscope revolving turret w/objective, Nd:YAG laser entry port, coarse/fine focus knobs, xy-stage mounts, microscope filter-sets, and CCD camera coupled to a computer for analysis is also well-known in the art (abstract; fig 1-2; table 1-5; fig 5-7; p 215, para 3). The prior art to Penault-Llorca et al. and Powell et al. (Hum Pathol. 2007;38:1145–1159) disclose that a fully automated technique to detect chromogenic signals has recently been introduced by Ventana Medical Systems, Tucson, AZ, using INFORM HER2 SISH technology with automated sample preparation, pretreatment, hybridization, detection and counterstaining steps, using receptors that bind to HER2for gene determination in breast cancer and other biopsy specimens using automated image analysis (Penault-Llorca et al.: p 542, col 1, para 2-4; Powell et al.: abstract; table 1; p 1151, col 2, para 2-p 1154, col 1, para 2).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods of Liu for use with the images produced by the automated systems as disclosed by Gupta, Abraham et al., Penault-Llorca et al., and Powell et al., since automated microscopy and cytometry for use in automated image analysis was a known device and technique that was recognized as part of the ordinary capabilities of one skilled in the art, as demonstrated by Gupta, Abraham et al., Penault-Llorca et al. and Powell et al.. One of ordinary skill in the art would have been capable of applying this known technique to a known device that was ready for improvement and the results would have been predictable to one of ordinary skill in the art.
With respect to claim 18-20, 26, 31-33 and 39, Liu discloses using TMA images of breast adenocarcinomas from the NPI+ set, as disclosed by Rakha (p 622, col 1, para 2). Rakha discloses determining immunohistochemical reactivity biomarkers used for classification were ER, progesterone receptor (PgR), cytokeratin (CK) 5/6, CK7/8, epidermal growth factor receptor (EGFR; HER1), c-erbB2 (HER2), c-erbB3 (HER3), c-erbB4 (HER4), p53 and Mucin 1, associated with breast cancer, and that levels of immunohistochemical reactivity were determined by microscopic analysis using the modified Histochemical score (H-score), giving a semiquantitative assessment of both the intensity of staining and the percentage of positive cells (p 1689, col 2, para 3-p1690, col 1, para 1). Rakha’s previous study, Abd El-Rehim, discloses, immunohistochemical staining for the sections was performed using the streptavidin-Biotin Complex method (p 341, col 1, para 4).
Therefore, the invention is prima facie obvious.
Conclusion
No claims allowed.
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/N.D./
Examiner, Art Unit 1686
/Karlheinz R. Skowronek/Supervisory Patent Examiner, Art Unit 1687