DETAILED ACTION
This action is in reply to papers filed 11/26/2025. Claims 1-9 are pending and examined herein.
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 .
Withdrawn Objection(s) and Rejection(s)
The cancellation of claims 10-11 renders any rejections thereof moot.
The objections to claims 2-4 and 6-7 are withdrawn in light of amendments to the claims, which corrects the phrase “antibody with” to “antibody conjugated to.”
The rejection of claim 1 under 35 U.S.C. 102(a)(1) as being anticipated by Sun (EBioMedicine, 2019, 46: 133-149) is withdrawn in light of amendment to claim 1, which incorporates the limitations of cancelled claims 10-11.
The rejection of claims 1, 2, and 5-7 under 35 U.S.C. 103 over Sun (EBioMedicine, 2019, 46: 133-149), in view of Goudar (Sensors and Actuators B: Chemical, 2020, 316: 128002) and Bucevicius (Chemosensors, 2018, 6(2): 18) is withdrawn in light of amendment to claim 1, which incorporates the limitations of cancelled claims 10-11.
The rejection of claims 1 and 3 under 35 U.S.C. 103 over Sun (EBioMedicine, 2019, 46: 133-149), in view of Wei (Sensors and Actuators B: Chemical, 2019, 281: 131-138) and Sikes Johnson (WO 2022/103797 A1) is withdrawn in light of amendment to claim 1, which incorporates the limitations of cancelled claims 10-11.
The rejection of claims 1 and 4 under 35 U.S.C. 103 over Sun (EBioMedicine, 2019, 46: 133-149), in view of Mao (US 2019/0262836 A1) and Sikes Johnson (WO 2022/103797 A1) is withdrawn in light of amendment to claim 1, which incorporates the limitations of cancelled claims 10-11.
Claim Rejections - 35 USC § 112(a)
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 1-8 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.
Amended claim 1 recites the limitation “comparing a cell contour of the second preliminary target cells marked in the white light image photo with a cell contour located by the valid fluorescence signals in the second fluorescence image photo, and if a relative position difference of the cell contours between the white light image photo and the second fluorescence image photo is less than or equal to 5% of the diameter size of the target cells, the second preliminary target cells are determined and identified as the target cells” in the last 6 lines, which constitute new matter.
Applicant argues that this amendment has support in cancelled claims 10-11 and in paragraphs [0040] and [0060] of the as-filed specification. Applicant argues that the those skilled in the art can understand that "the relative position error of the cell contour displayed in the white light image photo and the cell contour circled according to the fluorescence signal in the fluorescence image photo" should be understood or explained as "a relative position difference or distance of the cell contours between the white light image photo and the second fluorescence image photo" since the relative position error is compared with "the average diameter of the target cells" and this is a parameter relative to both of the cell contour displayed in the white light image photo and the cell contour circled according to the fluorescence signal in the fluorescence image photo.
This argument has been fully considered, but is not persuasive. First, the phrase “relative position difference” does not appear in the original claims or in the specification, and therefore, there is no support for this amended phrase in the specification. Furthermore, the phrase “relative position error” is not defined in the specification. In the absence of a definition, one of ordinary skill in the art would not equate the phrase “relative position error” with “relative position difference,” as the word “difference” is not a synonym for “error.
For the sake of compact prosecution, the limitation “relative position difference” in amended claim 1 is interpreted as “relative position error.” Claims 2-8 depend from claim 1, and are therefore included in the rejection.
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.
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.
Claim 1 is rejected, and claims 5-7 remain 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, as amended, incorporates the limitation of cancelled claims 10-11, and is rejected for the same reason as set forth previously for claims 10-11. Amended claim 1 recites the phrase “if a relative position difference of the cell contours between the white light image photo and the second fluorescence image photo is less than or equal to 5% of the diameter size of the target cells” (last 4 lines of claim 1). The limitation “of the diameter size of the target cells” at the end of this phrase renders the claim indefinite. If relative position difference is measured according to the contours of the cells in the white-light image and second-fluorescence image, it is unclear how relative position difference relates back to a percentage of a diameter of the cells. Therefore, although the metes and bounds of the phrase “relative position difference of the cell contours between the white light image photo and the second fluorescence image photo is less than or equal to 5%” is clear, it is unclear what is meant by the additional limitation “of the diameter size of the target cells.” The specification defines “relative position” as “localization” (p 10, para 37), but this does not further clarify the language of claim 1. For the purposes of examination, this phrase is interpreted as “if a relative position difference of the cell contours between the white light image photo and the second fluorescence image photo is less than or equal to 5%.” Furthermore, the phrase “the diameter size of the target cells” lacks antecedent basis.
Claims 5-7, as amended, clarifies that the unit of measurement of fluorescent signal is measured in arbitrary units. Arbitrary units (A.U.) are often used as a unit of measurement for fluorescence (see, e.g., Fig 3 of Sun, EBioMedicine, 2019, 46: 133-149), but an A.U. is dependent on the instrument settings and experimental conditions (Kamat, ASC Energy Letters, 2019, 4: 2005-2006, p. 2005, col 2, para 2). The claims do not set forth a method for determining said arbitrary unit, nor does the instant specification provide enough details to allow a person of ordinary skill in the art to reproduce the specific arbitrary unit to be used in the method of claim 1. Therefore, the metes and bounds of claims 5-7 are unclear.
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.
Claim(s) 1 and 8-9 remain rejected under 35 U.S.C. 103 as being unpatentable over Sun (EBioMedicine, 2019, 46: 133-149), in view of Wu (J Clin Oncol 2020, 38: e15530, ASCO Meeting Abstract).
Wu was cited in the previous Office Action mailed 08/26/2025, but was missing from PTO-892. A copy of Wu has been attached to the instant Office Action.
Regarding claims 1 and 8: Sun discloses a method for detecting circulating tumor cells (CTCs) based on phenotypic criteria (Abstract). Sun discloses preparing blood from patient samples (reads on analysis sample), introducing the sample into a microfluidic chip, then identifying CTCs (reads on target cells) using an immunofluorescent (IF) staining technique. After fixing and permeabilizing the isolated cells inside the chip, the chip was perfused with DAPI to stain the cell nuclei (reads on a first fluorescent marker), Alexa Fluor 488 conjugated anti-CD45 to mark white blood cells (reads on a third fluorescent marker for marking the non-target cells), Alexa Fluor 555 conjugated anti-E-cadherin to mark epithelial cells (reads on a second or third fluorescent marker), and Alexa Fluor 647 conjugated anti-vimentin to mark mesenchymal cells (reads on a second or third fluorescent marker) (Section 2.7). The chip was imaged using an inverted fluorescence microscope in both the bright field (reads on white light scan) and fluorescence modes with appropriate filter cubes for each fluorescent marker (first, second and third fluorescence wave band). ImageJ software was used for measurement of fluorescent intensity and analysis of cell size (Sections 2.2, 2.4).
Sun discloses defining CTC phenotypes based on the IF staining result and a combined morphologic criterion (round or oval) (Fig 4a). CTCs were identified with immunofluorescence staining results of DAPI+/CD45−/E-cad+/vimentin- for epithelial CTC, DAPI+/CD45−/E-cad−/vimentin+ for mesenchymal CTC, or DAPI+/CD45−/E-cad+/vimentin+ for hybrid CTC (Sections 2.7; 3.2). Morphologically, CTCs were defined as having a circular or oval shape (Section 3.2; reads on identifying and screening the second preliminary target cells with a specific cell phenotype and shape as the target cells).
Sun discloses calculating the diameter of cells, and using a round or oval cell morphology as a phenotype criterion for CTC cells (Section 3.2; Fig 4d; reads on a standard shape of the target cells).
Figure 4A of Sun shows a cross-comparison of white-light image photos (Fig 4a, “Bright Field” column) with second fluorescence image photos (Fig 4a, “E-cadherin” and “Vimentin” columns). In Figure 4A, cells in the bright field photos which are positive for E-Cadherin (1), Vimentin (2), or both E-Cadherin and Vimentin (3) are identified as the target CTC cells (Fig 4 caption). For each of these target cells, the contour of the target CTC cell in the bright field photo and the counter of the target CTC cell in the second fluorescent image (i.e., E-Cadherin or Vimentin) appear to have relative position error that is less than or equal to 5%.
Sun does not teach comparing a cell contour of the second preliminary target cells marked in the white light image photo with a cell contour located by the valid fluorescence signals in the second fluorescence image photo, and if a relative position difference of the cell contours between the white light image photo and the second fluorescence image photo is less than or equal to 5% of the diameter size of the target cells, the second preliminary target cells are determined and identified as the target cells.
Wu teaches a method to classify CTCs based on immunofluorescent methods and cell morphology. Wu teaches that the size and shape of CTCs, combined with fluorescent intensity from immunofluorescent methods, provide useful morphological information for monitoring the recurrence of disease for patients with lung cancer (Background; Methods; Conclusions).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Sun by calculating the perimeter and area of CTCs to determine the size and shape of CTCs. One of ordinary skill in the art would have been motivated to make this modification because Wu teaches that information regarding the shape and size of CTCs is useful for morphological classification. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Wu teaches that the size and shape can be determined for a CTC (Methods).
Regarding claim 9: Sun teaches that CTCs were defined as having a circular or oval shape (Section 3.2, para 2). A circle has an eccentricity of 0. Figure 4a of Sun shows bright field images of epithelial CTCs, mesenchymal CTCs, and hybrid CTCs. The CTCs depicted in the bright field images in Figure 4a appear to be circles or micro-ellipses with an eccentricity less than 0.8.
Claims 1, 2, and 5-7 are rejected under 35 U.S.C. 103 as being unpatentable over Sun (EBioMedicine, 2019, 46: 133-149), in view of Wu (J Clin Oncol 2020, 38: e15530, ASCO Meeting Abstract), Goudar (Sensors and Actuators B: Chemical, 2020, 316: 128002) and Bucevicius (Chemosensors, 2018, 6(2): 18).
The teachings of Sun and Wu are set forth above. Sun, in view of Wu, renders obvious claim 1.
Regarding claims 2 and 5-7: Sun teaches a cell identification method, wherein the target cells are circulating tumor cells, the first fluorescent marker is DAPI, and the third fluorescent marker is an anti-CD45 antibody conjugated to Alexa Fluor 488.
Sun does not teach the method of claim 1, wherein the first fluorescent marker is Hoechst 33342, the second fluorescent marker is an anti-EpCAM antibody conjugated to FITC, and the third fluorescent marker is an anti-CD45 antibody conjugated to PE.
Goudar teaches a method for selecting CTCs from whole blood on digitized self-assembled cell array chips (Abstract; Title). The method comprises obtaining peripheral blood samples from human patients, centrifuging the whole-blood sample to obtain a mixture comprising CTCs (reads on target cells) and white blood cells (reads on non-target cells), staining the samples with fluorescent markers, loading the cells onto the chip, and using an automatic imaging system to scan and count CTCs based on fluorescent signals (p 3, Section 2.3; Fig 2).
Goudar teaches using Hoechst 33258 as a nuclear marker, an anti-EpCAM antibody conjugated to FITC (hereinafter EpCAM-FITC) as a positive marker for CTCs, and an anti-CD45 antibody conjugated to PE (hereinafter CD-45 PE) as a negative marker for CTCs and positive marker for white blood cells (Fig 5; Fig 7; Section 3.2, para 3). Goudar teaches that Hoechst 33258 (Fig 5, 7), EpCAM-FITC (Fig 5, 7), and CD-45 PE (Fig 5) emit detectable fluorescent signal (see Claim Interpretation for claims 5-7).
Regarding the first fluorescent marker, Hoechst 33342, as recited in claims 2 and 5:
Bucevicius teaches that both DAPI and Hoechst are DNA-specific blue fluorescent dyes, but Hoechst exhibits greater cell permeability and lower cytotoxicity, and is therefore generally preferred over DAPI (1. Introduction). Bucevicius further teaches that Hoechst 33342 is significantly more cell permeable compared to Hoechst 33258 (2. Properties of Hoechst Dyes, para 2).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Sun by using Hoechst 33258 for nuclear staining, as taught in Goudar. One of ordinary skill in the art would have been motivated to make this modification because Bucevicius teaches that Hoechst exhibits greater cell permeability compared to DAPI. One of ordinary skill in the art would have had a reasonable expectation of making this modification because Goudar and Bucevicius teach that Hoechst 33258 can be used as a fluorescent stain for DNA.
Given the teachings of Bucevicius, it would have been further prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Sun, in view of Goudar and Bucevicius, by using Hoechst 33342 instead of Hoechst 33258 for nuclear staining. One of ordinary skill in the art would have been motivated to make this modification because Bucevicius teaches that Hoechst 33342 is significantly more cell permeable compared to Hoechst 33258. One of ordinary skill in the art would have had a reasonable expectation of making this modification because Bucevicius teaches that Hoechst 33342 can be used as a fluorescent stain for DNA.
Regarding the second fluorescent marker, EpCAM-FITC, as recited in claims 2 and 6: Sun does not teach EpCAM-FITC as a marker for target cells.
Goudar teaches the use of EpCAM-FITC as a positive marker for identifying CTCs in IF staining (Fig 7e; Section 3.2, para 3). Given the teachings of Goudar, there was a reasonable expectation that EpCAM-FITC would work equivalently to mark CTCs as an anti-E-Cadherin or anti-vimentin antibody conjugated to Alexa Fluor fluorophores, as taught in Sun. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted the anti-E-Cadherin or anti-vimentin antibody conjugated to Alexa Fluor fluorophores with EpCAM-FITC in the method of Sun with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Regarding the third fluorescent marker, CD45-PE, as recited in claims 2 and 7: Sun does not teach CD45-PE as third fluorescent marker.
Goudar teaches the use of CD45-PE as a marker for white blood cells (non-target cells) in IF staining (Fig 5; Fig 7; Section 3.2, para 3). Given the teachings of Goudar, there was a reasonable expectation that CD45-PE would work equivalently to mark white blood cells as an anti-CD45 antibody conjugated to Alexa Fluor 488, as taught in Sun. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted the anti-CD45 conjugated to Alexa Fluor 488 with CD45-PE in the method of Sun with predictable results. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Claims 1 and 3 are rejected under 35 U.S.C. 103 as being unpatentable over Sun (EBioMedicine, 2019, 46: 133-149), in view of Wu (J Clin Oncol 2020, 38: e15530, ASCO Meeting Abstract), Wei (Sensors and Actuators B: Chemical, 2019, 281: 131-138) and Sikes Johnson (WO 2022/103797 A1).
The teachings of Sun and Wu are set forth above. Sun, in view of Wu, renders obvious claim 1.
Regarding claim 3: Sun teaches a cell identification method, wherein the first fluorescent marker is DAPI.
Sun does not teach the method of claim 1, wherein the target cells are fetal nucleated red blood cells, the second fluorescent marker is an anti-CD147 antibody conjugated to FITC, and the third fluorescent marker is an anti-CD71 antibody conjugated to PE.
Wei teaches a method for the isolation of fetal nucleated red blood cells from maternal peripheral blood (Abstract), by performing immunofluorescence using DAPI (p 132, col 2, para 2; p 136, col 2, para 1), FITC-labeled anti-CD71 (p 133, col 2, para 3; p 136, col 2, para 1), and biotinylated anti-CD147 (Section 2.1). Wei teaches that the target fetal nucleated red blood cells are positive for CD71 and CD147 (p 136, Section 3.4; Fig 5A, C).
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Sun to use anti-CD147 and anti-CD71 antibodies to mark fNRBCs as the target cells. One of ordinary skill in the art would have been motivated to make this modification to target fNRBCs from a sample comprising fNRBCs and non-target cells, because Wei teaches that fNRBCs carry the total genetic information of the fetus, and therefore has the potential for non-invasive prenatal diagnostics (Abstract). One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Wei teaches that anti-CD147 and anti-CD71 antibodies can be used as markers for fNRBCs.
Sun, in view of Wei, does not teach the method of claim 1, wherein the anti-CD147 antibody is conjugated to FITC, and the anti-CD71 antibody is conjugated to PE.
Sikes Johnson teaches that Alexa Fluor 488, Alexa Fluor 555, Alexa Fluor 647, FITC, and PE are fluorophores known to one of ordinary skill in the art, which can be used as a detection reagent for an antibody (p 22 ln 29 – p 23, ln 4; p 23, ln 29 – p 24, ln 6). Given the teachings of Sikes Johnson, there was a reasonable expectation that Alexa Fluor 488, Alexa Fluor 555, Alexa Fluor 647, FITC, and PE would work equivalently as fluorophores to detect an antibody of interest. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted the Alexa Fluor fluorophores taught in Sun with FITC and PE with predictable results to arrive at the claimed invention. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Claims 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Sun (EBioMedicine, 2019, 46: 133-149), in view of Wu (J Clin Oncol 2020, 38: e15530, ASCO Meeting Abstract), Mao (US 2019/0262836 A1) and Sikes Johnson (WO 2022/103797 A1).
The teachings of Sun and Wu are set forth above. Sun, in view of Wu, renders obvious claim 1.
Regarding claim 4: Sun teaches a cell identification method, wherein the target cells are undergoing epithelial-mesenchymal transition, the first fluorescent marker is DAPI, and the third fluorescent marker is an anti-vimentin antibody conjugated to Alexa Fluor 647.
Sun does not teach the method of claim 1, wherein the second fluorescent marker is an anti-EpCAM antibody conjugated to FITC, and the third fluorescent marker is an anti-vimentin antibody conjugated to PE.
Mao teaches using EpCAM-Alexa Fluor 488 and vimentin-Alexa Fluor 647 for IF staining of CTC cells (para 36, 119). Mao teaches that EpCAM is an epithelial CTC maker and vimentin is a mesenchymal CTC marker (para 36).
Regarding the second marker, EpCAM: It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to have modified the method of Sun to use EpCAM as a marker for marking epithelial CTCs (target cells). One of ordinary skill in the art would have been motivated to make this modification to mark epithelial CTCs, because Sun teaches a cell identification method wherein the target cells are CTCs undergoing epithelial-mesenchymal transition. One of ordinary skill in the art would have had a reasonable expectation of successfully making this modification because Mao teaches that EpCAM can be used as a marker for epithelial CTCs in IF staining of CTC cells.
Regarding the fluorophores conjugated to the second and third markers: Sun, in view of Mao, teaches the use of an anti-EpCAM antibody as a second marker and an anti-vimentin antibody as a third marker. Sun, in view of Mao, does not teach an anti-EpCAM antibody conjugated to FITC or an anti-vimentin antibody conjugated to PE.Sikes Johnson teaches that Alexa Fluor 488, Alexa Fluor 555, Alexa Fluor 647, FITC, and PE are fluorophores known to one of ordinary skill in the art, which can be used as a detection reagent for an antibody (p 22 ln 29 – p 23, ln 4; p 23, ln 29 – p 24, ln 6). Given the teachings of Sikes Johnson, there was a reasonable expectation that Alexa Fluor 488, Alexa Fluor 555, Alexa Fluor 647, FITC, and PE would work equivalently as fluorophores to detect an antibody of interest. Therefore, it would have been prima facie obvious to a person of ordinary skill before the effective filing date of the claimed invention to have substituted the Alexa Fluor fluorophores taught in Sun with FITC and PE with predictable results to arrive at the claimed invention. Substitution of one element for another known in the field, wherein the result of the substitution would have been predictable, is considered to be obvious. See KSR International Co. v Teleflex Inc 82 USPQ2d 1385 (US 2007) at page 1395.
Response to Arguments
Claim Rejections - 35 USC § 112(b)
Regarding claims 5-7, Applicant argues: Paragraph [0028] of the specification is partially read: " ...... The brightness range of the valid fluorescence signals of various fluorescent markers was obtained based on the linear brightness range provided by the calibration of the linear concentration curve of standard epithelial cancer cells." This calibration method provides a clear and reproducible standard for defining the unit for those skilled in the art.
The amended claims 5-7 clearly recite the unit of the brightness. The Specification also provide the method to obtain the brightness. Those skilled in the art will know how to obtain the brightness recited in the amended claims 5-7 based on the description of the specification and the common knowledge in the art.
In response: Applicant’s arguments have been fully considered, but are not persuasive. An arbitrary unit is dependent on the instrument settings and experimental conditions (Kamat, ASC Energy Letters, 2019, 4: 2005-2006, p. 2005, col 2, para 2). The description in the paragraph 28 of the instant specification does not provide enough details to allow a person of ordinary skill in the art to reproduce the specific arbitrary unit to be used in the method of claim 1. Therefore, the metes and bounds of claims 5-7 remain unclear.
Regarding claims 10-11 (limitations now incorporated into claim 1), Applicant argues: The Office indicated that the phrase "a relative position error of the two contours is less than or equal to a specific ratio of a diameter of the target cells" is indefinite. This rejection is moot since claims 10 and 11 are canceled and the phrase "a relative position error of the two contours is less than or equal to a specific ratio of a diameter of the target cells" recited in the original claim 10 was not incorporated into claim 1.
In response: Applicant’s arguments have been fully considered, but are not persuasive. The rejection of claims 10-11 under 35 USC § 112(b) was specifically regarding the limitation “of a diameter of the target cells” in the phrase “a relative position error of the two contours is less than or equal to a specific ratio of a diameter of the target cells.” Amended claim 1 recites the limitation “of the diameter size of the target cells,” which unclear as set forth in the rejection of claim 1 under 35 USC § 112(b).
Claim Rejections - 35 USC § 102 and 103
Applicant argues: Sun fails to disclose or teach to compare the relative position difference of the cell contours between the white light image photo and the second fluorescence image photo and the diameter size of the target cells. Specifically, Sun is silent about the calculation of the relative position difference or distance of the cell contours between the white light image photo and the second fluorescence image photo, not to mentioned the comparisons between the relative position difference and the diameter size of the target cells.
Sun merely presented the bright field of view and the fluorescent image side by side (Fig. 4a), without teaching, implying, or providing any motivation to "calculate" the "relative position difference" between the cell contours of the white light and the fluorescent image, let alone comparing this difference with the diameter of the target cell as a screening criterion. The Office's statement that "appear to have relative position error that is less than or equal to 5%" is purely subjective conjecture based on the illustration and cannot be considered a valid technical disclosure. This step recited in claim 1 is an objective step, not a subjective visual interpretation.
In response: Applicant’s arguments have been fully considered, but are not persuasive. As acknowledged in the instant and the previous Office Actions, although Sun teaches calculating the diameter of cells, and using a round or oval cell morphology as a phenotype criterion for CTC cells, Sun does not teach calculating the perimeter or area of cells to determine the shape and size of cells. As discussed above in the rejection of claim 1 under 35 USC § 103, Wu teaches a method to calculate the perimeter and area of CTCs to determine the size and shape of CTCs, and therefore cures the deficiency of Sun. In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant argues: The invention of claim 1 explicitly defines two intermediate candidate pools: "first preliminary target cells" and "second preliminary target cells." Sun's methodology completely lacks the concept of such "preliminary" or "intermediate" candidate pools; it uses fluorescence criteria (DAPI+/CD45-) and morphological criteria (circularity) as a set of parallel judgment criteria to "identify" the final target in one go.
In response: Applicant’s arguments have been fully considered, but are not persuasive. The term “preliminary target cells” is not defined in the specification. Therefore, the broadest reasonable interpretation of the phrase “preliminary target cells” is used in the interpretation of claim 1, which includes the cells disclosed in Sun.
Furthermore, the term “preliminary” is not tantamount to “intermediate.” Rather, one of ordinary skill in the art would construe “preliminary target cells” to mean “candidate target cells,” as opposed to “final target cells” or “cells ultimately determined as target cells.” Therefore, it is noted that the features upon which applicant relies (i.e., that the “first preliminary target cells” and “second preliminary target cells” are to be interpreted explicitly as two intermediate candidate pools) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Applicant argues: The object of the "white light scan" in the invention of claim 1 is the "second preliminary target cell" screened in the aforementioned steps, which is a subsequent and independent verification stage. Sun's method, however, combines fluorescence and morphological standards, meaning they are parallel judgment criteria. Sun's method and the invention of claim 1 are completely different in the order and logic of information processing.
In response: Applicant’s arguments have been fully considered, but are not persuasive. In response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., that the “white light scan” is a subsequent and independent step, which takes place after fluorescence measurements) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993). Furthermore, selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. See MPEP 2144.04(IV)(C).
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/RISA TAKENAKA/Examiner, Art Unit 1632
/TITILAYO MOLOYE/Primary Examiner, Art Unit 1632