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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 07/29/2025 has been entered.
Priority
This application is the U.S. National Stage (371) application of PCT/US2018/056129 filed on 10/16/2018 and claims priority to U.S. Provisional Application No. 62/572,666 filed on 10/16/2017.
Claim Status
Claim 1 is amended and the Applicant notes that no new matter is added. Claims 2, 9-18 and 24 are cancelled at the applicant’s request. Claim 5 is original. Claims 6-8 are withdrawn. Claims 3-4, 19-23 and 25-27 are previously presented.
Thus, claims 1, 3-5,19-23 and 25-27 are pending and under examination.
Withdrawn Objections/ Rejections
The previous rejection of claims 1, 3-5, 19-23, and 25-27 under 35 U.S.C. 112(b), regarding indefiniteness, is withdrawn in response to Applicant’s amendments of claims.
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 (PHOSITA) to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1, 3-5, 19-21 and 26-27 are rejected under 35 U.S.C. 103 as being unpatentable over Wiktor et al. (US 2014/0371091 A1) in view of Labaer et al. (US 2016/0041159 A1).
Regarding claim 1, Wiktor teaches a gene array (Sheet 23 of 24, Figure 26, , (a), “Genes”, “Nanowell array”; page 2, [0036]; page 12, [0146]).
Wiktor teaches that the target gene products and one or more variant of the target gene products are expressed protein from an in vitro transcription and translation system (Page 4, [0053]).
Wiktor teaches a discrete location is a single well or tube of the array (Page 4, [0054], “Physical confinement of the discrete locations prevents diffusion during, for example, in vitro protein expression of NAPPA. In certain embodiments, each of the physically confined discrete locations can comprise a well”)
Wiktor teaches that each discrete location of the array comprises a distinct gene product at each discrete location of the array (Page 3, [0043], “wherein each nucleic acid and/or polypeptide is physically confined at a discrete location on the first substrate, and wherein each nucleic acid is capable of expressing its encoded product in situ at its discrete location on the substrate, and/or wherein each polypeptide is capable of a characteristic activity in situ at its discrete location on the substrate; wherein the discrete locations are separated from each other on the first substrate”).
Regarding claim 3, Wiktor teaches that the plurality of gene products are immobilized at each discrete location as expressed proteins (Page 4, [0053]).
Regarding claim 4, Wiktor teaches that a target gene product and one or more variant of the target gene product are expressed in situ at each discrete location of the array by in vitro transcription and translation of target gene nucleic acids and nucleic acids of the variants of the target gene product obtained from one or more biological samples (Page 4, [0053]).
Regarding claim 5, Wiktor teaches that the substrate is selected from the group consisting of a slide, a microwell plate, and a nanowell plate (Page 11, [0140]; page 12, [0145] and [0146]).
Regarding claim 21, Wiktor teaches that wherein the amino acid sequence difference is associated with a nucleotide sequence difference (Page2, [0036]).
Regarding claim 1, Wiktor does not teach that a plurality of gene products are associated with one or more diseases arrayed on a substrate.
Wiktor does not teach that, at each discrete location, the target gene product and the one or more variants of the target gene product are coupled to one or more biosensors positioned on the substrate.
Regarding claim 19, Wiktor does not teach that a first discrete location of the array comprises a first target gene product and one or more variants of the first target gene product.
Wiktor does not teach that a second discrete location of the array comprises a second target gene product and one or more variants of the second target gene product.
Regarding claim 20, Wiktor does not teach that one of the one or more variants of the target gene product comprises an amino acid sequence difference relative to the target gene product.
Regarding claim 26, Wiktor does not teach that the one or more biosensors comprise a calorimetric sensor, a potentiometric sensor, a SERS (Surface Enhanced Raman Spectroscopy) sensor, an amperometric sensor, a conductometric sensor, an ion channel sensor, an ion sensitive sensor, an impedance spectroscopy-based sensor, or a combination thereof.
Regarding claim 27, Wiktor does not teach that the one or more biosensors comprise a field effect transistor sensor.
Regarding claim 1, Labaer teaches that a plurality of gene products associated with one or more diseases arrayed on a substrate (Sheet 12 of 19, Figure 12, “Proteins expressed form breast cancer tumor genes, captured on sensor in array”).
Labaer teaches that the plurality of gene products comprises target gene products and one or more variant of the target gene products (Page 6, [0067], “In other embodiments, the detector polypeptides comprise at least 500 to about 50,000 separate human protein sequences or variants thereof having at least about 90% ( e.g., 95%, 97%, 99%) sequence identity to the naturally occurring human protein sequences”).
Labaer teaches that wherein the array comprises a plurality of discrete locations (Sheet 12 of 19, Figure 12, “Coating sensors with tumor/disease specific proteins”, “Proteins expressed from breast cancer tumor genes, captured on sensors” ).
Labaer teaches that wherein each discrete location of the array comprises a target gene product and one or more variants of the target gene product (Page 6, [0067], Sheet 12 of 19, Figure 12).
Labaer teaches that the target gene product and one or more variant of the target gene product in each discrete location are distinct from the target gene product and one or more variant of the target gene product in another discrete location (Sheet 12 of 19, Figure 12, “Coating sensors with tumor/disease specific proteins”, “Proteins expressed from breast cancer tumor genes, captured on sensors”, “Proteins from leukemia cell lines”, “Panel of proteins from inflammatory diseases”, “Proteins expressed from lung cancer tumor genes”, “Panel of proteins from prostate cancer cell lines”, “Proteins from other diseases”).
Labaer teaches that, at each discrete location, the target gene product and the one or more variants of the target gene product are coupled to one or more biosensors positioned on the
substrate (Page3, [0043], [0044]; Sheet 3 of 19, Figure 3, “Surface capture protein biosensors”).
Labaer teaches that the one or more biosensor positioned on the substrate is configured to capture the target gene product and one or more variant of the target gene product (Page 4, [0050-0051], “In some embodiments, a biosensor microarray generated by the methods described herein comprises (i) a solid support substrate surface; (ii) a plurality of capture moieties linked to the solid support substrate surface; (iii) a plurality of detector polypeptides or detector peptides specifically bound by the capture moieties; and (iv) a plurality of sensors; wherein each sensor in the plurality of sensors is in direct contact or in proximity to a capture moiety in the plurality of capture moieties,”).
Regarding claim 19, Labaer teaches that a first discrete location of the array comprises a first target gene product and one or more variants of the first target gene product (Page 6, [0067]).
Labaer teaches that a second discrete location of the array comprises a second target gene product and one or more variants of the second target gene product (Page 5, [0063]; page 7, [0083]).
Regarding claim 20, Labaer teaches that one of the one or more variants of the target gene product comprises an amino acid sequence difference relative to the target gene product (page 7, [0083]).
Regarding claim 26, Labaer teaches that the one or more biosensors comprise a calorimetric sensor, a potentiometric sensor, a SERS (Surface Enhanced Raman Spectroscopy) sensor, an
amperometric sensor, a conductometric sensor, an ion channel sensor, an ion sensitive sensor, an
impedance spectroscopy-based sensor, or a combination thereof (Page 2, [0015]; page 6, [0071]; page 11, claim 61).
Regarding claim 27, Labaer teaches that the one or more biosensors comprise a field effect transistor sensor (Page 8, [0090]).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine coupled biosensors of Labaer with the gene array of Wiktor to improve the detection limit of a gene array for diagnosing one or more diseases because Labaer showed that coupling biosensors to gene products on the substrate of a microarray leads to increasing the detection of a signal (Abstract; page 1, [0003]; page 4, [0050]) and mentioned that current microarrays suffer from low specificity, low sensitivity and low signal to noise ratios (Page 4, [0050])). Labaer offered an array that reduced many of the limitations that current microarrays face (Page 4, [0050]) and Wiktor introduced a simple gene array that can be modified according to the usage needs (Abstract). A skilled artisan would have been further motivated to combine the above methods and inventions to specifically associate the signal profile of an array with a particular disease such as with cancer. A PHOSITA would have had a reasonable expectation of success in combining the methods of Labaer and Wiktor based on the methods being in the scope of biomolecule arrays.
It would have been obvious for a PHOSITA to further modify the gene array of Wiktor with the biosensors of Labaer to increase the accuracy of differential diagnosis of diseases.
Claims 22-23 and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Wiktor et al. (US 2014/0371091 A1) and Labaer et al. (US 2016/0041159 A1) as applied to claims 1 and 21 above, and further in view of Boutell et al. (US 2004/0002078 A1).
Regarding claims 22-23 and 25, Wiktor and Labaer teaches all of the limitations of the claims but Wiktor fails to teach the following limitations.
Regarding claim 22, Wiktor does not teach that the nucleotide sequence difference comprises a single nucleotide polymorphism.
Regarding claim 23, Wiktor does not teach that the nucleotide sequence difference comprises an insertion of a plurality of nucleotides.
Regarding claim 25, Wiktor does not teach that the nucleotide sequence difference comprises a structural variant such as proteins with related DNA molecules.
Regarding claim 22, Boutell teaches that the nucleotide sequence difference comprises a single nucleotide polymorphism (Abstract; page 1, [0004]; page 37, claim 5).
Regarding claim 23, Boutell teaches that the nucleotide sequence difference comprises an insertion of a plurality of nucleotides (Abstract; page 1, [0004]; page 37, claim 5).
Regarding claim 25, Boutell teaches that the nucleotide sequence difference comprises a structural variant such as proteins with related DNA molecules (Page 3, [0040], “Thus, it is envisaged that proteins derived from related DNA molecules can be quite different in structure”).
It would have been obvious for a PHOSITA before the effective filing date of the application to combine the expanded range of coverage of an array of Boutell with the methods of Wiktor and Labaer to improve the detection limit of a gene array for diagnosing one or more diseases because Boutell expanded the range of coverage of an array by including different variants of the gene product (Abstract). A skilled artisan would have been further motivated to combine the above methods and inventions to specifically associate the signal profile of an array with a particular disease such as with cancer. A PHOSITA would have had a reasonable expectation of success in combining the methods of Labaer and Wiktor based on the methods being in the scope of biomolecule arrays.
It would have been obvious for a PHOSITA to further modify the gene array of Wiktor with the biosensors of Labaer and the expanded range of coverage of Boutell to increase the accuracy of differential diagnosis of diseases.
Response to Arguments
Applicant's arguments filed on 07/29/2025 have been fully considered but they are not persuasive.
The Applicant alleged that the References of Wiktor, Labaer and Boutell do not teach or suggest a claimed array that require "each discrete location of the array comprises a distinct target gene product and one or more variant of the target gene product from the target gene product and one or more variant of the target gene product in any other discrete location" wherein each "discrete location is a single well or tube of the array."
The Applicant alleged that Labaer does not disclose each discrete location being a single well or tube and having a distinct target gene product and one or more variant from any other discrete location.
However, Wiktor teaches a discrete location is a single well or tube of the array (Page 4, [0054], “Physical confinement of the discrete locations prevents diffusion during, for example, in vitro protein expression of NAPPA. In certain embodiments, each of the physically confined discrete locations can comprise a well”)
Wiktor teaches that each discrete location of the array comprises a distinct gene product at each discrete location of the array (Page 3, [0043], “wherein each nucleic acid and/or polypeptide is physically confined at a discrete location on the first substrate, and wherein each nucleic acid is capable of expressing its encoded product in situ at its discrete location on the substrate, and/or wherein each polypeptide is capable of a characteristic activity in situ at its discrete location on the substrate; wherein the discrete locations are separated from each other on the first substrate”).
Furthermore, Labaer teaches that the plurality of gene products comprises target gene products and one or more variant of the target gene products (Page 6, [0067], “In other embodiments, the detector polypeptides comprise at least 500 to about 50,000 separate human protein sequences or variants thereof having at least about 90% ( e.g., 95%, 97%, 99%) sequence identity to the naturally occurring human protein sequences”).
Labaer teaches that wherein the array comprises a plurality of discrete locations (Sheet 12 of 19, Figure 12, “Coating sensors with tumor/disease specific proteins”, “Proteins expressed from breast cancer tumor genes, captured on sensors” ).
Labaer teaches that wherein each discrete location of the array comprises a target gene product and one or more variants of the target gene product (Page 6, [0067], Sheet 12 of 19, Figure 12).
Labaer teaches that the target gene product and one or more variant of the target gene product in each discrete location are distinct from the target gene product and one or more variant of the target gene product in another discrete location (Sheet 12 of 19, Figure 12, “Coating sensors with tumor/disease specific proteins”, “Proteins expressed from breast cancer tumor genes, captured on sensors”, “Proteins from leukemia cell lines”, “Panel of proteins from inflammatory diseases”, “Proteins expressed from lung cancer tumor genes”, “Panel of proteins from prostate cancer cell lines”, “Proteins from other diseases”).
Labaer teaches that the arrayed in vitro translation reactions are arrayed in microwells or nanowells (Page 3, [0032], page 7, [0085]).
In summary, The Applicant alleged that Labaer does not disclose each discrete location being a single well or tube and having a distinct target gene product and one or more variant from any other discrete location. However, the rejection of claims is based on the combination of references where both Wiktor and Labaer teach the alleged missing limitation of the instant application as noted above.
Thus, the references of Wiktor and Labaer teach the introduced amendments to claim 1 and the previous rejection of claims 1, 3-5, 19-23 and 25-27 under 35 U.S.C. 103 is maintained.
Conclusion
No claims are allowed.
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/OMAR RAMADAN/Examiner, Art Unit 1678
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678