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 .
The Examiner of your application has changed. Please address future correspondence to Amy M. Bunker, AU1684.
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office Action has been withdrawn pursuant to 37 CFR 1.114.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 April 9, 2026 has been entered.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Status of Claims
Claims 1, 2, 4, 5, 8-10, 12-14 and 21-30 are currently pending in the instant application. Claims 1 and 22 have been amended by Applicants’ amendment filed 04-09-2026. No claims have been added or canceled by Applicants’ amendment filed 04-09-2026.
Therefore, claims 1, 2, 4, 5, 8-10, 12-14 and 21-30 are under consideration to which the following grounds of rejection are applicable.
Priority
The present application filed April 26, 2022 is a CON of US Patent Application 17333337, filed May 28, 2021 (now US11358147); which is a CON of US Patent Application 16673416, filed November 4, 2019 (now US11052396; which is a CON of US Patent Application 16049173, filed July 30, 2018 (now US10512914); which is a CON of US Patent 15442222, filed February 24, 2017 (now US10391490); which claims the benefit of US Provisional Patent Application 62423322, filed November 17, 2016; and US Provisional Patent Application 62299427, filed February 24, 2016, which is a CIP of US Patent Application 14289155, filed May 28, 2014 (now US9856535), which claims the benefit of US Provisional Patent Application 61829537, filed May 31, 2013.
Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 120 as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of the first paragraph of 35 U.S.C. 112. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, US Provisional Patent Application 62299427, filed February 24, 2016, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. The specific method steps recited in independent claim 1 does not have support for; “a hexagonal lattice recessed into the surface of the substrate”. Therefore, the priority date for the presently claimed invention is November 17, 2016, the filing date of US Patent Provisional Patent Application 62423322.
The disclosure of the prior-filed application, instant Application 17/729,760, filed February April 26, 2022, fails to provide adequate support or enablement in the manner provided by the first paragraph of 35 U.S.C. 112 for one or more claims of this application. The specific method steps recited in independent claim 22 does not have support for; “common channel spanning open surfaces of the wells of the plurality of wells” and/or “flowing an immiscible fluid through the common channel to form a continuous encapsulation layer” and the substrate cannot be made of just any rigid material. Therefore, the priority date for the presently claimed invention is April 26, 2022, the filing date of instant Application 17/729,760.
Applicants are invited to specifically indicate the location of the cited phrase pertinent to claims 1, 2, 4, 5, 8-10, 12-14 and 21-30 of the instant application.
Withdrawn Objections/Rejections
Applicants’ amendment and arguments filed April 9, 2026 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below are herein withdrawn.
Double Patenting
The rejection of claims 1-2, 4, 5, 8-10, 12-14, and 21-30 is withdrawn on the ground of non-statutory double patenting as being unpatentable over:
claims 14-18 of U.S. Patent No. US 10851426,
claims 1-20 of U.S. Patent No. US 10449543,
claims 12-20 of U.S. Patent No. US 10782226, and
claims 11-20 of U.S. Patent No. US 11073468, due to Applicant’s filing of a terminal disclaimer with respect to US10851426, US10449543, US10782226, US11073468, and US 11345951, in the reply filed 04-09-2026.
Claim Rejections - 35 USC § 103
The rejection of claims 1-2, 4-6, 8-10, 12-14, 21 and 30 is withdrawn under 35 U.S.C. 103 as being unpatentable over McNeely et al. (US-20040109793, of record) in view of Collins (US20130244906, of record) and Gong et al. (WO 2014/065758; of record).
The combined references of McNeely, Collins and Gong do not specifically exemplify hexagonal wells and/or a hexagonal lattice.
In view of the withdrawn rejection, Applicant’s arguments are rendered moot.
The rejection of claims 22-29 is withdrawn under 35 U.S.C. 103 as being unpatentable over McNeely et al. (US-20040109793, of record) in view of Collins (US20130244906, of record); and Deutsch et al. (WO2004/113492, of record); and Gong et al. (WO 2014/065758; of record).
The combined references of McNeely, Collins, Deutsch and Gong do not specifically exemplify hexagonal wells and/or a hexagonal lattice.
In view of the withdrawn rejection, Applicant’s arguments are rendered moot.
Maintained Objections/Rejections
Claim Interpretation
The term “preventing egress” as recited in claim 1 is interpreted to refer to slowing, stopping, inhibiting, blocking, etc. any number of nucleic acids from exiting, leaving, escaping and/or being withdrawn from a well by any method.
The term “flowing an immiscible fluid through the common channel” in claim 22 is interpreted to refer to: (a) flowing a single fluid having a property wherein it is immiscible with any other fluid; (b) to refer to flowing a mixture of at least two fluids, wherein the first fluid is immiscible with a second fluid, and/or (c) to refer to a plurality of wells comprising a first fluid, and then flowing a second fluid through the channel which is immiscible with the first fluid.
Double Patenting
The provisional rejection of claims 1, 2, 4, 5, 8-10, 12-14, and 21-30 is maintained on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 and 7-12 of copending Application No. 17/728,789 in view of McNeely et al. (US-20040109793; of record); Collins (US20130244906; of record); Deutsch et al. (WO 2004/113492, of record); and Gong et al. (WO 2014/065758) for the reasons of record.
New Objections/Rejections
Drawing Objection
(1) The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference signs mentioned in the description:
(a) The as-filed Specification teaches in Figures 10 and 11: “an encapsulation volume spanning the set of wells 112 and the set of channels 140 for each well 113 in the set of wells 112, up to the first encapsulation layer 191” (paragraph [0065]), which is not illustrated in claims 10 or 11 of the drawings filed April 26, 2022.
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. 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.
(2) The drawings are objected to as failing to comply with 37 CFR 1.84(p)(5) because they do not include the following reference signs mentioned in the description:
(a) The as-filed Specification teaches in Figures 10 and 11: removal of one or both of the first encapsulation layer 191 and the second encapsulation layer 192 (paragraphs [0067] and [0076]). However, first encapsulation layer 191 is not illustrated in Figures 10 or 11 of the drawings filed April 26, 2022.
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. 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.
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.
Claims 1, 2, 4, 5, 8-10, 12-14 and 21-30 are rejected under 35 U.S.C 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claims 1 and 22 are indefinite for the recitation of the term “rigid material” such as recited in claim 1, line 3 because the term “rigid” is relative terms that renders the claim indefinite. The term “rigid” is not defined by the claim, and the Specification does not provide a standard for ascertaining the requisite amount of rigidity as compared to some other value that qualifies the substrate being composed of a “rigid material” (e.g., having a specific tensile strength, being bendable, more rigid than glass, etc.), such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention. Moreover, the as-filed Specification is clear that the substrate cannot be just any rigid material, it must have a high transparency and/or be composed of a material with suitable optical properties (See; as-filed Specification paragraph [0032]) and, thus, the metes and bounds of the claim cannot be determined.
Claims 1, 2 and 22 are indefinite for the recitation of the term “a plurality of wells of the set of wells” such as recited in claim 1, lines 10 and 14-15. There is insufficient antecedent basis for the term “a plurality of wells of the set of wells” in the claim because claim 1, lines 3-4 recites the term “a set of wells comprising at least 20,000 hexagonal wells”. The Examiner suggests that Applicant amend the claim to recite, for example, “the set of wells”, or amending line 3 to recite “a plurality of wells comprising at least 20,000 hexagonal wells”.
Claim 1 is indefinite for the recitation of the term “flowing a continuous encapsulation layer” such as recited in claim 1, line 11 because the as-filed Specification does not teach “continuous encapsulation layer”, such that the identity of a “continuous encapsulation layer” is unclear including how one flows an entire “continuous encapsulation layer” through a channel and, thus, the metes and bounds of the claim cannot be determined.
Claim 1 is indefinite for the recitation of the term “spanning all open surfaces” such as recited in claim 1, line 11 because claim 1 does not recite the presence of “open surfaces” such that it is completely unclear what surfaces of the substrate and/or wells are “open surfaces” and, thus, the metes and bounds of the claim cannot be determined. It is noted that wells that are “open to a channel” does not recite an “open surface”.
Claim 8 and 10 are indefinite for the recitation of the term “captured within the set of wells” such as recited in claim 8, lines 2-3 because claim 8 depends from instant claim 1, wherein claim 1 does not recite the capture of nucleic acids within a well, but instead recites delivering nucleic acids into a plurality of wells, such that it is unclear what step claim 8 is referring to and, thus, the metes and bounds of the claim cannot be determined.
Claim 10 is indefinite for the recitation of the term “at least one PCR and an immunoassay” such as recited in claim 10, line 2 because claim 10 depends from claims 1 and 9, wherein claims 1 and 9 do not recite carrying out PCR and/or an immunoassay. Moreover, a step of “transmitting heat” does not comprise the recited assays and, thus, the metes and bounds of the claim cannot be determined.
Claim 13 is indefinite for the recitation of the term “cancer cell phenotype” such as recited in claim 13, line 2 because claim 13 depends from claim 1, wherein claim 1 does not recite the presence of a cell, a cancer cell, and/or a cancer cell phenotype and, thus, the metes and bounds of the claim cannot be determined.
Claim 21 is indefinite for the recitation of the term “flowing the sample into the inlet” such as recited in claim 21, lines 2-3 because claim 21 depends from claim 1, wherein amended claim 1 does not recite a step of flowing the sample. Moreover, claim 1 recites that delivery is into a plurality of wells and, thus, the metes and bounds of the claim cannot be determined.
Claim 22 is indefinite for the recitation of the term “a plurality of wells in a hexagonal configuration” such as recited in claim 22, line 3 because it is unclear whether the wells themselves are in a hexagonal shape, or whether the plurality of wells together form a hexagon and, thus, the metes and bounds of the claim cannot be determined.
Claim 22 is indefinite for the recitation of the terms “common channel” and “flowing an immiscible fluid through the common channel to form a continuous encapsulation layer” such as recited in claim 22, lines 6-8 because the instant as-filed Specification, and/or the originally filed claims do not teach a “common channel” and/or “flowing an immiscible fluid through the common channel to form a continuous encapsulation layer” and, thus, the metes and bounds of the claim cannot be determined.
Claim 22 is indefinite for the recitation of the term “adjacent to the substrate” such as recited in claim 22, line 6 because the location of the common channel is unclear including whether the common channel is part of the substrate or whether it is located outside of the substrate. Moreover, the term “adjacent” is a relative term that renders the claim indefinite. The term “adjacent” is not defined by the claim, and the Specification does not provide a standard for ascertaining the requisite location as compared to some other position that qualifies the channel to be “adjacent” to the substrate, such that one of ordinary skill in the art would not be reasonably appraised of the scope of the invention.
Claim 22 is indefinite for the recitation of the term “open surfaces of the wells” such as recited in claim 22, line 8 because claim 22 does not recite that the wells comprise open surfaces and, thus, the metes and bounds of the claim cannot be determined.
Claim 22 is indefinite for the recitation of the terms “the wells” such as recited in claim 22, line 8. There is insufficient antecedent basis for the term “the wells” in the claim because claim 22, line 3 recites the term “a plurality of wells”.
Claims 22, 23 and 29 are indefinite for the recitation of the term “the at least one well” such as recited in claim 22, line 10. There is insufficient antecedent basis for the term “the at least one well” in the claim because claim 22, line 3 recites the term “a plurality of wells”.
Claims 1, 4, 5, 9, 12, 14 and 30 are indefinite insofar as they ultimately depend from instant claim 1. Claims 24-28 are indefinite insofar as they ultimately depend from instant claim 22.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 10, 13 and 21 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 10 recites (in part): “wherein transmitting heat comprises transmitting heat for at least one of PCR and an immunoassay with nucleic acid molecules captured within the set of wells” such as recited in claim 10, lines 1-2 because claim 10 depends from instant claims 1 and 9, wherein claims 1 and 9 do not recite performing PCR and/or an immunoassay; and the step of transmitting heat does not comprise performing PCR and/or an immunoassay. Thus, claim 10 is an improper dependent claim for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 13 recites (in part): “further comprising returning a result characterizing a cancer cell phenotype represented in the sample” such as recited in claim 13, lines 1-2 because claim 13 depends from instant claim 1, wherein claim 1 does not recite the presence of a cell, a cancer cell, and/or a cancer cell phenotype in the sample. Thus, claim 13 is an improper dependent claim for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 21 recites (in part): “wherein delivering the sample comprises capturing contents…upon flowing the sample into the inlet and allowing the sample to enter into wells” such as recited in claim 21, lines 1-3 because claim 21 depends from instant claim 1, wherein claim 1 amended claim 1 does not recite a step of flowing the sample. Moreover, claim 1 recites that delivery is into a plurality of wells. Thus, claim 21 is an improper dependent claim for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a) – New Matter
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 22-29 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
MPEP § 2163.II.A.3.(b) states, “when filing an amendment an applicant should show support in the original disclosure for new or amended claims” and “[i]f the originally filed disclosure does not provide support for each claim limitation, or if an element which applicant describes as essential or critical is not claimed, a new or amended claim must be rejected under 35 U.S.C. 112, para. 1, as lacking adequate written description”. According to MPEP § 2163.I.B, “While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure” and “The fundamental factual inquiry is whether the specification conveys with reasonable clarity to those skilled in the art that, as of the filing date sought, applicant was in possession of the invention as now claimed. See, e.g., Vas-Cath, Inc., 935 F.2d at 1563-64, 19 USPQ2d at 1117”.
The claim contains subject matter that was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art (hereafter the Artisan), that the inventor(s), at the time the application was filed, had possession of the claimed invention. 37 CFR §1.118 (a) states that "No amendment shall introduce new matter into the disclosure of an application after the filing date of the application". Claim 22 recites in part: “the plurality of wells includes…interconnected with each other by a common channel adjacent the substrate”; and “flowing an immiscible fluid through the common channel to form a continuous encapsulation layer in the common channel spanning open surfaces of the wells of the plurality of wells”. However, support was not found for these limitations in the as-filed Specification and/or the original claims.
Upon review of the instant as-filed Specification and original claims, support was not found for the plurality of wells interconnected through a common channel adjacent the substrate, and flowing an immiscible fluid through the common channel to form a continuous encapsulation layer in the common channel spanning open surfaces of the wells of the plurality of wells as recited in instant claim 22. The instant as-filed Specification, filed April 26, 2022 teaches, for example: “wall 116 extending between the base surface 120 and the open surface 130 and defining a set of channels 140 that fluidly couple each well to at least one adjacent well in the set of wells” (as-filed Specification, paragraph [0027], lines 5-7); “the system 100 can further include a perimeter channel 150 surrounding the set of wells 112 and fluidly coupled to each well in an exterior subset 115 of the set of wells by way of at least one channel in the set of channels of each well in the exterior subset of the set of wells” (as-filed Specification, paragraph [0027], lines 8-11); and “the set of wells 112 can further include a perimeter channel 150 surrounding the set of wells 112 and fluidly coupled to each well 113 in an exterior subset 115 of the set of wells 112 by way of at least one channel in the set of channels 140 of each well in the exterior subset 115 of the set of wells” (as-filed Specification, paragraph [0038]); “an encapsulation matrix 199 can be flowed into the set of wells 112 with the encapsulation module 190 at any suitable portion of the set of wells 112, forming an encapsulation volume 198 spanning the set of wells 112 and the set of channels 140 for each well 113 in the set of wells 112, up to the first encapsulation layer 191” (as-filed Specification, paragraph [0065], lines 5-9); and “the encapsulation matrix 199 is preferably substantially viscous, such that the encapsulation matrix 199 “does not flow into the wells 113 during introduction into the system 100. In the set state, the encapsulation matrix 199 is preferably a solid or gel that prevents particle egress from the wells 113 (e.g., egress of cells and/or large nucleic acid molecules from the pores)” (as-filed Specification, paragraph [0065], lines 10-14). No such corresponding teaching of flowing an immiscible fluid through the common channel to form a continuous encapsulation layer in the common channel spanning open surfaces of the wells of the plurality of wells is taught by the instant as-filed Specification and/or the original claims.
A claim-by-claim analysis and for dependent claim 28, and a method step by method step analysis regarding where support can be found for the broad teachings of partitions comprising a nucleic acid molecule comprising a epigenetic feature, using an epigenetic feature and a barcode sequence to determine an epigenetic state, partitions comprising a barcode nucleic acid molecule comprising a barcode sequence or complement thereof, and/or processing a barcode nucleic acid or derivative thereof to identify an epigenetic feature in the originally filed specification is respectfully suggested. See MPEP § 2163 particularly § 2163.06.
Claims 22-29 will remain rejected until Applicant cancels all new matter.
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 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.
Claims 1, 2, 4, 5, 8-10, 12, 14, 21-25 and 27-30 are rejected under 35 U.S.C. 102(a1)/102(a2) as being anticipated by Barnard et al. (hereinafter “Barnard”) (US Patent Application Publication 20140243224, published August 28, 2014; filed March 6, 2013; effective filing date February 26, 2013).
Regarding claims 1 and 22, Barnard teaches an array including a solid support having a surface, wherein the surface has a plurality of wells, the wells containing a gel material, the wells being separated from each other be interstitial regions on the surface, the interstitial region segregating the gel material in each of the wells from the gel material in other wells of the plurality; and a library of target nucleic acids in the gel material, wherein the gel material in each of the wells comprises a single species of the target nucleic acids of the library, wherein the gel material is attached to or contains target analytes (interpreted as a substrate having a set of wells including a plurality of wells; and interpreting the gel material as a process reagent; comprising nucleic acids; and also as an encapsulation layer that seals and prevents egress of nucleic acids from the wells, claims 1 and 22) (Abstract, paragraph [0004]). Barnard teaches a method of making an array can include the steps of: (a) providing a solid support having a surface with a plurality of wells, the wells containing a gel material, the wells being separated from each other by interstitial regions on the surface, the interstitial regions segregating the gel material in each of the wells from the gel material in other wells of the plurality; (b) delivering a library of target nucleic acids to the wells of the solid support to produce an array of wells that have a single species of target nucleic acid attached to the gel material in each well, wherein different wells in the array have different target nucleic acid species from the library; and (c) amplifying the target nucleic acids attached to the gel material in the wells of the array to produce a clonal population of an individual target nucleic acid at each of the wells of the array (interpreted as delivering a sample comprising nucleic acids and a process reagent into the plurality of wells, claims 1 and 22) (paragraph [0008]). Barnard teaches that Figure 1 shows a DNA patterned substrate comprising wells containing gel to be located below the solid support and proximate the first bottom of the first set of wells (interpreted as wells comprising nucleic acids and gel material as an encapsulation layer, claims 1 and 22) (paragraph [0012], and Figure 1). Barnard teaches that patterned arrays are exemplified; and the gel material is exemplary and can be replaced with other organic materials that can be used to mediate localization of analytes to features on a surface, wherein organic materials include for example, polymers that can form a surface coating and may not necessarily be considered as gels, per se (interpreted as an encapsulation layers, claims 1 and 22) (paragraph [0027], lines 1-9). Barnard teaches that the solid support used in a structured substrate can be made of a variety of materials including glass, polymeric materials, plastics, silicon, quartz, borofloat glass, silica, fused silica, carbon, metals, an optical fiber or optical fiber bundles, sapphire, COC, COP, etc. (interpreted as a rigid substrate, claims 1 and 22) (paragraphs [0050], lines 1-9 and [0052], lines 1-4). Barnard teaches that the gel material has been coated on the surface of a solid support, wherein it can be covalently attached to the support including before or after attaching an analyte to the gel material (interpreted as flowing an encapsulation layer, claims 1 and 22) (paragraph [0078], lines 1-7). Barnard teaches that the surface can have surface features such as wells, pits, channels, ridges, raised regions, posts or the like; and that solid supports can be located within a flow cell apparatus (interpreted as a set of wells; and interpreting a flow cell to comprising sets of channels, claims 1 and 22) (paragraphs [0043], lines 6-8 and [0045], last four lines). Barnard teaches that a structured substrate of the present disclosure can occur in a flow cell, such that exemplary flow cells, methods for their manufacture and methods for their use are described in US Pat. App. Publ. Nos. 2010/0111768Al or 2012-0270305; or WO05/065814, each of which is incorporated herein by reference, wherein flow cells provide a convenient format for housing an array (paragraph [0066], lines 1-5). Barnard teaches that the surface can be in contact with another material such as a gas, liquid, gel, polymer, organic polymer, second surface of a similar of different material, metal, or coats (interpreted as flowing a continuous encapsulation layer spanning all open surfaces of the set of wells, claims 1 and 22) (paragraph [0043], lines 3-5). Barnard teaches that one or more concave features, such as wells, can be coated with preformed gel material or with a liquid that subsequently forms a gel material including coating a substrate with preformed PAZAM using spin coating, dipping, flow of the gel under positive or negative pressure or techniques set forth in US 61/753,833, which is incorporated herein by reference; as well as, coating of an array of wells with preformed PAZAM is demonstrated below in Example III, wherein an example of applying liquid that subsequently forms a gel material is the coating of an array of wells with silane free acrylamide and N-[5-(2-bromoacetyl) aminopentyl]acrylamide (BRAPA) in liquid form and allowing the reagents to form a gel by polymerization on the surface as demonstrated in Example I and as set forth in US 2011/0059865, which is incorporated herein by reference (interpreted as flowing a continuous encapsulation layer to the surfaces of the wells; and interpreting the gel material and BRAPA as immiscible fluids, claims 1 and 22) (paragraph [0069]). Barnard teaches that various analytes can be added prior to gel formation and others can be added after gel formation, such that primer nucleic acids are added to a gel forming solution and the solution is then allowed to form into a gel (e.g. by polymerization as occurs for SFA and PAZAM), wherein primer nucleic acids can be used for capture and/or amplification of template nucleic acids (interpreted as delivering a sample and process reagents, wherein nucleic acids, primers, and the gel are interpreted to be PCR process reagents; and performing an assay, claims 1 and 22) (paragraph [0070], lines 6-10; and [0071], lines 1-3). Barnard teaches that chip substrates normally used for manufacture of BeadChips were obtained from Illumina, wherein the chips were made of silicon or Zeonor having 0.5 µm wells arranged in a hexagonal pattern having a pitch of 1.5 µm; and the chips were patterned with gel pads as set forth below and diagrammed in Figure 1 (interpreted as hexagonal wells, claims 1 and 22) (paragraph [0104]; and Figure 1). Figure 1 is shown below:
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Barnard teaches that exemplary repeating patterns of wells on the surface include rectilinear patterns and hexagonal patterns, wherein a repeating pattern can include multiple repetitions of a sub-pattern (interpreted as a hexagonal lattice, claims 1 and 22) (paragraph [0041], lines 1-5 and 10-13). Barnard teaches that many different layouts of wells or other concave features can be envisaged including regular, repeating, and non-regular patterns, such wells can be disposed in hexagonal grid for close packing and improved density (interpreted as a hexagonal lattice, claims 1 and 22) (paragraph [0057], lines 1-6). Barnard teaches that wells can have any of a variety of shapes at their opening in a surface including but not limited to round, elliptical, square, polygonal, star shaped (with any number of vertices) etc. (interpreted as including hexagonal, claims 1 and 22) (paragraph [0046]). Barnard teaches that a pattern of wells can also be characterized with respect to the density of wells (i.e. number of wells) in a defined area such as, for example, the wells can be present at a density of approximately 2 million per mm2 (interpreted as a set of > 20K wells, claims 1 and 22) (paragraph [0059], lines 1-4). Barnard teaches that the methods can be used to carry out a variety of amplification techniques including PCR, RCA, MDA, and/or RPA (interpreted as performing an assay including PCR, claims 1 and 22) (paragraph [0072], lines 1-7). Barnard teaches that a flow cell containing the cluster-containing substrate was sequenced on a HiSeq 2000 (interpreted as performing an assay, claims 1 and 22) (paragraph [0115], lines 1-2).
Regarding claims 2 and 23, Barnard teaches that the gel can function to support capture of a DNA template and amplification of the template, wherein the gel can be grafted with oligonucleotide primers prior to surface coating, after surface coating and before polishing, or after polishing (interpreted as capturing nucleic acid molecules within the wells, claims 2 and 23) (paragraph [0020], lines 10-14).
Regarding claim 4, Barnard teaches that one or more concave features, such as wells, can be coated with preformed gel material or with a liquid that subsequently forms a gel material including coating a substrate with preformed PAZAM using spin coating, dipping, flow of the gel under positive or negative pressure or techniques set forth in US 61/753,833, which is incorporated herein by reference (interpreted as using pressure differential to deliver the sample, claim 4) (paragraph [0069], lines 11-18).
Regarding claim 5, Barnard teaches that the size or volume of the wells can be adjusted to influence the purity of analytes captured (interpreted as encompassing an area of at least 144 mm2, claim 5) (paragraph [0085], lines 1-3). Barnard teaches that a pattern of wells can also be characterized with respect to the density of wells (i.e. number of wells) in a defined area such as, for example, the wells can be present at a density of approximately 2 million per mm2 (interpreted as encompassing an area of at least 144 mm2, claim 5) (paragraph [0059], lines 1-4).
Regarding claim 8, Barnard teaches that target nucleic acids that are complementary to the primers can be added to the primer-containing gel such that the target nucleic acids become attached to the gel via hybridization (interpreted as a hybridization assay for nucleic acid molecules, claim 8) (paragraph [0070], lines 14-17). Barnard teaches the use of the nucleic acids to serve as capture probes that hybridize to target nucleic acids having complementary sequences (paragraph [0093], lines 3-5).
Regarding claims 9 and 25, Barnard teaches that subsequent heating of the PAZAM-coated substrate at 60° C for 1 hour resulted in a covalent linkage between the polymer and surface (interpreted as transmitting heat through the substrate, claims 9 and 25) (paragraph [0109], lines 10-15).
Regarding claim 10, Barnard teaches that the methods can be used to carry out a variety of amplification techniques including PCR, RCA, MDA, and/or RPA (interpreted as performing PCR, claim 10) (paragraph [0072], lines 1-7). Barnard teaches that a flow cell containing the cluster-containing substrate was sequenced on a HiSeq 2000 (interpreted as performing a hybridization assay, claims 1 and 22) (paragraph [0115], lines 1-2). Barnard teaches a method of detecting analytes, comprising the steps of: (a) providing a solid support having a planar surface interrupted by one or more concave features, wherein the concave features contain gel material, wherein the one or more concave features are bordered by one or more interstitial regions on the planar surface, the interstitial regions being substantially devoid of the gel material, and wherein the gel material is attached to or contains target analytes; (b) contacting the solid support with probes under conditions wherein the target analytes interact specifically with the probes; and (c) detecting the solid support to distinguish at least a subset of the target analytes that interact with one or more of the probes, wherein analytes include antibodies (interpreted as comprising an immunoassay and PCR, claim 10) (paragraphs [0062], lines 8-12; and [0091]).
Regarding claims 12 and 24, Barnard teaches that Figures 2A-C show images from a BeadChip substrate modified to have gel material in the wells instead of beads; and that images captured using fluorescence microscope showed that this approach was capable of yielding polymer features with clean interstitial regions (Figures 2B and 2C (interpreted as imaging to enable identification, claims 12 and 24) (paragraphs [0013]; [0106], lines 12-15; and Figures 2A-C).
Regarding claims 14 and 27, Barard teaches an exemplary format that uses a combination of one solid phase attached primer and a solution phase primer is emulsion PCR as described, for example, in Dressman et al., Proc. Natl. Acad. Sci. USA 100:8817-8822 (2003), WO 05/010145, or US 2005/0130173 or 2005/0064460, each of which is incorporated herein by reference (interpreted as encompassing primers, probes, and fluorophores, claim 14) (paragraph [0072], lines 22-28). Barnard teaches a method of detecting analytes, comprising the steps of: (a) providing a solid support having a planar surface interrupted by one or more concave features, wherein the concave features contain gel material, wherein the one or more concave features are bordered by one or more interstitial regions on the planar surface, the interstitial regions being substantially devoid of the gel material, and wherein the gel material is attached to or contains target analytes; (b) contacting the solid support with probes under conditions wherein the target analytes interact specifically with the probes; and (c) detecting the solid support to distinguish at least a subset of the target analytes that interact with one or more of the probes (interpreted as encompassing delivering PCR reagents including primers, probes, and fluorophores, claims 14 and 27) (paragraph [0091]). Barnard teaches that a nucleic acid array can be used for sequencing-by-synthesis, which can be initiated by contacting the target nucleic acids with one or more labeled nucleotides, DNA polymerase, etc. (interpreted as a polymerase, claim 14) (paragraph [0094], lines 1-5).
Regarding claim 21, Barnard teaches that the pattern of gel-containing wells (or other concave features) on the structured substrate and the efficiency of loading can be adjusted to obtain arrays having desired characteristics such as analyte density and purity of each feature with respect to having a single analyte species (interpreted as adjusting for capture efficiency, claim 21) (paragraph [0084], lines 9-13).
Barnard does not specifically exemplify a result characterizing a cancer cell phenotype (claims 13 and 26).
Barnard meets all the limitations of the claims and, therefore, anticipates the claimed invention.
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 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 2, 4, 5, 8-10, 12-14 and 21-30 are rejected under 35 U.S.C. 103 as being unpatentable over Barnard et al. (hereinafter “Barnard”) (US Patent Application Publication 20140243224, published August 28, 2014; filed March 6, 2013; effective filing date February 26, 2013)in view of Kartalov et. al. (hereinafter “Kartalov”) (US Patent Application Publication 20130210646, published August 15, 2013; effective filing date February 9, 2012).
The teachings of Barnard as applied to claims 1, 2, 4, 5, 8-10, 12, 14, 21-25 and 27-30 are described supra.
Barnard does not specifically exemplify a result characterizing a cancer cell phenotype (claims 13 and 26).
Regarding claims 13 and 26, Kartalov teaches microfluidic technology focused on: (1) direct integration of microfluidic devices with solidified liquid tissue samples, (2) subordination of architectural and operational principles of microfluidic devices specific tissue structure and needs and/or (3) on-chip sample acquisition integrated with the detection measurement within the same device, such that in contrast to conventional methods of off-chip sample prep and subsequent insertion into a detection device, new applications are possible on solidified liquid or solid tissue samples, such as in situ PCR (Abstract). Kartalov teaches that Figure 1 depicts photolithographic masking of apparatus including a top view wherein a photocurable substance (gray) is exposed to UV light through a (A) photolithographic mask bearing a hexagonal matrix pattern, such that the dark areas in the mask absorb the UV and thus protect the photoresist under them, while the light areas transmit the UV light to the underlying photoresist; (B) the result is a matrix of hexagonal access wells on top of the tissue, wherein based on the size of the access wells, as few as one cell (blue circle) per well can be isolated (C) defined access wells can then be filled with PCR reagents, and positively detected (green) in the presence of a cell of interest (interpreted as hexagonal wells, claims 1 and 22) (paragraph [0006]; and Figure 1). Kartalov teaches wells of a masked or maskless matrix of access can include one or more of reaction mixtures containing components necessary for a biochemical reaction to occur including, but not limited to, components necessary for PCR, real-time PCR, RT-PCR, flow cytometry, fluorescent labeling, FRET, DNA sequencing, protein-protein interaction assays, immunoassays, protein-nucleic acid assays, and any other biological reaction known in the art (interpreted as a plurality of wells; and assays including PCR and immunoassays, claims 1 and 22) (paragraph [0048]). Kartalov teaches that the methods and devices described overcome various problems, such as by providing a general microfluidic bottoms-up sample-specific customization method, which naturally leads to rapid, parallelized, and highly specific micro-isolation of the desired cell subpopulation (e.g. cancer cells from a tumor) directly from solidified liquid tissue samples, more specifically the massively parallel technique achieves digital noise reduction in liquid tissues for detection of rare cells without bias caused by sample manipulation or preparation (interpreted as cancer, claims 13 and 26) (paragraph [0083], lines 1-11). Kartalov teaches in Figure 11, an exemplary illustration of how a matrix of microfluidic wells can provide access to individual cell nuclei for independent reactions, wherein microfluidic access wells (910) are defined in a substrate (920) (e.g. glass or silicon); and next, the access wells (910) are filled with a fluid mixture (930) containing digestion and reaction agents (e.g. Polymerase Chain Reaction (PCR) reagents, and fluorescent probes) (interpreted as assay reagents, claims 1 and 22) (paragraph [0108], lines 1-8; and Figure 11). Kartalov teaches that data acquisition can be performed on a fluorescence scanner or by an optical fluorescence microscope, where the wells are optically accessed by the side of the glass slide in patent 1 (paragraph [0109], last four lines). Kartalov teaches that CTC/DTC analyses could be evaluated in the context of predicting the prognosis of cancer patients, selecting the most efficient therapy and monitoring these therapies by repeated blood analyses, wherein the molecular profiling of CTCs/DTCs could significantly impact prognosis and benefit from therapy, as well as be utilized in the context of new therapeutic agents to determine efficacy (interpreted as returning a result characterizing a cancer cell type phenotype, claims 13 and 26) (paragraph [0005], lines 6-12).
It is prima facie obvious to combine prior art elements according to known methods to yield predictable results; the court held that, "…a conclusion that a claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded nothing more than predictable results to one of ordinary skill in the art. KSR International Co. v. Teleflex Inc., 550 U.S. ___, ___, 82 USPQ2d 1385, 1395 (2007); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atlantic & P. Tea Co. v. Supermarket Equipment Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950)”. Therefore, in view of the benefits of a microfluidic support for carrying out biochemical reactions as exemplified by Kartalov, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the methods of assaying target nucleic acids in a sample using an array of wells comprising a gel material and a target analyte for use in assays including PCR and/or NGS as disclosed by Barnard to include the methods of integrating a microfluidic device with tissue samples including micro-isolating and/or analyzing cellular material from a tissue sample including in a sample from a cancer patient as taught by Kartalov with a reasonable expectation of success in producing an ultra-sensitive, cost-effective method of detecting nucleic acids in the peripheral blood of cancer patients in order to predict a disease prognosis, to monitor therapies, and/or to determine therapy efficacy; and/or to increase the density of array features and to reduce processing requirements for image registration as compared to random arrays.
Thus, in view of the foregoing, the claimed invention, as a whole, would have been obvious to one of ordinary skill in the art at the time the invention was made. Therefore, the claims are properly
rejected under 35 USC §103(a) as obvious over the art.
Conclusion
Claims 1, 2, 4, 5, 8-10, 12-14 and 21-30 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to AMY M BUNKER whose telephone number is (313) 446-4833. The examiner can normally
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/AMY M BUNKER/Primary Examiner, Art Unit 1684
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