DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
Status of the Application
Claims 1-22 are pending and under examination
The following Office Action is in response to Applicant's communication dated 05/01/2024.
Claim Interpretation
Claim 6 and 17 recites “stochastic sequence”, which Examiner interpreted as random molecular tagging that allow allows accurate count individual molecules, eliminate PCR amplification bias, and correct sequencing errors. This interpretation is consistent with Applicant’s specification [¶0110].
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of pre-AIA 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 –
(b) the invention was patented or described in a printed publication in this or a foreign country or in public use or on sale in this country, more than one year prior to the date of application for patent in the United States.
Claim(s)1-5, 7, 8, 10, 13, 14-16, and 19 rejected under pre-AIA 35 U.S.C. 102(b) as being anticipated by Chee et al. (US8460865B2, Published: October 4th 2007).
Regarding claims 1 and 14, Chee discloses method/kit, comprising:
(a) providing a surface comprising a population of beads, wherein the beads comprise a plurality of oligonucleotides, wherein an oligonucleotide of the plurality of oligonucleotides comprises: a primer site, a unique identifier sequence, and a probe configured to label a target nucleic acid of a sample; (e.g. the present invention provides array compositions comprising a substrate with a surface comprising discrete sites. The composition further comprises a population of microspheres comprising at least a first and a second subpopulation; each subpopulation comprises a bioactive agent [column 4, lines 19-33] (e.g. nucleic acids sequence) [column 7, line 32]. Bioactive agent further comprises encoding sequences (e.g. gene-specific sequence) [column 25, lines 24-25 and column 26, lines 34-14], primer region [column 25, line 30], and unique identifier [column 18, lines 30-41].)
(b) contacting the sample comprising target nucleic acids with the surface; (c) labeling the target nucleic acid with the probe, thereby generating a modified target nucleic acid; (e.g. upon binding between analyte to a bioactive agent, nucleic acid analytes are labeled with fluorochromes [Column 58, line 65-column 59, line 17])
(d) determining a location of the target nucleic acid upon sequencing an amplicon generated using the modified target nucleic acid. (e.g. The sample containing the target analytes is added, and only those locations exhibiting a change in the optical signal are decoded. [column 22, lines 28-30])
Regarding claims 2 and 15, Chee discloses the surface is a rigid surface or semi-rigid surface of a substrate. (e.g. “substrate” or “solid support” include, but are not limited to, glass and modified or functionalized glass, plastics (including acrylics, polystyrene and copolymers of styrene and other materials, polypropylene, polyethylene, polybutylene, polyurethanes, Teflon, etc.) [column 8, lines 24-39]).
Regarding claims 3 and 16, Chee discloses the surface is substantially flat. (e.g. the substrate is flat (planar) [column 8, line 40])
Regarding claim 4, Chee discloses the population of beads is coupled to a rigid surface. (e.g. microspheres are distributed on a substrate [column 6, lines 40-41])
Regarding claim 5, Chee discloses the sample comprises a plurality of cells. (e.g. analytes are from tumors or other tissue samples [column 62, lines 32-50])
Regarding claims 7 and 19, Chee discloses the target nucleic acid comprises a messenger RNA (mRNA) sequence. (e.g. target sequence can be mRNA [column 15, line 52])
Regarding claims 8, Chee discloses the probe comprises a complementary sequence configured to hybridize with a portion of the target nucleic acid. (e.g. the bioactive agents (i.e. probes) [column 13, lines 16-17] are designed to be complementary to a target sequence (either the target analyte sequence of the sample or to other probe sequences, as is described herein), such that hybridization of the target and the probes of the present invention occurs. [column 15, lines 3-7])
Regarding claims 10, Chee discloses the plurality of oligonucleotides comprises at least 10,000 different sequences. (e.g. Arrays many millions bioactive agents [column 7, lines 55-56])
Regarding claim 13, Chee discloses characterizing a status of a tissue upon determining a level of expression of the target nucleic acid in the sample. (e.g. Under BRI, “characterizing a status of a tissue “ is interpreted as characterizing tissue’s molecular or expression state base on variations in its RNA expression profile. Chee discloses RNA expression profiling using decoded cDNA bead arrays, including Comparative analysis allows the detection of differences in the expression levels of individual RNAs and quantify RNA amount from biological sample (e.g. tissue and tumor samples) [column 61, line 61-column 62, line 67])
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Chee et al and Brenner et al.
Claim 6, 9, 17, and 18 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Chee et al. (US8460865B2, Published: October 4th 2007) in view of Brenner et al. (US20070172873A1, Published: July 26th 2007).
Regarding claims 6 and 17, Chee does not disclose the unique identifier sequence comprises a stochastic sequence.
Brenner discloses labeling each molecules in a sample with unique oligonucleotide tag. In one aspect, molecules to be counted are each associated with or linked to an oligonucleotide tag randomly selected from a set that is much larger than the number of target molecules, such that substantially every target molecule is associated with a unique oligonucleotide tag [¶0005]. Brenner further discloses combinatorial synthesized oligonucleotide tags comprising a sequence of subunits aligned linearly such that for a randomly selected tag there is an equal probability that any subunit will be at any given position [¶0113].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to modify Chee’s identifier sequence to include Brenner’s stochastic sequence because Brenner expressly teaches selecting tags from sufficiently large so that such a sample contains substantially all unique tags, thus, enable more accurate identification and counting of individual target nucleic acids. Additionally, Brenner’s method is built exility for conveniently and accurately providing digital measurements of quantities of biomolecules in a cost-effective manner [Abstract and ¶0004]. The modification still allows Chee’s identifier sequences to perform their identifying function and produce predictable result of improved differentiation of target molecules. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143).
Regarding claims 9 and 18, Chee does not disclose a ratio between a) a first number of diverse oligonucleotides of the plurality of oligonucleotides and b) a second number of target nucleic acids, is greater than 10.
Brenner discloses target polynucleotides population to be labeled are each linked to an oligonucleotide tag from a population that has a much larger size than that of the target polynucleotide population. For example, the size of the population of oligonucleotide tags is at least 100 times the size of the population of polynucleotides to be labeled [¶0064].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to select Brenner’s ratio of at least 100 to reduce identifier collisions and improve the accuracy with which individual target molecules are distinguished and counted. Selecting the taught ratio would predictably enable more accurate identification and counting of individual target nucleic acids. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143).
Chee et al and Klein et al.
Claim 11 and 12 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Chee et al. (US8460865B2, Published: October 4th 2007) in view of Klein et al. (US6673541B1, Published: January 6th 2004).
Regarding claims 11 and 12, Chee discloses identifying nucleic acids and whole mammalian tumor cells as suitable target analytes [column 56, lines 65-67]. However, Klein does not expressly teach that sample used in the claimed nucleic acid analysis comprise single cell (e.g. isolated single tumor cell).
Klein teaches method for the amplification of the DNA or the whole genome of a single cell, such as a single (tumorous) cell [column 6, lines 1-12].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to obtain target nucleic acids from Klein’s isolated tumor cell for analysis using Chee’s bead base nucleic assay because as cancer progress genetic changes that are not found in primary tumors, can be found in their metastases, which allow one to pinpoint genetic changes and genes with important roles in the metastatic progression. However, the vast majority of these cells will be eliminated by the immune system or undergo apoptosis, hence these cells are few and dispersed, represents the “Achilles' Heel” of cancer [Klein column 9 line 57-column 10 line 43]. A skilled artisan would have been motivated to perform Chee’s nucleic analysis method on Klein’s isolated tumor cell is desirable to uniformly and accurately amplify the whole genome of such a cell, allowing early diagnosis [Klein column 9 line 57-column 10 line 43]. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143)
Chee et al. and Gormley et al.
Claim 20 and 21 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Chee et al. (US8460865B2, Published: October 4th 2007) in view of Gormley et al. (US7741463B2, Published June 7th 2007).
Regarding claims 20 and 21, Chee discloses amplification libraries of clonal nucleic acids using conventional methods PCR [column 15, lines 12-17] and sequencing libraries using Sanger sequencing [column 59, line 62-column 60 line 14]. However, Chee does not go into details on reagents for generating amplicons and generating a sequencing library.
Gormley discloses method/reagents for use in preparing libraries of template polynucleotides for PCR and/or sequencing [¶0142-0167].
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to use reagents suggested by Gormley to prepare oligonucleotide library in Chee’s PCR and sequencing assays. The modification would predictably allow successful amplification and sequencing of target nucleic acid analytes using Chee’s decoding of array system. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143).
Chee et al. and Adessi et al.
Claim 22 is/are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Chee et al. (US8460865B2, Published: October 4th 2007) in view of Adessi et al. (US7115400B1, Published October 3rd 2006).
Regarding claims 22, Chee does not disclose the plurality of oligonucleotides has a spacing of at least 104 molecules per micron2.
Adessi teaches immobilize primers to a support at the density of 30-60 fmol/mm2 [column 12, lines 33-45], which is approximately 1.807x1010 -3.613x1010 molecules/mm2, which is approximately 1.807x104 -3.613x104 molecules/ μm2.
As of the application’ s effective filing date, it would have been prima facie obvious to a person of ordinary skill in the art to employ Adessi’s oligonucleotide density in Chee’s bead supported system to ensure that sufficient number of surface bound oligonucleotides are available in proximity to target nucleic acid for reliable hybridization, primer extension, amplification, and detection. The modification represents selecting a known, expressly taught oligonucleotides loading density for a known support and would predictably improve the efficiency and reliability od the nucleic acid analysis. See KSR International Co. v. Teleflex Inc., 550 U.S. 398, 415-421, USPQ2d 1385, 1395 — 97 (2007) (MPEP § 2143).
Conclusion
No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Khai Quynh Tien Pham whose telephone number is (571)272-6998. The examiner can normally be reached M-T, 9-4 ET.
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/KHAI QUYNH TIEN PHAM/ Examiner, Art Unit 1684
/JEREMY C FLINDERS/ Primary Examiner, Art Unit 1684
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