DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 15 January 2026 has been entered.
Claims 8, 12-13, and 15-18 have been amended, and claims 9-11 have been canceled. All prior rejections of claims 9-11 are moot in view of the cancelation of those claims. Claims 2-8 remain withdrawn, and claims 1 and 12-25 remain under consideration herein. The Terminal Disclaimer filed 29 December 2025 has been approved (see also paragraph 4 below), and the nonstatutory double patenting rejection of record has therefore been withdrawn. Applicant’s amendments have also overcome some prior rejections under 35 USC 112(b) (although some claims remain indefinite as set forth below). However, claims 1 and 12-25 remain rejected for the reasons given below. Any rejections and/or objections not reiterated in this action have been withdrawn. This action is non-final.
Election/Restrictions
Applicant’s election without traverse of the species of MAPT, CD2, and QDPR (for a)), and LDHA (for b)) in the reply filed on February 18, 2025 is acknowledged. While it is noted that LDHA is no longer recited in independent claim 1, MAPT, CD2, and QDPR continue to be recited in claim 1 (as members of a larger, ten gene group). The prior art continues to apply against the claims as amended.
Claims 2-8 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on February 18, 2025.
Terminal Disclaimer
The terminal disclaimer filed on 29 December 2025 disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of any patent granted on Application No. 18/338,974 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Claim Rejections - 35 USC § 112(b)/second paragraph
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 12-14 and 17-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 12-14 are indefinite because the claims depend from a canceled claim (claim 11), such that it is unclear what is encompassed by these claims. In the interest of compact prosecution, and because independent claim 1 recites a “biological sample of a subject”, for purposes of further examination the claims have been interpreted as requiring a mixture as set forth in independent claim 1 including nucleic acids from a biological sample of a subject having breast cancer. However, correction/clarification is required, and the actual metes and bounds of the claims are presently entirely unclear
Claims 17-18 are indefinite over the recitation in claim 17 (from which claim 18 depends) of the limitations “the at least one reference gene”/”the at least one reference gene for determining the mRNA expression levels via reverse transcription-quantitative real-time PCR…..and reverse transcription”, as there is insufficient antecedent basis for these references to such an “at least one reference gene” in claim 1 (from which claim 17 depends).
Claims 17-18 are also indefinite over the recitation in claim 17 (lines 5-8) of the limitation “or RNA sequencing of said at least one reference gene….in the mixture”. While the reference to “or RNA sequencing” has been interpreted as an alternative to the previously recited intended use of the “at least one nucleic acid probe(s)”, antecedent basis is lacking for the limitation “said at least one reference gene selected from LDHA….TRIM2 in the nucleic acids…” (as neither claim 1 nor claim 17 previously reference this type of “at least one reference gene”).
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.
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.
Claim(s) 1 and 12-25 remain rejected under 35 U.S.C. 103 as being unpatentable over Reeve et al (WO 99/47706 A1 [23 Sept 1999]; cited in IDS) in view of Nilsson et al (Journal of Molecular Recognition 10:7-17 [1997]; previously cited).
Reeve et al teach compositions, including arrays, comprising all possible “N mer” oligonucleotides or subsets thereof “where N is preferably from 5 to 10, particularly 8 or 9” (see entire reference, particularly pages 4-5; quotation from page 5, lines 10-11). Reeve et al teach that their N mers may be DNA, RNA, PNA or “mimetics or mixtures thereof” (see page 5, lines 12-13), and state that the molecules may be in solution (page 4) or "immobilised at a spaced location on a surface of a support” (page 5). Reeve et al also teach preferred embodiments in which their oligonucleotides are labeled (page 4), and further teach methods in which “target nucleic acid is incubated under hybridization conditions with the mixture of labeled oligonucleotides” (page 5; see also page 2); thus, Reeve et al teach mixtures including target nucleic acids and labeled Nmers having the features noted above. Reeve et al disclose the use of their reagents in sequencing by hybridization, and particularly in determining difference between target and reference sequences (see entire reference, particularly, e.g., pages 2-3). The combinations of all possible 5mers-10mers taught by Reeve et al comprise molecules that inherently constitute both fragments and complements of each of the genes recited in the claims, including a variety of combinations thereof that could be employed as probes/labeled probes in detecting expression levels of each of those genes (for example, via hybridization to sample mRNA, amplification of cDNA generated therefrom, etc.). With further regard to claims 15-20, Reeve et al’s compositions inherently include Nmers complementary to each of the genes of the claims and usable in the techniques set forth in the claims (and Reeve et al further disclose the use of their Nmers in hybridization, amplification, microarray analysis, etc.); with further regard to claims 17-18, it is noted that Reeve et al’s compositions of all possible Nmers also inherently include fragments/complements of each of the recited reference genes. Regarding dependent claim 20, it is noted that the probes of Reeve et al may also be employed as primers, which meets the requirements of the claim (i.e., as the Nmers of Reeve et al may be employed in amplification, nucleic acid extension, etc., they inherently constitute “primers”; the claim is directed to a mixture including the recited components, and no particular use of those materials is required). With further regard to dependent claims 22-23, it is noted that Reeve et al teach the use of fluorescent labels, and that labels as taught by Reeve et al meet the requirement of “a tag” (see, e.g., page 4).
While Reeve et al teach mixtures including probes meeting the requirements of the claims and a “target nucleic acid”, Reeve et al do not teach the analysis of nucleic acids “from a biological sample of a subject”, as required by claim 1. Additionally, Reeve et al do not disclose the use of biotin as a label (claim 21), and do not teach the use of nucleic acids from a biological sample of a subject with (human) breast cancer (as recited in claims 12-14 and 24-25).
Nilsson et al summarize a variety of known methods for DNA analysis, including sequencing by hybridization (i.e., the methodology disclosed by Reeve et al), as well as alternative methods that also rely on nucleic acid hybridization (see entire reference, particularly page 7-page 8, left column). Nilsson et al disclose and exemplify the preparation of biotinylated PCR products via the use of biotinylated oligonucleotides (see, e.g., page 8, right column, and page 9, including Figure 1, and page 12, left column), and further teach that such methods facilitate analysis of mutations in cancers including breast cancer samples (see Abstract, page 8 left column). Nilsson et al also teach immobilization of biotinylated oligonucleotides on chips for use in DNA analysis (see, e.g., page 8, right column, first full paragraph, and discussion of “Format 2” on pages 9-12).
In view of the teachings of Nilsson et al, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have prepared mixtures as taught by Reeve et al in which the target nucleic acids were “from a biological sample”, including a (human) breast cancer sample (meeting the requirements of present claims 12-14 and 24-25), and to have prepared mixtures of oligonucleotides as taught by Reeve et al in which biotin was substituted for, e.g., a fluorophore as taught by Reeve et al (meeting the requirements of claim 21), and also to have employed such oligonucleotides in analysis of breast cancer nucleic acids via the preparation of mixtures/substrates including such oligonucleotides and breast cancer nucleic acids. An ordinary artisan would have been motivated to have made such modifications for the benefit of detecting and analyzing breast cancer associated mutations in a subject sample – i.e., for the application and benefit taught and exemplified by Nilsson et al – either via sequencing by hybridization (as taught/suggested by both Reeve et al and Nilsson et al) and/or via the alternative methodologies disclosed and exemplified by Nilsson et al. Further, given the detailed guidance provided by Reeve et al and Nilsson et al, an ordinary artisan would have had a reasonable expectation of success in preparing such mixtures.
The reply of 15 January 2026 traverses the prior rejection under 35 USC 103 on the following grounds.
The Reply summarizes the requirements of a proper obviousness rejection, citing to KSR International Co. v. Teleflex Inc., 550 US 398, 82 USPQ2d 1385 (2007) and MPEP 2143.03 (pages 8-10), and argues that Reeve “neither teaches not suggests ER/PR expression panels” but rather “teaches a generic sequencing-by-hybridization platform” (Reply page 10).
Applicant urges that the focus of Reeve is on detecting sequence differences not measuring mRNA expression levels, and not “the particular ER/PR-associated gene set recited in claim 1” (Reply page 10).
Applicant further argues that Nilsson “fails to cure these deficiencies”, as Nilsson’s teaching relate to point mutation detection using “label-free” formats, whereas “the probes in the claims require nucleic acid probes each labeled with a marker” (Reply pages 10-11).
The Reply also argues that Nilsson “does not teach measuring mRNA expression levels, does not teach ER/PR-associated gene panels, does not teach multi-gene quantitative panels with reference genes, and does not propose the breast-cancer endocrine signaling panel” of claim 1 (Reply page 11).
While Applicant acknowledges Nilsson’s use of “immobilized biotinylated oligonucleotides for SPR chip attachment”, Applicant argues that Nilsson do not use biotin “as labels in a multiplex expression assay mixture as claimed” (Reply page 11).
Further, the Reply argues that the “Office’s reliance on Nilsson for biotin and ‘breast cancer sample’ generally conflates materially difference contexts”, and particularly that Nilsson’s teachings of biotinylated primers/probes “does not render obvious a mixture in which at least ten probes are each labeled with a marker (e.g., biotin) for expression detection of the specific ER/PR gene panel” of the claims (Reply page 11).
Finally, Applicant also argues that “the Office’s assertion that a library of all N-mers ‘inherently’ constitutes probes for detecting expression levels of the claimed ER/PR genes is legally insufficient”, as inherency “requires that the missing limitation be necessarily present in the prior art composition, not merely possibly present” (Reply page 11). The Reply urges that Reeve’s “N-mer soup is not the claimed composition of ‘at least ten’ probes ‘for detecting mRNA expression levels’ of the recited ER/PR-associated genes”, and that one of skill in the art would have to modify the composition of Reeve to select ER/PR-associated genes, design “expression-grade gene-specific probes and reference probes”, etc., to arrive at the claimed invention (Reply page 11 bridging to page 12).
These arguments have been thoroughly considered, but are not persuasive for the following reasons.
With regard to Applicant’s arguments that Reeve teaches “generic sequencing-by-hybridization” rather than ER/PR expression panels, and is focused on detecting sequence differences rather than measuring mRNA expression levels, Applicant’s claims are to a product (a mixture) comprising the components recited in the claims, which include “at least ten nucleic acid probes each labeled with a marker for detecting mRNA expression levels of at least ten ESR1 or PGR associated genes” (as recited in independent claim 1). The claim recites the open transitional language “comprising”, and the probes of the claims are not limited to particular structures, but are rather described as being “for detecting mRNA expression”, i.e., an intended use of the probes. The claims do not require the actual use of the product claimed in any particular way (given that the claims are to a product, not a method), and further, the probe compositions of Reeve could clearly be employed in various methods to achieve detection of mRNA expression levels of any target genes of interest (including the preferred group of the claims), i.e., the prior art structure(s) of Reeve et al is/are capable of performing the intended use of “detecting mRNA expression levels” (particularly as no specific manner of achieving this use is required). Thus, this argument is non-persuasive, given what is actually required by Applicant’s claim language.
Regarding Applicant’s arguments that Nilsson teaches point mutation detection, and fails to teach gene panels of the claim as well as measurement of mRNA expression levels, it is reiterated that probe combinations meeting the requirements of claim 1 are taught by Reeve (i.e., Nilsson was not relied upon for the teachings referenced in these arguments). 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). Additionally, the claims do not require the use of the claimed mixtures in any particular way (i.e., it is the features/characteristics of the claimed product that must be taught and suggested by the cited art, not any particular method in which the product is used).
Regarding the argument that Nilsson does not use biotin as “labels in a multiplex expression assay mixture”, again the claim requires a mixture including nucleic acids from a biological sample, and probes having the properties required by the claims. The claimed invention is not directed to a method, and does not require a use of the claimed product in a “multiplex expression assay”. 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).
Regarding Applicant’s argument that Nilsson “does not render obvious a mixture in which at least ten probes are each labeled with a marker”, it is reiterated that Reeve (the primary reference) teaches embodiments including labeled or unlabeled Nmer compositions, with Nilsson being relied upon for its teaching of the alternative label of biotin (which is only recited in claim 21, which also does not include any sample requirements beyond “nucleic acids from a biological sample”). Again, the rejection relies upon the combination of Reeve and Nilsson, and the limitations that must be addressed are those that are actually set forth in the claims.
Finally, regarding Applicant’s argument that the “Nmer soup” of Reeve would require modification to function in detection of mRNA expression levels, any manner of use of probe combinations as disclosed by Reeve functional to detect mRNA expression levels – including in, e.g., the sequencing of quantitated mRNA via methods taught by Reeve – is sufficient to meet what is actually required by the instant claims. It is also noted that neither the specification nor the claims set forth, e.g., any minimum required length for the probes of the claims.
Accordingly, Applicant’s arguments are non-persuasive with respect to the invention as it is presently claimed.
Conclusion
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/DIANA B JOHANNSEN/Primary Examiner, Art Unit 1682