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 .
Election/Restrictions
Applicant’s election without traverse of species SEQ ID NO: 85, 60, and 62 in the response filed 12/9/2025 is acknowledged.
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 111-114, 121-130, 137, and 138 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huletsky et al. (US2008/0227087) in view of Olivier et al. (Mutation Research 573 (2005) 103–110) and Ichimura et al. (JOURNAL OF CLINICAL MICROBIOLOGY, Oct. 2007, p. 3316–3322).
Instant SEQ ID NO: 85 and SEQ ID NO: 62 are oligonucleotides that have a 5’ portion followed by a 3’ target specific portion. In SEQ ID NO: 85, the 5’ portion is nucleotides CCGAGG and the remaining 3’ portion is specific to S. aureus. In SEQ ID NO: 62, the 5’ portion is nucleotides 1-10.
Instant SEQ ID NO: 85 is entirely comprised within instant SEQ ID NO: 62, therefore when this rejection addresses SEQ ID NO: 62, it also addresses an oligonucleotide that comprises instant SEQ ID NO: 85.
Huletsky et al. teach specific, ubiquitous and sensitive methods and compositions for determining the presence or amount of S. aureus methicillin-resistant strains, in particular for detecting MREJ types xi-xx. Huletsky et al. provide an alignment of 19 representative MREJ types comprising the orfX, the integration site and the first 535 nucleotides of the SSCmec right extremity (¶35).
The reference teaches that probes are provided that anneal to more than one MREJ strains (¶18).
The reference teaches targets can be detected by amplification with primers and then amplification products can be detected through detection of probes that anneal to the amplification products (¶48). Such probes are “detection oligomers.” The reference teaches probes used for detection after amplification can have labels such as the non-nucleotide labels radioisotopes, fluorescent molecules, biotin and the like (¶50). Thus, the reference teaches at least one detection oligomer comprising a non-nucleotide label.
The reference additionally teaches that oligonucleotide sequences other than those explicitly described and which are appropriate for detection and/or identification of MRSA may be derived from the MREJ sequences disclosed in the reference or from database sequences (¶55). The reference teaches that it is quite possible for the individual skilled in the art to derive, from the selected DNA fragments oligonucleotides which are suitable for diagnostic purposes (¶55). The reference provides guidance about constructing, design and synthesis of primers and probes on pages 5-7.
For reference and context the currently claimed are aligned to SEQ ID NO: 56 in Huletsky.
Instant SEQ ID NO: 62 comprises a portion, which is identical to instant SEQ ID NO: 97, which is identical to nucleotides 267-282 of SEQ ID NO: 56 in the reference, and is in a fully conserved portion of Figure 3E. Using the numbering at the top of the figure attention should be drawn to the portion beginning at nucleotide 276.
Huletsky et al. does not teach a detection oligomer that comprises instant SEQ ID NO: 97.
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have modified the detection oligomers taught by Huletsky et al. so as to have selected any additional oligonucleotide probe from the disclosed, conserved orfX region to be used in the amplification of MREJ junctions and identification of MRSA in samples. Followign the direct suggestion of Huletsky in paragraph 18, it would have been obvious to have selected a probe binding region from a portion of the sequences that is entirely conserved to provide an oligomer that is capable of detecting all MRSA targets.
An ordinary artisan would have been motivated to do so with a reasonable expectation of success, since: (i) Huletsky et al expressly taught designing oligonucleotide oligonucleotides from the known SCCmec sequences, and suggested explicitly that additional oligonucleotides could be selected, (ii) the sequences of target sequences for a variety of MRSA sequences were known, and Huletsky et al. provide many of these sequences in alignment with one another for identifying regions of similarity and difference (iii) Huletsky teach kits and compositions which include detection oligomers for the detection of amplified fragments, and further teach non-nucleotide labels for visualizing related amplicons and (iv) Huletsky provided extensive guidance for the design and construction of oligomers for detection of an MREJ target or targets. The combined teachings of the reference would have suggested a finite number of possible detection probes (i.e. detection oligomers) that could be designed from the disclosed MREJ sequences, and, based on the teachings of Huletsky et al., the ordinary artisan would have expected predictable results in obtaining and using these oligonucleotides MRSA detection methods.
Huletsky does not teach a detection oligomer that has a 5’ end as claimed in SEQ ID NO: 85 or SEQ ID NO: 62, or a method using such an oligonucleotide. Huletsky does not teach a secondary detection oligonucleotide configured to interact with a fragment of the detection oligomer.
Oliver teaches The Invader Assay which employs an invasive cleavage reaction that is highly specific, has a low failure rate, and can detect zeptomole quantities of target DNA.
Figure 1 illustrates that the method employs a probe (probe 1 therein) that is a labeled detection oligomer which has a 5’flap portion (i.e. does not hybridize to target) and a 3’ target specific portion.
Oliver further teaches an embodiment where a “FRET cassette” is used to amplify the signal of a primary invasive cleavage reaction (Figure 2).
An illustration of how the Invader assays work is provided in Figures 1 and 2.
Further, Oliver teaches secondary detection oligomer that is a FRET cassette and comprises at least two labels that is a FRET pair, namely a label and a quencher. See Figure 2.
Oliver does not give the sequence of the “flap” portions of the primary probe 1.
Ichimura et al. also teaches oligonucleotides and reagents designed to carry out the Invader assay, which is demonstrated in the reference to be a useful tool for detecting related mycobacterial species. The reference teaches sets of invader probes which include probes for detection mycobacteria generally and also different sets of probes for detecting species and sequevars of mycobacteria, demonstrating selecting probes of a range of specificities. The reference teaches a series of “signal probes” that have a 5’ end that is identical to nucleotides 1-10 of instant SEQ ID NO: 62 (CGCGCCGAGG, see probes in Table 1 of Ichimura et al.). The probes taught by Ichimura et al. are about 25 to about 45 nucleotides in length. The terminal flap taught by Ichimura is at least 6 nucleotides, as it is 10 nucleotides, and it comprises positions 1-6 of SEQ ID NO: 62.
Regarding claim 127, Huletsky teaches detecting MRSA, as discussed, by preparing a composition comprising a labeled detection oligomer. Further Oliver and Ichimura teach nucleic acid detection comprising preparing a composition with a detection oligomer, a sample suspected of comprising an amplicon of the target, and detecting the presence or absence of the amplicon by performing a hybridization assay and determining whether the oligomer hybridized to the target (See Figure 1 and 2, Oliver; and throughout Ichimura).
Regarding claims 128-129, the method taught by Oliver includes exposing the detection oligomer to a structure-specific nuclease and determining whether a 5’-terminal flap fragment of the detection oligomer produced by the structure-specific nuclease interacts with a secondary detection oligomer (i.e. the FRET cassette), see Figure 2 and throughout. Regarding claims 130 and 137, the detection composition further comprises at least one invasive oligomer that hybridizes to the target amplicon that overlaps the hybridization site of the detection oligomer, and in the presence of the detection oligomer and the target amplicon forms a structure recognized for cleavage by the structure-specific nuclease (Figure 1 and 2, “Invader oligo”). Regarding claim 138, insofar as the invasive oligomer hybridizes to the target, it is “configured” to produce an amplicon. There is no structure implied by this intended use that differentiates the claimed invasive oligomer from the invasive oligomer of Oliver and/or Ichimura.
It would have been obvious to have modified the detection oligomer selected from the sequence taught by Huletsky so as to have appended the 5’-flap taught by Oliver and Ichimura to the conserved sequence oligonucleotide probe in order to enable the practice of an Invader assay for the detection of MRSA, and to have practiced the invader assay for the detection of MRSA in a sample. One would have been motivated to do so in order to take advantage of the Invader format which Oliver teaches has excellent sensitivity and specificity and the exemplification of Ichimura that the method could be used for detecting bacterial targets.
Claim(s) 115-117 is/are rejected under 35 U.S.C. 103 as being unpatentable over Huletsky et al. (US2008/0227087) in view of Olivier et al. (Mutation Research 573 (2005) 103–110) and Ichimura et al. (JOURNAL OF CLINICAL MICROBIOLOGY, Oct. 2007, p. 3316–3322) as applied to claims 111-114, 121-130, 137, and 138 above, and further in view of Zou et al. (US8715937).
The teachings of Huletsky, Oliver, and Ichimura are given previously in this Office action and are fully incorporated here.
These do not teach that the labeled detection probe is blocked at the 3’ end, and with respect to claims 115 and 116, that the 3’ ultimate moiety has 3’-terminal hexanediol, as required by the disclosure of SEQ ID NO: 62 (elected) in the sequence listing.
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Zou et al. also teaches flap probe seuqences which have a 5’flap sequence and a 3’ target specific sequence, wherein the 3’end is blocked with a hexanediol group in order to inhibit extension (see Col. 16, lines 50-51, and all examples).
It would have been obvious to have modified the flap probes taught by Huletsky in view of Olivier and Ichimura so as to have blocked the 3’end with a hexanediol group in order to inhibit extension of the oligo, as taught by Zou et al. The claim would have been obvious because the technique for improving the flap oligonucleotide to prevent extension was part of the capabilities of a person of ordinary skill in the art, in view of the teaching of the technique for improvement in a similar situation, by Zou et al.
Claims 111, 112, 113, and 114 is/are rejected under 35 U.S.C. 103 as being unpatentable over NEB Catalog (1996/1997), pp. 111 in view of Rothstein et al. (1994) PNAS USA 91: 4155-4159.
The instantly rejected claims encompass compositions of nucleic acids that are unlimited in the number of different oligomers that can be contained in the composition, and in most cases require no minimum or maximum length to the claimed oligomers. The claims contain additional language that set for the intended use for many of the claimed oligomers. A recitation of the intended use of the claimed invention must result in a structural difference between the claimed invention and the prior art in order to patentably distinguish the claimed invention from the prior art.
The NEB catalog offered for sale a random primer mix of 24mer nucleotide primers. As the calculation below shows, about 9 molecules of every single 24 mer are present in each tube of the 24 nucleotide mixtures.
e. Molecular weight of 24-mer:
24 x 325 daltons/nucleotide = 7,800 daltons = 7,800 g/mol
f. Total number of possible 24-mers:
424 = 2.8 x 1014 molecules
g. How many molecules of 24-mer in a vial sold by NEB:
1 A260 unit = 33 mg = 3.3 x 10-5 g
3.3 x 10-5 g / 7,800 g/mol = 4.2 x 10-9 mol
(4.2 x 10-9 mol) x (6.02 x 1023 molecules/mol) = 2.5 x 1015 molecules
h. How many molecules of each 24-mer in a single vial:
2.5 x1015 molecules / 2.8 x 1014 molecules = 9 molecules/vial
The claims encompass a large genus of possible nucleic acid oligomers, called “detection oligomers” and “secondary detection oligomers” with no particular base composition or length. The NEB catalog kits will inherently and necessarily contain 24 nucleotides primers encompassed by the claimed recitation “about 25”. Instant elected SEQ ID NO: 85 is only 12 nucleotides in length, and the claim is of sufficient breadth that the remaining nucleotides are unidentified. The nucleotide sequence of the “secondary” oligomer is undefined except that it must be “configured to interact” with “a fragment” of the detection oligomer. Since all possible 24mers are in the disclosed primer mixes, there were inherently molecules that meet these requirements therein.
Thus, the prior art inherently teaches oligomers having sequences meeting each of the requirements set forth in the claims.
The NEB catalog does not detection oligomers that contains a non-nucleotide detectable label or polymerase.
The NEB Catalog suggests that the kit can be used for universal detection and visualization of DNA fragments, citing the method of Rothstein et al. The method used by Rothstein et al. utilizes a reporter group (fluorecein-conjugated dUTP and/or anti-fluorescein-conjugated horseradish peroxidase); p. 4156, first column). The methods also employ a polymerase.
It would have been prima facie obvious to one having ordinary skill in the art at the time the invention was made to have modified the kits taught by the NEB catalog so as to have included a reporter group in order to provide a more complete set of reagents for universal detection and visualization of DNA fragments and a polymerase for carrying out the modification. The resulting product would contain an unlimited number of detection oligomers with a non-nucleotide label.
Improper Markush Rejection
Claim 111-117, 121-130, and 137-138 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 706.03(y).
The Markush grouping oligomers claimed in the alternative identified by unique targets and/or SEQ ID NO is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: each oligomer has a unique structure that is not in common with any other in the group and is not claimed with any evident structure required in common.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Response to Remarks
Applicant argues that SEQ ID NO: 85 corresponds to the last nucleotide of SEQ ID NO: 60 that can function as an amplification oligomer and an invasive oligomer. This goes to the intended use of SEQ ID NO: 85, and does not structurally distinguish the molecule, especially since in the claimed kits and compositions, a molecule consisting of SEQ ID NO: 60 is not required, and the "last nucleotide" of SEQ ID NO: 60 is not necessarily the "last nucleotide" of any molecule in the claimed compositions or methods.
Furthermore, this is not persuasive because instant claims do not require a molecule consisting of instant SEQ ID NO: 85, which has only 12 nucleotides. Any argument of unexpected benefits or properties is not commensurate in scope with the claims, and in fact a detection oligomer consisting of SEQ ID NO: 85 is not within the scope of the claims.
Applicant argues that the claimed composition or kit "worked well" with other amplification and detection oligomers. There is no explanation or evidence that this was unexpected or that it was not routine to develop the multiplex amplification. Example 1 does not mention one of the elected SEQ ID NO.
Applicant argues that Example 2 shows "the use of such a detection oligomer" resulted in more accurate detection relative to commercial assays. Example 2 does not mention one of the elected SEQ ID NO, nor is there a comparison to any molecule in the primary reference, which is the closest prior art. Likewise the response points to Examples 3 and 5 which shows specific detection, but there is no evidence that that this is unexpected or that the result can be attributed to the presence of SEQ ID NO: 85 in particular.
Furthermore, it is noted that none of the examples state that they employ SEQ ID NO: 85 or 62, the elected detection oligomers, and of the examples use more extensive sets of oligomers than currently claimed. Therefore, any showing of unexpected results in the specification are not commensurate in scope with the instant claims.
Further still, it is taught in the secondary reference that Invader assays are specific and sensitive and able to be multiplexed (see Oliver, abstract and throughout.).
The rejection is modified to address the amended claims and maintained.
Applicant traverses the rejection over the NEB catalog saying that the reference does not teach the newly added portion of claim 111. However, the rejection has been updated to address the amended claim and is maintained.
Regarding the improper Markush grouping, initially it is noted that the cited PTAB decisions are non-precedential decisions. Further, unlike in Ren, the oligomers here do not share a common function of all being siRNA. The response focuses on Ex Parte Ren where the Board overturned an Improper Markush rejection of distinct siRNA sequences because the sequences share a nucleic acid backbone and the common use of modulating or silencing plant genes. It is noted that Ex Parte Ren appears to have an allowable generic claim and the Markush claim was dependent on the allowable generic claim. The instant oligomers do not share a common structure and they do not, by themselves, all function even to detect the same target gene, genes, or variants of Staphylococcus. There is no "core sequence" that is required by all members of any of the groupings of alternatives. Therefore, the rejection is maintained.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Juliet Switzer whose telephone number is (571)272-0753. The examiner can normally be reached Monday to Thursday, 8:00 AM-3:30 PM.
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Juliet Switzer
Primary Examiner
Art Unit 1682
/JULIET C SWITZER/Primary Examiner, Art Unit 1634
Prosecution Insights