DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Specification
The disclosure is objected to because of the following informalities:
The use of the terms BODIPY 493/503, ALEXA FLUOR 350, TRITON X, “CF dye™, DRAQ™, CyTRAK™, BODIPY™, Alexa Fluor™, Dy Light Fluor™, Atto™, Tracy™, FluoProbes™, Abberior Dyes™, DY™ dyes, MegaStokes Dyes™, Sulfo Cy™, Seta™ dyes, SeTau™ dyes, Square Dyes™, Quasar™ dyes, Cal Fluor™ dyes, SureLight Dyes™, PerCP™, Phycobilisomes™, APC™, APCXL™, RPE™, and/or BPE™” (page 29) which are trade names or marks used in commerce, have been noted in this application. The terms should be accompanied by their generic terminology; furthermore, the terms should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 40-55 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 40, 44, 47, 48-52 are indefinite with respect to what constitutes the metes and bounds of a “retarding moiety”. Acknowledgement is made of the definition found at paragraph [0065] (pages 25-26) of the as-filed disclosure. As stated therein:
[0065] The term "retardant moiety" or "retarding moiety" refers to a substance, agent (e.g., a detectable agent), or monovalent compound that, when linked to a nucleotide, is capable of slowing incorporation of the next nucleotide, in the absence of a reversible terminator. In embodiments, presence of a 3' terminal nucleotide including a retardant moiety increases the halftime of a further nucleotide extension to a level that is about or at least about 2-fold higher, 5-fold higher, 10-fold higher, 15-fold higher, 20-fold higher, 25-fold higher, 30-fold higher, or more, as compared to the 3' terminal nucleotide lacking a retardant moiety under conditions of a sequencing reaction. In embodiments, the retardant moiety raises the halftime of a further incorporation to at least 5-fold higher. In embodiments, the retardant moiety raises the halftime of a further incorporation to at least 10-fold higher. In embodiments, the halftime for polymerase extension of a primer including a 3 '-terminal nucleotide with a retardant moiety is about or at least about 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, or more minutes under conditions of a sequencing reaction. In embodiments, the halftime for polymerase extension of a 3' terminal nucleotide with a retardant moiety is at least about 5 minutes. In embodiments, the halftime for polymerase extension of a 3' terminal nucleotide with a retardant moiety is at least about 10 minutes. In embodiments, the retardant moiety slows the incorporation of the next nucleotide by a factor of about 2 to a factor of about 20. In
embodiments, the retardant moiety is detectable and does not interfere with sequencing
detection (e.g., distinguishable from the detectable labels used to identify the nucleotides
used in a sequencing reaction; e.g., less than 530 nm). In embodiments, the maximum
emission of the retardant moiety does not significantly overlap with the maximum emission of the detectable labels used to identify the nucleotides used in a sequencing reaction. (Emphasis added)
Attention is also directed to paragraph [0021] of the disclosure. As set forth therein:
It is to be understood that this disclosure is not limited to the particular methodology, protocols, and reagents described, as these may vary, depending upon the context in which they are used by those of skill in the art. (Emphasis added)
Attention is also directed to paragraph [0068] of the disclosure. As asserted to therein:
[0068] Examples of detectable agents include imaging agents, including fluorescent and luminescent substances, molecules, or compositions, including, but not limited to, a variety of organic or inorganic small molecules commonly referred to as "dyes," "labels," or "indicators." (Emphasis added)
As evidenced above, the definitions repeatedly relies upon the term “about” as well as adjectives “more” and “less” and adverb “significantly”. It is also noted that the definitions also include assertions that the examples are not limiting, which leaves in question just what are the various limits of the claimed method.
A review of the disclosure does find a definition for the term “about”; however, the definition does not clearly set limits for how it is to be interpreted. In support of this position the referenced definition is provided below.
[0023] As used herein, the term "about" means a range of values including the specified
value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, the term "about" means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about means the specified value. (Emphasis added)
It stands to reason that different individuals of ordinary skill in the art would arrive at differing values that each may “consider reasonably similar”. While applicant has indicated that “about means a range”, and that it could also “mean[] the specified value”, it is less than clear as to just what applicant considers the limit of any range. It is also unclear as to when specified value can vary and when it cannot vary- that it “means the specified value”.
Claims 40, 43-45 are indefinite with respect to what constitutes the metes and bounds for the terms “chase solution” and “chase nucleotides”. They are not defined in the specification.
Note that although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. Also see In re Van Geuns, 988 F.2d 1181,26 USPQ2d 1057 (Fed. Cir. 1993). Also see, In re Zetz, 13 USPQ2d 1320,1322. “An essential purpose of patent examination is to fashion claims that are precise, clear, correct and unambiguous.”
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) 40-46, 49-50, 54 is/are rejected under 35 U.S.C. 103 as being unpatentable over Dambacher et al. US 20180208983 in view of Dower et al. US 5,547,839 in view of Duer et al. US 20090312188 A1.
Dambacher et al. discloses method technique carried out using single-scan detection, where each of a plurality of distinguishably labeled nucleotides is detected in one step. For example, dynamic equilibrium binding of four distinguishable nucleotides (e.g., at least some harboring exogenous labels) can be detected in a single step following co-delivery of: (1) incorporable reversible terminator nucleotides; and (2) labeled nucleotides that are not incorporated. The disclosed approach can eliminate the need for separate steps to incorporate reversible terminators and then detect labeled nucleotide interaction using a blocked primed template nucleic acid molecule. In some embodiments, the enzymatic joining of the reversible terminator nucleotide and detection of the noncovalent association or binding of a detectably labeled nucleotide both take place in the same reaction mixture [0097].
Dambacher et al. discloses in certain embodiments, nucleotide-containing reagent delivered to a population or ensemble of primed template nucleic acids includes: (a) a polymerase; (b) four types of reversible terminator nucleotides; (c) four types of distinguishably labeled nucleotides; and (d) a catalytic metal ion. The components can be delivered as a single reagent or, alternatively, one or more components can be added sequentially to form the reagent in the presence of the primed template nucleic acid. The reversible terminator nucleotides can be unlabeled. In other embodiments, the reversible terminator nucleotides include a detectable label, such as a fluorescent label or a Raman label. The distinguishably labeled nucleotides used in the procedure optionally are nucleotide analogs that cannot be acted upon by a polymerase to covalently link to the primed template nucleic acid molecule via a phosphodiester bond (i.e., so-called “non-incorporable” nucleotides) [0099].
Dambacher et al. discloses positioning a label moiety and a reversible terminator moiety on separate nucleotides that are cognate for the same template base, where only the nucleotide carrying the reversible terminator moiety is incorporated into the primed template nucleic acid molecule, and where the detectable label identifies the cognate nucleotide, simplifies chemical reagent processing while allowing multiple different ternary complexes to be evaluated in parallel. For example, a single reaction mixture that includes reversible terminator nucleotides (e.g., unlabeled reversible terminator nucleotides); detectably labeled nucleotides that are not incorporated (e.g., labeled non-incorporable nucleotides); one or more polymerases; and a catalytic metal ion can be used to incorporate the reversible terminators and permit dynamic formation of ternary complexes that include the labeled nucleotide. As well, detecting ternary complexes containing the labeled cognate nucleotide in the same reaction mixture that incorporated reversible terminator nucleotides streamlines workflow not only by eliminating separate enzymatic steps, but also by eliminating the requirement for an intervening wash step. Moreover, specificity of ternary complex formation permits multiple different complexes to be in fluid communication with each other in a reaction vessel, such as a microarray or flow cell, while being analyzed in a detection method such as a fluorescence detection method (e.g., fluorometry) [0100].
Dambacher et al. discloses a Sequencing By Binding technique that, in a single processing step (i.e., a so-called “blocking-and-examination” step), advances a primed template nucleic acid molecule forward by adding a single reversible terminator nucleotide to the 3′-end of a primer, and detects label attached to the cognate nucleotide downstream of that extended and blocked primer. This is accomplished by combining a catalytic metal ion, at least one polymerase, at least one incorporable reversible terminator nucleotide (e.g., unlabeled reversible terminator nucleotides) and at least one detectably labeled nucleotide (e.g., labeled non-incorporable nucleotides) to form ternary complexes that can be detected by virtue of the label attached to the nucleotide. The reversible terminator nucleotides are either incorporated into the primed template nucleic acid molecule in preference to the labeled nucleotides (e.g., when reversible terminator nucleotides are pre-loaded into ternary complexes in the absence of labeled nucleotides), or incorporated exclusively because the labeled nucleotides are structured to prevent incorporation (i.e., they are non-incorporable). Detection of label associated with different nucleic acid features, under dynamic equilibrium conditions, is used for identifying cognate nucleotides [0106].
Dambacher et al. discloses “As used herein, a “kit” is a packaged unit containing one or more components that can be used for performing detection and/or sequencing reactions. Typical kits may include packaged combinations, in one or more containers or vials, of reagents to be used in the procedure” [0092].
Dower et al. teach composition/reaction mixture (see claim 1) comprising
i) a first plurality which is a first set of nucleotide analogues wherein each nucleotide analogue is labeled with a unique label and contains a removable chemical moiety capping the 3'-OH group (see column 25 lines 4-8, lines 25-34, and lines 41-64) which is reversible/cleavable chain/linker by chemical reagents (see column 25 lines 15-18); and
ii) a second plurality which is a second set of nucleotide analogues wherein each nucleotide analogue is unlabeled and contains a removable chemical moiety capping the 3'-OH group such as acetyl, tBOC, NBOC and NVOC (see column 25 lines 25-34 and lines 41-64).
Dower et al. teach that different 3’OH groups can be placed on the nucleotide analogues (see column 25 lines 35-37) and thus teach embodiments where the first set and second set of nucleotides are different as each set has different 3’OH groups and where the second set has 3'-OH groups such as acetyl, tBOC, NBOC and NVOC (see column 25 lines 25-34 and lines 41-64).
Dower et al. teach where the second set of unlabeled nucleotides are in high concentrations in solution relative to the first set of labeled nucleotides (see column 25 lines 60-64).
Dower et al. teach the first set is four different nucleotide analogue terminator (see column 25 lines 4-8) and the second set is also the terminators of four nucleotide analogues but without the fluorophore (see column 25 lines 41-64).
The structures of the fluorescently labeled and reversible terminator base analogs are selected to be compatible with efficient incorporation into the growing chains by the particular DNA polymerase(s) chosen to catalyze extension. For example, where two different chain terminators are used, they may be utilized by two different polymerases that are both present during the chain extension step. (column 26 lines 6-12).
Dower et al. teach that the concentrations of nucleotide analogues can be varied for control of the reaction: “The proportion of chains labeled in each round can be controlled by the concentration ratio of fluorescent to non-fluorescent terminators, and the reaction can be driven to completion with high concentrations of the unlabeled terminators” (see column 25 lines 60-64) and teaches concentrations of 10 M and 100 M (see column 27 line 67).
Dower et al. teach the fluorescent label also may provide the added advantage of fluorescing at different wavelengths for the different monomers, providing a convenient means to distinguish between different monomers. Other forms of label may be desired for various reasons, for example, magnetic labels, radioactive labels, heavy metal atoms, optically detectable labels, spectroscopically detectable labels, fluorescent labels, and magnetic labels (col.20-21, bridging paragraph).
Duer et al. discloses using a fluorescent dye attached to a dNTP (via the base) as both a tag and a stearic blocking group to stall the polymerase during a sequencing reaction. Duer et al. further teaches the fluorescent dye itself can be attached to the nucleotide base via a photocleavable linkage or alternatively, a dendrimer containing multiple fluorescent dyes attached to the nucleotide base via a photocleavable linkage can be used. In another embodiment a bead containing multiple fluorophores attached to the nucleotide base via a photocleavable linkage can be used. In a further embodiment a quantum dot can be attached to the nucleotide base via a photocleavable linkage. [0169]-[0170].
Duer et al. discloses the photo-cleaving light source can emit light having a wavelength ranging between 400 nm and 2000 nm. The photo-cleaving light source input can be coupled to an ultra-violet light source. In one embodiment he ultra-violet light source emits light having a wavelength ranging between 100 nm and 400 nm [0012].
Dambacher et al., Dower et al., Duer et al., and the instant application are all drawn to the same field of endeavor. Thus, the choice of specific groups/moieties and combination of these groups/moieties, for the nucleotide analogs comprising a plurality of detectable moieties comprising terminator moieties and/or retarding moieties, is merely one of several obvious options from which a person skilled in the art seeking to solve the stated problem would choose, according to the circumstances, without exercising inventive skill, for use in sequencing technologies (see Dambacher et al. [0008]). Additionally, Dambacher et al. teaches “the disclosed technique achieves rapid processing, in part, because extension of the primer and detection of dynamic nucleotide binding that indicates cognate nucleotide identity occur in the same reaction mixture, without intervening washes or reagent exchanges between those steps. As well, the ability to incorporate four types of reversible terminator nucleotides, and to process four distinguishable nucleotides during the examination step (i.e., without incorporation) makes it possible to employ single-scan imaging techniques. Still further, there can be enhancement of reaction efficiency or yield since it is only necessary to chemically cleave one covalent bond during each cycle of nucleotide binding and identification. This is because detectable label associates with the primed template nucleic acid molecule in a ternary complex noncovalently. In some embodiments, the non-incorporated nucleotide of the ternary complex that includes the blocked primer can be removed by a simple wash step that also cleaves the reversible terminator moiety from the blocked primed template nucleic acid molecule” [0103]; Duer et al. teaches “There remains a pressing need for improved systems for Next Generation Sequencing. An ideal system would provide increased sensitivity, eliminate or reduce washing steps and simplify integration with microfluidic technologies. The present invention satisfies this need and provides related advantages “[0005]; see also Dower et al. (col 2, lines 57-63). Therefore, one of ordinary skill in the art would have been motivated to modify the primary references in the manner of the claims to achieve the expected benefits, optimizations and/or expanded applications as this is well known practice in the art. MPEP states wherein the “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Alter, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Routine optimization is not considered inventive and no evidence has been presented that the selection of the nucleotide analogues was other than routine, that the products resulting from the optimization have any unexpected properties, or that the results should be considered unexpected in any way as compared to the closest prior art. Thus, an ordinary practitioner would have recognized that the choice of specific groups/moieties and combination of these groups/moieties for the type of nucleotide analogues used in the method of sequencing, could be adjusted to maximize the desired results.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEZIA RILEY whose telephone number is (571)272-0786. The examiner can normally be reached 7:30-6:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at 571-272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JEZIA RILEY/Primary Examiner, Art Unit 1681 27 September 2026
