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 .
DETAILED ACTION
Status of the Claims
Claims 1, 7-11, 13-15, 21, 24, 26, 30, 36-37 and 43-47 are pending and the subject of this FINAL Office Action.
Claim 36 is clear of the prior art. The specific detectable moieties of claim 36 are not taught in the prior art.
Claim Rejections - 35 USC § 112- Indefiniteness – Maintained-in-Part
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.
Claims 1, 7-11, 13-15, 21, 24, 26, 30, 36-37 and 43-47 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 pre-AIA the applicant regards as the invention.
The independent claims require “conventional dye,” which is a vague and subjective phrase. The specification fails to clearly define “conventional.” Nor would a skilled artisan understand the metes and bounds of “conventional dyes.” Thus, the phrase is indefinite.
Claim 10 recites “anti-species” antibodies. This term is unknown in the art, nor defined in the specification. It is unclear what these are.
Response to Arguments
As to “conventional dyes,” Applicants completely fail to provide a clear, bounded meaning. Instead, they resort to more vaguery: “the Specification uses the phrase ‘conventional dyes’ (also referred to as ‘conventional stains’1) in the context of known staining workflows, describing conventional dyes as those used in ‘routine stains’ and ‘special stains.’” Applicants fail to explain what is meant by “routine” and “special.” There are simply no clear bounds to these vague terms. Vagueness piled on vagueness does not provide clear metes and bounds. On the contrary, it only provides more confusion. Then, Applicants contradict their previous statement: “At least these passages of the Specification inform the skilled artisan that a ‘conventional dye’ refers to dyes commonly used to stain biological specimens for visualization (e.g., brightfield microscopy), as opposed to special-purpose biomarker labels or nonstandard detection chemistries.” A dye is a label. So, how is a “special-purpose” dye different from a “special” dye?
Moreover, examples do not define; they are merely that, examples. And they cannot be imported into the claims without express language doing so. Thus, even if the specification lists “non-limiting examples of such dyes (e.g., hematoxylin, eosin, and other common stains),” yet this limited group fails to provide clear metes and bounds to “conventional dyes.” What other dyes are encompassed, and where that line ends is impossible to determine because “conventional dyes” is not a well-defined term.
Applicants also argue that the spectral properties in the claims provide clear metes and bounds to “conventional dyes.” This is false. The claims require one to use, from a base of “conventional dyes,” a dye which meets the spectral characteristics. In other words, the “conventional dyes” provides the group from which the dye is selected. The spectral characteristics do not define “conventional dyes.” One could use a dye that is not “conventional” and meets the spectral qualities.
As to “anti-species antibody,” Applicants argue that this is an antibody that binds the primary antibody. However, similar to the “conventional dyes” issue, the “anti-species antibody” is the group from which the secondary antibody is selected. The issue is what is an “anti-species” antibody? Which species of what thing? This is never discussed, much less explained.
Claim Rejections - 35 USC § 102 - Maintained
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 –
(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.
Claims 1, 11, 14, 21, 26, 37 and 46 are rejected under 35 U.S.C. § 102(a)(2) as being anticipated by YANG (US20170314056).
As to claims 1, 11, 14, 21, 26, 37 and 46, YANG teaches a method of visualizing one or more targets within a biological specimen disposed on a substrate, comprising: (a) labeling a first biomarker with a first detectable moiety, wherein the first detectable moiety has a FWHM of less than about 200nm and an absorbance maximum (Amax) of either less than about 430nm or greater than about 670nm (ir-783/mhi-148 heptamethine cyanine dyes; Fig. 38, para. 0075); and (b) staining the biological specimen disposed on the substrate with at least one conventional dye having one or more peak absorbance wavelengths between about 400nm and about 700nm, wherein the peak absorbance wavelength of the first detectable moiety and the one or more peak absorbance wavelengths of the one or more conventional dyes are separated by at least 20nm (DAPI; id.)
Claims 1, 7-8 11, 13-15, 21, 24, 37, 43 and 47 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by CHOU (US20180246089).
As to claims 1, 7, 11, 13-15, 21, 24, 37, 43 and 47, CHOU teaches a method of visualizing one or more targets within a biological specimen disposed on a substrate, comprising: (a) labeling a first biomarker with a first detectable moiety, wherein the first detectable moiety has a FWHM of less than about 200nm and an absorbance maximum (Amax) of either less than about 430nm or greater than about 670nm (coumarin derivative dyes on primary or secondary antibodies, or nucleic acid probes; paras. 0004, 0202 & 1013-1014, claim 61); and (b) staining the biological specimen disposed on the substrate with at least one conventional dye having one or more peak absorbance wavelengths between about 400nm and about 700nm, wherein the peak absorbance wavelength of the first detectable moiety and the one or more peak absorbance wavelengths of the one or more conventional dyes are separated by at least 20nm (“After immunohistochemical staining of the antigen, the tissue sample may be stained with another dye, e.g., hematoxylin, Hoechst stain and DAPI, to provide contrast and/or identify other features”; para. 0203).
As to claims 8 and 44, another dye option is Fluorescein Isothiocyanate, or FITC (para. 1014).
Claims 1, 7-8 11, 13-15, 21, 24, 37, 43 and 47 are rejected under 35 U.S.C. § 102(a)(1) as being anticipated by TSENG (US 20100291584).
As to claims 1, 7, 11, 13-15, 21, 24, 37, 43 and 47, TSENG teaches a method of visualizing one or more targets within a biological specimen disposed on a substrate, comprising: (a) labeling a first biomarker with a first detectable moiety, wherein the first detectable moiety has a FWHM of less than about 200nm and an absorbance maximum (Amax) of either less than about 430nm or greater than about 670nm (cell mixture in the microchip was treated with an antibody cocktail containing Cy7-labeled anti-EFGR, Cy5-labeled anti-pAKT, TRITC-labeled anti-PTEN, and FITC-labeled-pS6, yielding a multi-color stain (DAPI[460], anti-EGFR (Cy7) [760], anti-PTEN (TRITC)[550nm], anti-pAKT (Cy5) [650nm] and anti-pS6 (FITC)[495nm]); para. 0312); and (b) staining the biological specimen disposed on the substrate with at least one conventional dye having one or more peak absorbance wavelengths between about 400nm and about 700nm, wherein the peak absorbance wavelength of the first detectable moiety and the one or more peak absorbance wavelengths of the one or more conventional dyes are separated by at least 20nm (id.)
Response to Arguments
As to YANG, DAPI has a peak absorption around 358nm, which is within “about” 400nm on the lower end of Applicants’ range. “About” is never defined and can encompass 15% difference from a stated number (400nm*0.85= 340nm). By any measure, DAPI is “conventional” in the art of biological stains. Furthermore, Applicants’ argument that it is not “conventional” only proves the inherent ambiguity in the term, contrary to Applicants’ bare assertions above. As to ir-783/mhi-148, these are heptamethine cyanine dyes, which Applicants’ own specification and claims explains meets the claim limitations (spec., paras. 0040-41, 0200-0210; claims 14 & 21). Furthermore, as is well-known, the 783 indicates the peak absorbance. Thus, Applicants’ arguments ignore their own specification and claims.
As to CHOU, once again, Applicants’ own specification and claims explain that coumarin dyes plus hematoxylin or Hoechst stain meet the claim limitations (Spec., paras. 0010-13, 0015, 0019-20, 0030, 0033, 0035, 0040-41, 0044, 0049, 0062-70, 0183-93; claims 6, 21 & 43). Applicants even argue above that “conventional dyes” examples include hematoxylin or Hoechst stain. Applicants cannot argue against their own specification, and themselves, unless they believe the specification is not enabled.
Finally, as to TSENG, yet again, these are dyes that Applicants disclose meet the claim limitations (Spec., paras. 0064-78, 0085, 0123, 0288).
Claim Rejections - 35 USC § 103 - Maintained
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.
Claim(s) 8 and 44 is/are rejected under 35 U.S.C. 103 as being unpatentable over YANG, CHOU or TSENG, in view of Wikipedia, Staining, available at https://web.archive.org/web/20201105231918/https://en.wikipedia.org/wiki/Staining, 11/05/2020.
The prior art as a whole demonstrates that it would have been obvious to a skilled artisan at the time of filing to substitute familiar cell stains based on the specific application with a reasonable expectation of success.
As explained above, YANG, CHOU and TSENG teach cell stains such as DAPI and H&E. They do not explicitly teach any of the dyes in claims 8 and 44.
However, these were known cell stains chosen based on their particular application. For example, Wikipedia teaches Sudan Black for lipids, Congo red for amyloid, and numerous others correlated to their specific use (see below; “Common biological stains”). A skilled artisan would have been motivated to substitute cell stain dyes in YANG, CHOU and TSENG based on the specific application as explained in Wikipedia.
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In sum, it was obvious to substitute the familiar cell stain dyes of Wikipedia for other cell stain dyes to achieve particular stained cell components with a reasonable expectation of success.
Claim(s) 9-10 is/are rejected under 35 U.S.C. 103 as being unpatentable over YANG, CHOU or TSENG, in view of BIENIARZ (US 20170254813).
The prior art as a whole demonstrates that it would have been obvious to a skilled artisan at the time of filing to substitute familiar antibody labeling scheme of claims 9-10 based on the specific application with a reasonable expectation of success.
As explained above, YANG, CHOU and TSENG teach antibody labeling. They do not explicitly teach the click chemistry and tyramide or quinone methide chemistry in claims 9-10.
However, these were known antibody chemistries chosen based on their particular application. For example, BIENIARZ teaches fluorescent-labeled antibodies with “Tyramide Signal Amplification: An enzyme-mediated detection method that utilizes the catalytic activity of a peroxidase (such as horseradish peroxidase) to generate high-density labeling of a target molecule (such as a protein or nucleic acid sequence) in situ” (para. 0144).
TSA typically involves three basic steps: (1) binding of a specific binding member (e.g., an antibody) to the target followed by secondary detection of the specific binding member with a second peroxidase-labeled specific binding member; (2) activation of multiple copies of a labeled tyramide derivative (e.g., a hapten-labeled tyramide) by the peroxidase; and (3) covalent coupling of the resulting highly reactive tyramide radicals to residues (e.g., the phenol moiety of protein tyrosine residues) proximal to the peroxidase-target interaction site, resulting in deposition of haptens proximally (diffusion and reactivity mediated) to the target. In some examples of TSA, more or fewer steps are involved; for example, the TSA method can be repeated sequentially to increase signal. Methods of performing TSA and commercial kits and reagents for performing TSA are available (see, e.g., VENTANA Amplification Kit, Cat. No. 760-080, AmpMap Detection Kit with TSA™, Cat. No. 760-121, Ventana Medical Systems, Tucson, Ariz.; Invitrogen; kit No. T-20911, Invitrogen Corp, Carlsbad, Calif.). In some embodiments, TSA is a component of the provided PTDM. Other enzyme-catalyzed, hapten or signaling linked reactive species can be alternatively used as they may become available. Suitable conditions for TSA as well as reagents and kits for use for tyramide signal amplification are known to a person of ordinary skill in the art (see, e.g., Bobrow et al., J. Immuno. Meth., 125:279-285, 1989)
(id.) BIENIARZ further teaches to use click chemistry (paras. 0170ff, Example 4). A skilled artisan would have been motivated to apply this known antibody labeling scheme to achieve greater signal amplification.
In sum, it was obvious to substitute the familiar antibody labeling scheme of BIENIARZ for other antibody labeling to achieve greater signal amplification with a reasonable expectation of success.
Response to Arguments
The rejections are maintained because Applicants completely miss the point: Wikipedia demonstrates that other stains are routinely used with success based on the specific application. A skilled artisan is not an automaton, rather a PhD-trained cytologist, for example, with extensive training with various stains and dyes capable of choosing specific stains and dyes based on the application. The prior art was cited to demonstrate this fundamental fact. The guidance provided from the prior art yields the claimed dye/stain combination; and skilled artisan would merely plug and play with whatever dye or stain was best suited for the particular application because the claimed dyes and stains are so familiar in the art. The rejection is maintained.
As to click chemistry, Applicants bizarrely argue that BIENARZ disclosure does “not automatically render it obvious to retrofit click chemistry into any antibody labeling system.” The Examiner never argued for “retrofitting.” Rather, the Examiner made clear that click chemistry for antibodies was routine in the art, and regularly applied with ease based on the application to achieve greater signal. Applicants have completely mischaracterized the rejection in order to create a straw man. The rejection is maintained.
Prior Art
The following prior art also teaches combination of dyes that meet the claims: US 20180273758 (para. 0033); US 20190204330; US 20180155275; IPRP in PCT/EP2021/073738.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. 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 Aaron Priest whose telephone number is (571)270-1095. The examiner can normally be reached 8am-6pm.
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/AARON A PRIEST/Primary Examiner, Art Unit 1681
1 Not all stains are dyes. A stain is any substance that changes the appearance of a material by adding color, while a dye is a specific type of stain that is soluble in a solvent and can be applied to a wide range of materials.
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