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
Claims 18-26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected group II, a method of staining a biological material, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 4/10/2026.
Applicant's election with traverse of group I, a staining composition, in the reply filed on 4/10/2026 is acknowledged. The traversal is on the ground(s) that there is no serious search burden justifying restriction. This is not found persuasive because the claimed composition and the claimed method require materially different searches directed towards different subject matter.
The composition claims require searching for specialized chemical formulations, discrete reagents categorized down to specific chemical homologs, critical solution properties, and their precise concentration bounds. The method claims require searches directed towards procedural limitations and processing steps that are distinct from the composition claims. For instance, the methods recite fixation procedures, incubations, embedding materials, gradient dehydration procedures, hydrogels, and slide/sample preparations. These search considerations are distinct/differ significantly from the those required for examination of the composition claims and therefore require different search strategies (eg; searching different classifications, keywords, and their combinations). Thus, examination of the methods and composition together would impose a serious search burden.
The requirement is still deemed proper and is therefore made FINAL.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-17 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1,4-8,10,12,14-18,20-21 of copending Application No. 17623250 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because they both claim a composition for clearing and staining a biological material wherein all the claimed components between the instant and reference application overlap (eg; octylphenol ethoxylates = Tritons and polysorbates = Tween), except for the use of a bromine derivative of fluorescein (specifically eosin Y or B) in the instant application. However, addition of eosin stains to the composition is an obvious variation as reasoned below (see Simonson P et al 2021). In addition, specific limitations with regards to component concentrations are obvious variations of one another due to their optimizable nature, as rationalized below.
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 4-5,11,15 contain the trademark/trade names Triton X-102, Triton X-165, Triton X-305, Triton X-405 (claim 4). Tween 20, Tween 40, Tween 60, Tween 80 (claim 5). Triton X-100 (claim 11). Additionally, SYTO 16, SYTO 40, NucRed or NucGreen (claim 15). Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade names are used to identify/describe homogeneity excipients (Triton X-102, Triton X-165, Triton X-305, Triton X-405, Tween 20, Tween 40, Tween 60, Tween 80 (claims 4-5)), surfactants (Triton X-100 (claim 11)), and labeling materials (SYTO 16, SYTO 40, NucRed or NucGreen (claim 15)), and, accordingly, the identification/description is indefinite.
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 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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 1-17 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021023289 A1, and further in view of Simonson P et al 2021 and both the Triton X-405/X-100 SDS (pre-2022) and as evidenced by Xu N et al 2017.
WO 2021023289 A1 discloses a composition for optical clearing and staining of a biological specimen (thickness of 100-1000um), comprising an amide dye adjuvant (urea), a refractive index matching material comprising a contrast agent and a sugar (wherein the sugar can be any combination of mono-oligosaccharides), a permeating agent comprising a surfactant (Triton-X-100 and/or SDS), a first and second labeling material, wherein DAPI, Propidium Iodide, SYTO 16, SYTO 40, NucRed, or NucGreen is one of the labels, a solvent comprising DMSO (and glycerol and/or PBS as well), a homogeneity excipient of Tween-20 and/or Tween-80, and wherein the pH of the composition is acidic or neutral (pH is 6.5-8.4). They also disclose the use of an anti-freezer and/or humectant with the composition. Specifically, “The present disclosure reveals a clearing composition…includes a Refractive Index (RI) matching material, a permeating agent including a surfactant, a first labeling material, a second labeling material, and a solvent…pH value of the biological material transparent is about 6.5 to 8.4… RI matching material includes a radiocontrast agent, monosaccharide, oligosaccharide… surfactant includes Triton X-100, Tween-20, Tween-80, Sodium dodecyl sulfate (SDS), n-Dodecyl-P-D-maltoside (DDM), Urea… solvent includes phosphate buffered saline (PBS), dimethyl sulfoxide (DMSO), glycerol, ddH2O or any combination… labeling dye includes DAPI, Propidium Iodide, SYTO 16, SYTO 40, NucRed or NucGreen… includes an anti-freezer, a humectant…” (paragraphs 009-0022).
WO 2021023289 A1 does not disclose use of a bromine derivative of fluorescein (eosin Y or eosin B), the use of Triton X-102, Triton X-165, Triton X-305, or Triton X-405, a homogeneity excipient with a hydrophilic-lipophilic balance (HLB) of 14-18, or the specific concentrations of materials found in claims 1,6, and 12-13.
Simonson P et al 2021 discloses a staining composition containing both eosin Y and DAPI. Specifically, “An 8.2% eosin Y working solution was prepared… solution with 0.5 µl of DAPI solution (Akoya Nuclear Reagent; Akoya cat. no. 7000003) and 0.5 µl of eosin working solution added.” (paragraph “Eosin and 4′,6-diamidino-2-phenylindole staining protocol” in the methods section).
According to the Triton X-405 SDS (pre-2022), Triton X-405 is a polyethylene glycol mono-(4-tert-octylphenyl) ether defined by CAS registry number 9002-93-1. It is a non-ionic surfactant supplied as a laboratory chemical in aqueous solution. Therefore, it is a member of the nonionic ethoxylated surfactant class capable of reducing surface tension and stabilizing hydrophobic compounds in aqueous solution. Comparison of the Triton X-100 SDS (pre-2022) and X-405 SDS (pre-2022) also indicates that the Triton X series (including X-100 and X-405) is a graded ethoxylated surfactant family wherein members differ primarily in their degree of ethoxylation and hydrophilic-lipophilic balance (HLB). Thus, Triton X-100 and X-405 are interchangeable nonionic surfactants based on their HLB profiles, wherein increasing ethoxylation increases aqueous compatibility and dispersion stability.
Therefore, it would be obvious to a person of ordinary skill in the art, before the effective filing date, to use both eosin Y and nucleic acid fluorescent dyes (DAPI, PI, SYTO, ect) together as disclosed in Simonson P et al 2021, in the single clearing and staining composition of WO 2021023289 A1. The combination allows the simultaneous and differential staining of both the nucleus (DNA/RNA), and the cytoplasm/extracellular matrix (proteins including collagen). This provides spatial and morphological context, especially when evaluating targeted protein biomarkers. Importantly, the addition of eosin Y (a hydrophilic, anionic fluorescent xanthene dye) shifts the HLB towards the polar end. Therefore, a homogeneity excipient with a higher HLB value is required to maintain emulsion and formulation stability. Therefore, it would be obvious to a person of ordinary skill in the art, before the effective filing date, to substitute Triton X-405 (HLB value of 17.6) for other Triton surfactants (particularly X-100, HLB value of 13.5) in aqueous staining solutions to achieve routine improvements in wetting, solubilization, and dispersion of staining reagents. Importantly, a person of ordinary skill in the art would reasonably expect that replacing Triton X-100 with a higher HLB homolog (eg X-405) would increase aqueous solubility, improve dispersion of hydrophilic staining solutions, and reduce hydrophobic partitioning.
The specific concentration limitations of claim 1 (amide dye adjuvant is from 10-30% w/v), claim 6 (homogeneity excipient is about 0.5 to 5% v/v), claim 12 (surfactant is about 1-5% v/v) and claim 13 (“dye” concentration), all refer to standard and routine optimization parameters in clearing/staining composition construction as supported by Xu N et al 2017 for surfactant concentrations, and by Kim K et al 2022 for amide dye adjuvant and homogeneity excipient concentrations, and by extension, dye concentrations. Support for dye concentrations is founded in the fact that they affect the same outcomes used to assess optimization of the paper’s aforementioned parameters ([adjuvant] and [excipient]).
Additionally, it would also be obvious to a person of ordinary skill in the art, before the effective filing date, to assemble all of the disclosed reagents/compositions and teachings provided above, together. The assembly of known reagents/components disclosed in the prior art into a “kit” and supplementing them with the written instructions and teaching of the prior art does not impart additional meaningful structural limitations to the claims in this scenario.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Adam M Smith whose telephone number is (571)272-7517. The examiner can normally be reached Monday- Friday 10:30AM-5PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at (571) 272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Tracy Vivlemore/ Supervisory Primary Examiner, Art Unit 1638
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