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 .
Acknowledgement of Receipt
Applicant’s Response, filed 3/5/2026, in reply to the Office Action mailed 11/6/2026, is acknowledged and has been entered. Claims 1-3 and 7-9 have been amended. Claims 12 and 13 are newly added. Claims 1-13 are pending and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn as being overcome by claim amendment. The Examiner’s response to Applicant’s arguments is incorporated below. New grounds for rejection are set forth herein, necessitated by claim amendment.
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.
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.
Claim(s) 1-11 are rejected under 35 U.S.C. 103 as being unpatentable over Sato et al. (J. Am. Chem. Soc., 2017, 139, p. 17397-17404 and Supporting Information) in view of Kemnitzer et al. (US 2019/0100653), for reasons set forth in the previous Office Action.
Response to arguments
Applicant argues that Sato teaches intracellular protein-labeling probes derived from silicon rhodamine-methyl (SiR-Me, Compound 7) and fluorescence always-on rhodamine fluorophore) and SiR-carboxyl (Compound 20, zwitterionic and environmentally sensitive rhodamine fluorophore), which are conjugated to ß- lactam ligands for intracellular BL-tag labeling. Applicant asserts that Sato explicitly reports that SiR-Me derived probes show strong subcellular off-target localization and limited organelle adsorption, and this behavior is attributed to the cationic nature of SiR-Me. Applicant asserts that Sato's work focuses on investigating probe performance, rather than providing a new fluorophore scaffold that is water-soluble, cell- membrane-permeable fluorescence always-on, and environmentally inert. Applicant asserts that Kemnitzer teaches polysulfonated fluorescent dye design as a strategy to improve water solubility for bioconjugation by incorporating multiple sulfonate groups on the fluorophores. The design provides fluorophores that are not only highly water soluble but also highly anionic, which eliminates their cell membrane permeability, making them unsuitable for live-cell intracellular imaging. Kemnitzer does not teach or suggest a charge-balanced, net-neutral, and fluorescence always-on derivative that preserves cell-membrane permeability for intracellular live-cell imaging.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that each of Sato and Kemnitzer are directed to
decreasing hydrophobicity/increasing hydrophilicity of (silicon) rhodamine-based dyes, including for use in live-cell imaging. With regard to the assertion that Kemnizter’s fluorphores are unsuitable for live-cell intracellular imaging, see paragraph 0112-3 of Kemnitzer: The fluorogenicity of compounds gains importance for modern imaging procedures such as fluorescence imaging of living cells or as molecular switches in microscopic and nanoscopic procedures, e.g. STED, PALM, (d)STORM etc. There are even novel silico-rhodamines developed for this purpose… The mentioned subgroup of the novel and inventive dyes provided herein may therefore in principle also be used in such procedures, and should allow significant advances (paragraph 0112-3). Accordingly it is respectfully submitted that Kemnitzer envisages the use of the compounds in live cell imaging.
Applicant further argues that the teachings of Kemnitzer do not support the Office's position that one would be motivated to provide a single sulfonate substituent (SO₃H group) at position B. Of the more than thirty compounds disclosed in Tables 2 and 3 of Kemnitzer that are closest in structure to Applicant's claimed compounds, none have a single SO₃H group. Applicant cites Table 1 and Figure 3 and notes that the compounds of Kemnitzer with the best fluorescence quantum yield are Compounds 6, 12, and 25, each of which has six SO₃H groups. Accordingly, Kemnitzer teaches away from adding a single SO₃H group at position B.
Applicant’s arguments have been fully considered but are not found to be persuasive. With regard to the argument that Kemnitzer teaches away from adding a single SO3H group at position B, see MPEP 2145. A prior art reference that “teaches away” from the claimed invention is a significant factor to be considered in determining obviousness. However, “the nature of the teaching is highly relevant and must be weighed in substance. A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use.” In reGurley, 27 F.3d 551, 553, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (Claims were directed to an epoxy resin based printed circuit material. A prior art reference disclosed a polyester-imide resin based printed circuit material, and taught that although epoxy resin based materials have acceptable stability and some degree of flexibility, they are inferior to polyester-imide resin based materials. The court held the claims would have been obvious over the prior art because the reference taught epoxy resin based material was useful for the inventor’s purpose, applicant did not distinguish the claimed epoxy from the prior art epoxy, and applicant asserted no discovery beyond what was known to the art.).
Furthermore, “the prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed….” In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). See also UCB, Inc. v. Actavis Labs, UT, Inc., 65 F.4th 679, 692, 2023 USPQ2d 448 (Fed. Cir. 2023) (“a reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed.”)
In the instant case it is respectfully submitted that the broader teaching of Kemnitzer teaches silico rhodamine derivatives having at least one SO3H substituent is introduced at variable B.
PNG
media_image1.png
292
634
media_image1.png
Greyscale
, see paragraph 0023+, wherein B means either an aliphatic hydrocarbon group having 1-6 C atoms, preferably 1-2 C atoms, and which carries at least one SO3H substituent (paragraph 0040). See also claim 1, in which variables R⁸ and R⁹ of compounds of Formula I-IV has the structure B, wherein B means either an aliphatic hydrocarbon group having 1-6 C atoms, preferably 1-2 C atoms., and which carries at least one SO3H substituent. Accordingly, it is submitted that the reference does not rise to the level of teaching away from one sulfonic acid moiety.
See also MPEP 2123. Patents are relevant as prior art for all they contain.
“The use of patents as references is not limited to what the patentees describe as their own inventions or to the problems with which they are concerned. They are part of the literature of the art, relevant for all they contain.” In re Heck, 699 F.2d 1331, 1332-33, 216 USPQ 1038, 1039 (Fed. Cir. 1983) (quoting In re Lemelson, 397 F.2d 1006, 1009, 158 USPQ 275, 277 (CCPA 1968)). A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments. Merck & Co. v.Biocraft Labs., Inc. 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir. 1989), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005).
New Grounds for Rejection
Claim Rejections - 35 USC § 102
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 –
(a)(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.
Claim(s) 9, 12 and 13 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Lukinavicius et al. (Nature Chem., 2013, Advance Online Publication, page 1-8).
Lukinavicius discloses that the ideal fluorescent probe for bioimaging is bright, absorbs at long wavelengths and can be implemented flexibly in living cells and in vivo. However, the design of synthetic fluorophores that combine all of these properties has proved to be extremely difficult. Here, we introduce a biocompatible near-infrared silicon–rhodamine probe that can be coupled specifically to proteins using different labelling techniques. Importantly, its high permeability and fluorogenic character permit the imaging of proteins in living cells and tissues, and its brightness and photostability make it ideally suited for live-cell super-resolution microscopy. The excellent spectroscopic properties of the probe combined with its ease of use in live-cell applications make it a powerful new tool for bioimaging (page 1). Sir-Halo is taught in Figure 1:
PNG
media_image2.png
206
220
media_image2.png
Greyscale
, wherein
PNG
media_image3.png
106
260
media_image3.png
Greyscale
Figure1 shows SiR dyes used for SNAP-, CLIP-, Halo-tag and tetrazine labelling.
CLIP-tag and Halo tag are two other popular protein tags utilized for the covalent labelling of proteins in living cells. All three tags can be labelled readily with their corresponding substrates, with rate constants comparable to those reported for other substrates (page 2).
With regard to claims 12 and 13, solutions of the dyes are taught, as well as methods of labeling a biomolecule / cellular imaging (page 7).
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.
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.
Claim(s) 1-5, 7, 10 and 11 are rejected under 35 U.S.C. 103 as being unpatentable over Brabetz et al. (US 8,614,061) in view of Kumar et al. (WO 04/072238).
Brabetz teaches combinations of fluorescent dyes used in molecular biology, particularly in multiplex PCR. In particular, the present invention relates to a combination of dyes for amplification reactions, wherein at least four different dyes are used, wherein the first dye is 5-FAM or 6-FAM or a blend thereof, the second dye is selected from the group consisting of DY-530, HEX, CAL Fluor Orange 560 and ATTO 532, the third dye is selected from the group consisting of ATTO 550, DY-555 and DY-556, the fourth dye is selected from the group consisting of ROX, DY-510XL and ATTO 565, and optionally a fifth dye is selected from the group consisting of DY-632 and DY-520XL (abstract).
In one embodiment, a kit for multiplex PCR comprising (i) at least one first nucleic acid to which a fluorescent dye selected from the group consisting of 5-FAM and 6-FAM or a blend thereof is covalently attached; (ii) at least one second nucleic to which a fluorescent dye selected from the group consisting of DY-530, HEX, CAL Fluor Orange 560 and ATTO 532 is covalently attached; (iii) at least one third nucleic acid to which a fluorescent dye selected from the group consisting of ATTO 550, DY-555 and DY-556 is covalently attached, and (iv) at least one fourth nucleic acid to which a fluorescent dye selected from the group consisting of ROX, DY-510XL, and ATTO 565 is covalently attached (column 8).
PNG
media_image4.png
312
380
media_image4.png
Greyscale
DY 556 NHS Ester is show in Figure 1.
The compound is encompassed by the instant claims such that R1 and R2 are alkyl; X is O, R3 is alkyl; n1 is 1; R6 and R7 are H; R4a is H; R4b is carboxyl.
With regard to variable R5, it is noted that the NHS ester linker between the rhodamine-based structure and biomolecule differs from the instant claims.
Brabetz does not specifically recite the NHS ester linker of the instant claims.
Kumar teaches methods of using terminal-phosphate-labeled nucleotides in the presence of a manganese salt to enhance their substrate properties towards various enzymes. Particularly described are methods of detecting a nucleic acid in a sample, based on the use of terminal-phosphate-labeled nucleotides as substrates for nucleic acid polymerases, in the presence of a manganese salt. Further provided are manganese complexes of terminal-phosphate-labeled nucleotides as well as terminal-
An exemplary embodiment is synthesis of dA4P-diaminoheptyl-TAMRA is shown on pages 58-59.
PNG
media_image5.png
438
924
media_image5.png
Greyscale
From conjugation of dA4P-Diaminoheptyl with TAMRA 5 NHS Ester:
PNG
media_image6.png
242
224
media_image6.png
Greyscale
(pages 58-59).
It would have been obvious to one of ordinary skill in the art a the time of the invention to substitute one known NHS ester linker for another on the rhodamine-based dye structures taught by Brabetz for linking a rhodamine-based dye to a biomolecule when the teaching of Brabetz is taken in view of Kumar. The Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. ___, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper “functional approach” to the determination of obviousness as laid down in Graham. One such rationale includes the simple substitution of one known element for another to obtain predictable results. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. See MPEP 2143. In the instant case, the substituted components and their functions were known in the art at the time of the instant invention. One of ordinary skill in the art could have substituted one known linker for another, and the results of the substitution would have been predictable, that is linkage of a rhodamine-based dye to a biomolecule. Regarding claim 5, methyl equivalent to instantly claimed variable R3 is further taught by Kumar as a suitable substituent for use in a fluorescent rhodamine-based dye structure. With regard to claims 10 and 11, solutions of the dyes are taught, as well as methods of labeling a biomolecule.
Conclusion
No claims are allowed at this time.
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 LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, MICHAEL HARTLEY can be reached at 571-272-0616. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/LHS/
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
Prosecution Insights