DETAILED ACTION
STATUS OF THE APPLICATION
Receipt is acknowledged of Applicant’s Amendments and Remarks, filed 19 September 2025, the matter of Application No. 17/624,882. Said documents have been entered onto the record. The Examiner notes the following:
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 1-3, 5-14, 16, 18-25 and 27-35 are pending.
Claims 1, 8, 21, and 30 have been amended.
Thus, claims 1-3, 5-14, 16, 18-25 and 27-35 represent all claims currently under consideration.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 19 September 2025 has been entered.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
Specification
The disclosure is objected to because of the following informalities:
In paragraph [0079], line 1, “…Aspectms 21-29…” should read “…Aspects 21-29…”
Appropriate correction is required.
Claim Objections
Claim 10 is objected to because of the following informalities:
In line 2, “…(1 faraday)…” should read “…(faraday)…”
Claim 19 is objected to because of the following informalities:
In line 1, “…has…” should read “…having…”
Claim 32 is objected to because of the following informalities:
In line 2, “…(1 faraday)…” should read “…(faraday)…”
Appropriate correction is required.
Claim Interpretation
The term “noble metal” as recited in claims 1, 8, 21, and 30 will be interpreted as a group of metals consisting of platinum, palladium, ruthenium, gold, silver, copper, rhodium, iridium, osmium, and rhenium, as defined in the art (c.f., Medici et al. Coord. Chem. Rev. 2015, 284, 329-350; pages 330, 334, 336, 338, 339, 341, and 343-346).
Claims 19-20 recite the phrase “…contains silver below the detectable limit as measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS)…” For the purposes of examination, the lowest detectable limit threshold will be interpreted as < 1 ppm, in a manner consistent with paragraph [0045] of the instant specification.
Claim 33 recites the phrase “…wherein the voltage is about 0.5 V up to the electrochemical window of the solvent.” wherein the solvent is defined as an aqueous solvent, per the newly amended dependent claim 21. For the purposes of examination, a suitable range for the electrochemical window includes about 1 to about 6 V, specifically about 1.5 to about 4 V, as stated in paragraph [0031] of the instant specification.
Claim 35 recites the term “continuous flow electrolysis cell.” For the purposes of examination, a continuous flow electrolysis cell will be interpreted as including an electrolysis cell in which the electrolyte solution is continuously recycled via pump, as defined in the art (c.f., Kanapathy et al., Sep. Purif. Technol. 2013, 118, 279-284; PTO-892 of 05-29-2025; page 280, Col. 2, paragraph 3). This is but one example of a continuous flow electrolysis, and is not meant to narrow the interpretation of the instant claim. Other suitable continuous electrolysis cell approaches (e.g., single-pass flow electrolysis) will also be considered, as indicated by Applicant on p. 16-17 in the response filed 19 September 2025.
NEW 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 19-20 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 19-20 recite the phrase “free of metal”, yet it is unclear how this term is substantially different from the other options recited, such as “contains 0 ppb metal” and “below the detectable limit as measured by Atomic Absorption spectrometry (flame or electrothermal), Inductively Coupled Plasma (ICP), or ICP Mass Spectrometry (ICP-MS)”, thus rendering the instant claims indefinite. Further clarification is required. The Examiner notes that adequately addressing this ambiguity would ameliorate these claim rejections.
The term “pure as determined by CHN analysis” in claims 19-20 is a relative term which renders the claim indefinite. The term “pure as determined by CHN analysis” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The lack of defining what constitutes pure as determined by CHN analysis renders the instant claims indefinite. Further clarification is required. The Examiner notes that adequately addressing this ambiguity would ameliorate these claim rejections.
NEW Claim Rejections - 35 USC § 102
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.
(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.
Claims 16 and 18, although dependent on claim 1, contain product-by-process limitations for preparing the compound of claim 1. MPEP § 2113(I) states that “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” Thus, these process steps only considered to the extent that they limit the structure of Isosulfan Blue.
Claims 16 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kovi et al. (US 2008/0293963 A1; IDS of 01-05-2022; hereinafter “Kovi”).
Regarding claim 16 depending from claim 1, Kovi teaches that Isosulfan Blue is an active pharmaceutical ingredient used in the LymphazurinTM blue dye pharmaceutical dosage form, available as a 1% (10 mg/mL) 5 mL solution in phosphate buffer for injection (Kovi; paragraph [0003]).
Claim 18 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by G. Del Priore (US 2014/0257098 A1; hereinafter “Del Priore”).
Regarding claim 18 depending from claim 1, Del Priore teaches that Isosulfan blue (LymphazurinTM) is a synthetic visual lymphatic agent that is typically injected into the periphery of a tumor site and localizes to the lymphatic system, causing sentinel nodes to stain blue for surgical identification (Del Priore; paragraph [0035]).
NEW Claim Rejections - 35 USC § 103
In the recent response filed 19 September 2025, Applicant’s amendment to claim 1 incorporated limitations from claim 8 (now amended) which further introduced the conditional limitation wherein when the anode is graphite, the cathode is a noble metal or nickel. In addition, Applicant’s amendment to claim 21 further limited the genus of formulae (IIa) and (IIb) to exclude C1-C4 substituted alkylphenyl from the definition of R1-R4. As a result of these claim amendments, the previous 102 and 103 prior art rejections from the previous Office Action mailed 29 May 2025, were withdrawn. A new search necessitated by amendment resulted in new 103 claim rejections are detailed herein, wherein Kawamata et al. is relied upon in addition to the previously cited prior art of Kovi et al. and Kern et al., whose combined teachings adequately meet the limitations of claim 1 and dependent claims 2-3, 5-6, 8-14, 16, and 18-20. In addition, newly cited prior art of Habermann et al. and Gessner et al. resulted in new 103 claim rejections of claims 21-25, 27-28, 30, and 32-34, and Habermann et al. and Gessner et al. were further combined with Kern et al. and Kawamata et al. that resulted in new 103 claim rejections of claims 21-25, 27-28, 30-35. Finally, the previously cited prior art of Anderson was relied upon in combination with Kovi et al. and Kern et al. or in combination with Kern et al., Habermann et al., Gessner et al., and Kawamata et al. that resulted in new 103 claim rejections of claims 7 and 29, respectively. The previously issued claim rejections can be found on pages 4-17 of the previous Office Action mailed 29 May 2025.
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.
Claims 1-3, 5-6, 8-14, 19–25, 27-28, and 30-35 are rejected under 35 U.S.C. 103 as being unpatentable over Kovi et al. (US 2008/0293963 A1; IDS of 01-05-2022; hereinafter “Kovi”), in view of Kern et al. (US 2004/0163968 A1; PTO-892 of 05-29-2025; hereinafter “Kern”) and Kawamata et al. (J. Am. Chem. Soc. 2017, 139, 7448-7451; hereinafter “Kawamata”).
Regarding claim 1, Kovi teaches a process for the preparation of Isosulfan Blue (Active Pharmaceutical Ingredient), comprising a final step oxidation of 2-[bis-(4-diethylamino-phenyl)-methyl]-benzene-1,4-disulfonic acid in the presence of Ag2O in methanol (paragraph [0013], formula (5), compound 4 to compound 5; paragraph [0033]).
Kovi fails to teach a (1) process of preparing Isosulfan Blue comprising an electrochemical process in the presence of an aqueous solvent; (2) the process is conducted using electrodes comprising a material that is a noble metal, a metal oxide, a mixed metal oxide, graphite, carbon, iron, steel, stainless steel, nickel, or a combination thereof; and (3) wherein the electrodes comprise an anode and a cathode, wherein when the anode is graphite, the cathode is a noble metal or nickel, as recited in instant claim 1.
Regarding point (1), Kern teaches an electrochemical process for the preparation of Acid Blue 9 (C.I. 42090; [26050-18-2]) from the anodic oxidation of its corresponding leuco compound in an aqueous solvent, as depicted in the reaction scheme below (Kern; claims 1, 8, 13-14; paragraph [0022], Example 1):
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Kern further teaches that the reaction is particularly useful for the preparation of triphenylmethane colorants, and particularly diaminotriphenylmethane colorants containing from two to four sulfo groups (Kern; paragraph [0011]). The skilled artisan would recognize that these structural features apply to both Acid Blue 9 and the instantly claimed Isosulfan Blue.
Regarding points (2)-(3), Kern teaches that the electrochemical oxidation process uses graphite carbon felt electrodes, and Example 1 of Kern teaches the use of graphite felt on solid graphite anode and a cathode consisting of two stainless steel electrodes (Kern; paragraphs [0005] and [0022]; Example 1), and Example 1 of Kern shows a faster reaction rate and conversion compared with a solid graphite anode/stainless steel cathode and a smooth platinum on titanium anode/stainless steel cathode (Kern; paragraph [0025]; Table 1). Although Example 1 of Kern does not expressly teach wherein when the anode is graphite, the cathode is a noble metal or nickel, as recited in instant claim 1, the teachings of Kern do not strictly limit the material of the cathode to stainless steel. However, Kern teaches that any standard material, such as stainless steel, may be used to form the cathode in the present invention (Kern; paragraph [0015]).
Furthermore, Kawamata reviews the electrochemical oxidation of C-H bonds, including reaction development and optimization tactics (Kawamata; Title; Scheme 1B). Of particular note, Kawamata teaches a C-H oxidation reaction wherein reticulated vitreous carbon electrode was used as the anode, while nickel, copper, and even stainless steel were all found to be viable materials for the cathode (Kawamata; page 7448, Col. 2, paragraph 4 and page 7449, Col. 1, paragraph 1; Scheme 1B). Thus, one of ordinary skill in the art could reasonably select alternative cathodic materials for use in the method of Kern, such as nickel or copper as taught by Kawamata, with a reasonable expectation of success.
Finally, Kern teaches that one of the main advantages of an electrochemical process is that such processes use electricity to drive the reaction rather than using reactive chemicals and therefore electrochemistry eliminates the hazardous handling of these chemicals, the cost of buying them, and the final disposal costs of spent metal byproducts (Kern; paragraph [0002]). This is an excellent example of “green chemistry” which strives to develop environmentally benign process (Kern; paragraph [0002]).
The prior art as taught by Kovi, Kern, and Kawamata reside in the overlapping technical field of synthetic organic chemistry, and both Kovi and Kern teach the chemical synthesis of triphenylmethane dyes, and furthermore the chemical structure of Acid Blue 9 taught by Kern is a close structural analogue of Isosulfan Blue. Furthermore, Kern and Kawamata both teach electrochemical anodic oxidation processes in the context of chemical synthesis. Therefore, these prior art teachings are deemed analogous art, as described in MPEP § 2141.01(a). As such, the skilled artisan would be sufficiently motivated to substitute the chemical oxidation method step of Kovi with the electrochemical oxidation method of Kern to pursue a cost-effective and environmentally benign process with a reasonable expectation of success. Such an endeavor would result in the simple substitution of one known element for another to obtain predictable results, as described in MPEP § 2143(I)(B). In addition, the skilled artisan could reasonably select an alternative cathodic material such as copper or nickel as taught by Kawamata to implement into the method of Kovi in view of Kern. Such an endeavor would result in choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success, and would thus be “obvious to try,” as described in MPEP § 2143(I)(E).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have substituted the chemical oxidation method step of Kovi with the electrochemical oxidation step of Kern that includes a cathode comprising copper or nickel as taught by Kawamata to arrive at the claimed process. The motivation to do so would permit the skilled artisan to pursue, with a reasonable expectation of success, an improved process that achieve that eliminates the hazardous handling of chemical oxidizing agents, the cost of buying them, and the final disposal costs of spent metal byproducts, as described above.
Regarding claim 21, claim 22 depending from claim 21, and claim 23 depending from claim 22, the teachings of Kovi, Kern, and Kawamata were discussed in the previous rejection of claim 1 and are incorporated herein.
Kovi in view of Kern and Kawamata renders obvious the process of preparing Isosulfan Blue from 2-[bis-(4-diethylamino-phenyl)-methyl]-benzene-1,4-disulfonic acid via an electrochemical process, as detailed above, and this reaction is summarized as follows:
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The chemical structure of 2-[bis-(4-diethylamino-phenyl)-methyl]-benzene-1,4-disulfonic acid reads directly on the genus of formula (IIa) of instant claim 21 when R1-R4 = unsubstituted C2 alkyl, R5 and R6 = hydrogen, and Y = substituted phenyl. Furthermore, this chemical structure reads directly on the genus of formula (IIb) of instant claim 21 when R1-R4 = unsubstituted C2 alkyl, R5 and R6 = hydrogen, R7 = hydroxysulfonyl, and m = 2. In addition, the chemical structure of Isosulfan Blue reads directly on the genus of formula (Ib) of instant claim 22 when R1-R4 = unsubstituted C2 alkyl, R5 and R6 = hydrogen, R7 = hydroxysulfonyl, n = 1, and Z = an anion. Finally, Z a sulfonate anion and therefore reads directly on instant claim 23.
Thus, the teachings of Kovi in view of Kern and Kawamata teach every limitation of instant claims 21-23 and therefore, as with claim 1, it would have been prima facie obvious to have substituted the chemical oxidation method step of Kovi with the electrochemical oxidation step of Kern that includes a cathode comprising copper or nickel as taught by Kawamata to arrive at the claimed process.
Regarding claim 2 depending from claim 1, claim 6 depending from claim 2, claim 24 depending from claim 21, and claim 28 depending from claim 24, Kern teaches an electrochemical process as detailed above, wherein the process is conducted in an electrochemical cell with electrodes, the reaction solution comprises a leuco Acid Blue 9 (i.e., a compound structurally similar to Isosulfan Blue and formulae IIa and IIb), sodium chloride and sodium sulfate electrolytes, and the inorganic base sodium hydroxide (Kern; Title; Abstract; paragraph [0022], Example 1).
Regarding claim 3 depending from claim 2 and claim 25 depending from claim 21, Kovi teaches an initial reaction concentration of 2-[bis-(4-diethylamino-phenyl)-methyl]-benzene-1,4-disulfonic acid of 0.14 M (calculated from 0.027 mol of leuco compound of formula (4) and 225 mL of methanol solvent; Kovi; paragraphs [0013] and [0033]). Furthermore, Kern teaches an electrochemical process for the preparation of Acid Blue 9 as detailed above, wherein 1299 grams of 10.75% by weight aqueous leuco Acid Blue 9 (i.e., a compound structurally similar to Isosulfan Blue and formulae IIa and IIb) is added to the anolyte reservoir (Kern; paragraphs [0008], [0018], and [0022], Example 1). This corresponds to an initial concentration of 0.14 M (calculated from a molecular weight of leuco Acid Blue 9 is 750.90 g/mol in its unionized form). These concentrations taught by both Kovi and Kern and overlap with the instantly claimed range of about 0.01 M or greater. MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”
Regarding claim 5 depending from claim 2 and claim 27 depending from claim 24, Kern teaches an electrochemical process as detailed above, wherein 161 grams of sodium chloride was added to the 1299 grams of aqueous leuco Acid Blue 9 in the anolyte reservoir (Kern; paragraph [0022], Example 1). This corresponds to an electrolyte concentration of 2.1 M. Furthermore, 160 grams of sodium sulfate are added to 1080 grams of water in the catholyte reservoir (Kern; paragraph [0022], Example 1). This corresponds to an electrolyte concentration of 1.04 M. These electrolyte concentrations taught by Kern overlap with the instantly claimed range of about 0.01 M or greater. MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”
Regarding claims 8-9 depending from claim 2 and claims 30-31 depending from claim 24, Kern teaches an electrochemical process as detailed above, wherein the electrochemical cell comprises graphite and stainless steel electrodes, wherein the graphite is the anode and stainless steel is the cathode (Kern; paragraph [0022], Example 1). Kern further teaches an electrochemical process as detailed above, wherein the electrochemical cell comprises a platinum anode and stainless steel cathodes (Kern; paragraph [0024], Example 3 Comparative).
Although Example 1 of Kern teaches a graphite anode and a stainless steel electrode, Kawamata teaches a C-H oxidation reaction wherein reticulated vitreous carbon electrode was used as the anode, while nickel, copper, and even stainless steel were all found to be viable materials for the cathode (Kawamata; page 7448, Col. 2, paragraph 4 and page 7449, Col. 1, paragraph 1; Scheme 1B). Thus, one of ordinary skill in the art could reasonably select alternative cathodic materials for use in the method of Kern, such as copper or nickel as taught by Kawamata, with a reasonable expectation of success to arrive at a process wherein the electrodes comprise a graphite anode and a copper cathode in a manner consistent with instant claims 8 and 30, or to arrive at a process wherein the electrodes comprise a graphite anode and a nickel cathode as recited in instant claims 9 and 31, respectively. Therefore, as with claims 2 and 24, it would have been prima facie obvious to arrive at the claimed invention based on the teachings of Kovi in view of Kern and Kawamata.
Regarding claim 10 depending from claim 2 and claim 32 depending from claim 21, Kern teaches an electrochemical process as detailed above, wherein the voltage ranged from 2.0 V at the start of the electrooxidation to 2.2 V at the end (Kern; paragraph [0022], Example 1). Although Kern does not explicitly teach the claim limitation wherein a voltage is applied until a total charge equivalent greater than 0 to about 20 F (1 faraday) per mole of 2-[bis-(4-diethylamino-phenyl)-methyl]-benzene-1,4-disulfonic acid or of the compound of formula IIa or formula IIb has passed through the solution, this limitation is disclosed implicitly. The electrochemical oxidation of Acid Blue 9 from leuco Acid Blue 9 (i.e., a compound structurally similar to Isosulfan Blue and formulae IIa and IIb) consists of a two-electron oxidation process, as detailed in the reaction scheme above, and therefore at least two moles of electrons per mole of leuco compound is required to pass through the solution, which corresponds to a total charge equivalent of 2 F and reads directly on the range recited in the instant claim. MPEP § 2144.01 states that “[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom.” In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968).
Regarding claim 11 depending from claim 10 and claim 33 depending from claim 32, Kern teaches an electrochemical process for the preparation of Acid Blue 9 as detailed above, wherein the voltage ranged from 2.0 V at the start of the electrooxidation to 2.2 V at the end (Kern; paragraph [0022], Example 1). This reads directly on the instantly claimed range of 0.5 V or greater and further corresponds with the electrochemical window of an aqueous solvent defined in the instant specification.
Regarding claim 12 depending from claim 1 and claim 34 depending from claim 21, Kovi teaches the isolation of crude Isosulfan Blue from the reaction mixture by filtration, and the crude Isosulfan Blue thus obtained was then purified by recrystallization from aqueous isopropyl alcohol/acetone (Kovi; paragraphs [0024]-[0025]).
Claims 13-14, although dependent on claim 1, are product-by-process claims. MPEP § 2113(I) states that “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” Thus, these process steps only considered to the extent that they limit the structure of the 2-[bis-(4-diethylaminophenyl)-methyl]-benzene-1,4-disulfonic acid in claim 13 and the 2-formyl-benzene-1,4-disulfonic acid disodium salt in claim 14. Regardless, the teachings of Kovi does explicitly teach these process steps, as detailed below.
Regarding claim 13 depending from claim 1, Kovi teaches the preparation of 2-[bis-(4-diethylamino-phenyl)-methyl]-benzene-1,4-disulfonic acid by reacting 2-formyl-benzene-1,4-disulfonic acid disodium salt, urea, and N,N-diethylaniline (Kovi; paragraph [0013] and formula (5), compound 3 to compound 4).
Regarding claim 14 depending from claim 13, Kovi teaches the preparation of 2-formyl-benzene-1,4-disulfonic acid disodium salt by reacting 4-chloro-3-formyl-benzenesulfonic acid sodium salt in the presence of sodium sulfite and sodium bisulfite (Kovik; paragraph [0013] and formula (5), compound 2 to compound 3).
Regarding claim 19 depending from claim 1 and claim 20, Kovi teaches a process of preparing Isosulfan Blue having purity greater than 99.5% by HPLC and also free of silver with silver content estimated by atomic absorption spectrometry as less than 20 ppm (Kovi; paragraph [0026]).
Although Kovi teaches the preparation of Isosulfan Blue with a purity as measured by HPLC that is greater than 99.5%, both Kovi and Kern fail to explicitly teach a purity as measured by LC-MS that is greater than 95% and contains silver below the detectable limit as measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS), as recited in instant claims 19-20.
In spite of these deficiencies, one of ordinary skill in the art could reasonably surmise that a purity as measured by HPLC that is greater than 99.5% as taught by Kovi is at least equivalent to, if not superior than, a purity of 95% as measured by LC-MS. Furthermore, the combined teachings of Kovi, Kern, and Kawamata to arrive at the process of instant claim 1, as detailed above, results in an overall synthetic process that does not use silver or any metals. Therefore, the claim limitation silver below the detectable limit as measured by Inductively Coupled Plasma Mass Spectrometry (ICP-MS), as recited in instant claims 19-20 is deemed inherently taught by Kovi in view of Kern and Kawamata. MPEP § 2112.01 states that “The inherent teaching of a prior art reference, a question of fact, arises both in the context of anticipation and obviousness.” Furthermore, MPEP § 2112.01(II) states that “Products of identical chemical composition cannot have mutually exclusive properties.” A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). In the instant case, a chemical composition synthesized in the absence of silver cannot reasonably be expected to possess a detectable level of silver as measured by ICP-MS.
Regarding claim 35 depending from claim 21, Kern teaches an electrochemical process for the preparation of Acid Blue 9 as detailed above, wherein an anolyte reservoir containing the starting material and sodium chloride electrolyte is recirculated through an SU Electro MP Cell manufactured by ElectroCell AB (Sweden) using a centrifugal pump with a ½ HP motor (Kern; paragraph [0022], Example 1).
Claims 7 and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Kovi et al. (US 2008/0293963 A1; IDS of 01-05-2022; hereinafter “Kovi”), in view of Kern et al. (US 2004/0163968 A1; PTO-892 of 05-29-2025; hereinafter “Kern”) and Kawamata et al. (J. Am. Chem. Soc. 2017, 139, 7448-7451; hereinafter “Kawamata”) as applied to claims 1-3, 5-6, 8-14, 19–25, 27-28, and 30-35 above, and further in view of N.G. Anderson (Practical Process & Research Development, 2000, pages 117 and 168; PTO-892 of 05-29-2025; hereinafter “Anderson”).
Regarding claims 7 and 29, claims 6 and 28 are rendered obvious over Kovi in view Kern and Kawamata, as detailed above.
Kovi, Kern, and Kawamata fail to teach wherein the electrolyte or base is present at about 2 to about 4 molar equivalents per molar equivalent of 2-[bis-(4-diethylamino-phenyl)-methyl]-benzene-1,4-disulfonic acid or of the compound of formula IIa or formula IIb, as recited in instant claims 7 and 29. Instead, Kern teaches electrolyte concentrations higher than the instantly claimed range, and Kern does not specify the amount of sodium hydroxide used (Kern; paragraph [0022], Example 1).
However, Anderson teaches practical process research and development, including the optimization of reaction conditions in chemical synthesis (Anderson; Title; page 117). Of particular note, Anderson teaches that the charges of reagents, starting materials, and solvents to reactions are minimized to decrease the cost of inputs and to optimize vessel throughput (Anderson; page 117, paragraph 3). Anderson further teaches that waste disposal charges are also decreased by minimizing charges of reaction components; thus, this consideration can have considerable impact on overall product cost and productivity (Anderson; page 117, paragraph 3). Finally, Anderson teaches that changing the proportion of reaction compounds (i.e., varying the equivalents of reagents) allows the chemist to select conditions that lead to complete reactions while generating minimal impurities (Anderson; page 168; paragraph 1; Figure 8.5; Table 8.2).
The prior art as taught by Kovi, Kern, Kawamata, and Anderson reside in the overlapping technical field of synthetic organic chemistry, and are therefore deemed analogous art, as described in MPEP § 2141.01(a). As such, the skilled artisan would be sufficiently motivated to incorporate the teachings of Anderson into the process of Kovi, Kern, and Kawamata to pursue a process that decreases the cost of inputs and optimizes the vessel throughput with a reasonable expectation of success. Such an endeavor would result in combining prior art elements according to known methods to yield predictable results, as described in MPEP § 2143(I)(A). Furthermore, the teachings of Anderson indicates that the recited range of electrolyte or base concentration could be arrived at through routine optimization of synthetic processes by one of ordinary skill in the art. MPEP § 2144.05(II) states that “[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.”
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Kovi, Kern, and Kawamata to incorporate the teachings of Anderson to arrive at the claimed process through routine experimentation with a reasonable expectation of success. The motivation to do so would permit the skilled artisan to pursue, with a reasonable expectation of success, an improved process that minimizes the charges of reagents to decrease the cost of inputs, optimize vessel throughput, decrease waste disposal charges, and minimize the generation of impurities, as described above.
Claims 21-25, 27-28, 30, and 32-34 are rejected under 35 U.S.C. 103 as being unpatentable over Habermann et al. (US 4,775,451 A; hereinafter “Habermann”), as evidenced by Gessner et al. (Ullman’s Encyclopedia of Industrial Chemistry, 2012, 37, 425-478; hereinafter “Gessner”).
Regarding claim 21, claim 22 depending from claim 21, and claim 23 depending from claim 22, Habermann teaches the preparation of water-soluble food-grade triphenylmethane colors, the process comprising anodically oxidizing the corresponding leuco compound in an electrolysis cell divided into an anode space and a cathode space, wherein a leuco compound of the dye C.I. 42,090, 42,045, 42,051, 42,052, 42,053, 42,080, 42,105, 42,135 or 42,165 is oxidized (Habermann; Title; claims 1 and 3). One of ordinary skill in the art would recognize that the dyes C.I. 42,045 corresponds to Acid Blue 1 (R = ethyl), and the dye C.I. 42,080 corresponds to Acid Blue 7 (R = benzyl) that possesses the following structure as evidenced by Gessner (Gessner; page 441, Col. 1 paragraphs 1-2, compound 59):
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The structures of Acid Blue 1 and Acid Blue 7 anticipate formula (Ib) of instant claims 22-23 when R1 and R3 are ethyl and R2 and R4 are either ethyl (as in leuco Acid Blue 1) or benzyl (as in leuco Acid Blue 7), R7 is hydroxysulfonyl, n is 1, and Z is a sulfonate anion. Furthermore, the skilled artisan would recognize that the leuco compound of the dye C.I. 42,045 (i.e., leuco Acid Blue 1) and the leuco compound of the dye C.I. 42,080 (i.e., leuco Acid Blue 7) corresponds to the reduced general structure shown above (c.f., Gessner; page 431, Col. 1, compounds 20 and 22 for examples of the reduced leuco form of triarylmethane dyes), and therefore these compounds anticipate formula (IIa) of instant claim 21 when R1 and R3 are ethyl and R2 and R4 are either ethyl (as in leuco Acid Blue 1) or benzyl (as in leuco Acid Blue 7), and Y is substituted phenyl, and anticipate formula (IIb) of instant claim 21 when R1 and R3 are ethyl and R2 and R4 are either ethyl (as in leuco Acid Blue 1) or benzyl (as in leuco Acid Blue 7), R7 is hydroxysulfonyl, and m is 2.
In addition, Habermann teaches that aqueous solutions of the leuco compounds are used as anolytes, and in Example 1 Habermann teaches that the anolyte used is a 20% strength by weight aqueous solution of the leuco compound of Acid Blue 9 (C.I. no. 42,090) (Habermann; Col. 3, lines 10-11 and 61-63; Example 1).
The working examples of Habermann further disclose the preparation of Acid Blue 9 (C.I. no. 42,090) from its corresponding leuco compound in an electrolysis cell wherein the anode is a flat titanium electrode which is doped at the surface with a tantalum/iridium mixed oxide and has a titanium suboxide intermediate layer, and a copper electrode is used as the cathode (Habermann; Examples 1-9 and claim 20). Furthermore, Habermann teaches that suitable anode materials include valve metals, such as titanium, tantalum and niobium doped on the surface with mixed oxides of valve metals and metals of the group of the platinum group or platinum metal compounds (Habermann; Col. 2, lines 28-34). In addition, Habermann is silent regarding the preference for cathodic materials, such that the skilled artisan could reasonably deduce that the method of Habermann is not strictly limited to the copper cathode used in the working examples. This
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reaction is exemplified in the following scheme:
Acid Blue 9 and leuco Acid Blue 9 are analogous to the compounds of instant formula (Ib) and (IIb), respectively. The Acid Blue 9 compounds of Habermann differ from those claimed because they contain alkylphenyl groups substituted by hydroxysulfonyl (highlight above for emphasis) at instant variable R3, instead of one of the options claimed.
Thus, Habermann does not explicitly teach an anticipatory example wherein a compound of instant formula (IIb) is oxidized to a compound of instant formula (Ib) in an electrochemical process to meet the limitations of claims 21-23. Habermann does teach that the process can also be used to prepare Acid Blue 1 and Acid Blue 7 from their corresponding leuco compounds (Habermann; claims 1 and 3; Col. 2, lines 3-9), in a manner consistent with the structural formulae of instant claims 21-23 as detailed above. Thus, the skilled artisan would recognize from the teachings of Habermann alone as evidenced by Gessner that Acid Blue 1 and Acid Blue 7 can be prepared using the method described in Example 1 of Habermann from their corresponding leuco compounds via electrochemical anodic oxidation. Such an endeavor would result in the simple substitution of one known element for another to obtain predictable results, as described in MPEP § 2143(I)(B). Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified the working examples of Habermann to prepare Acid Blue 1 and Acid Blue 7 from their corresponding leuco compounds as taught by Habermann and evidenced by Gessner to arrive at the process of claims 21-23 with a reasonable expectation of success.
Regarding claim 24 depending from claim 21, Example 1 of Habermann teaches that the process is conducted in an electrolysis cell comprising electrodes, and the solution further contains ~0.9% of free sulfate (Habermann; Col. 3, lines 10-11, 61-63, and 65-66; Example 1). The skilled artisan would recognize free sulfate as an electrolyte, in a manner consistent with the instant claim.
Furthermore, since Habermann teaches that the process can also be used to prepare Acid Blue 1 and Acid Blue 7 from their corresponding leuco compounds (Habermann; claims 1 and 3), whose leuco structures read on formulae IIa and IIb as detailed above, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have arrived at the process of claim 24 based on the teachings of Habermann alone as evidenced by Gessner.
Regarding claim 25 depending on claim 21, Example 1 Habermann teaches that the anolyte used is a 20% strength by weight aqueous solution of the leuco compound of Acid Blue 9 (Habermann; Example 1), and Habermann further teaches that the process can also be used to prepare Acid Blue 1 and Acid Blue 7 from their corresponding leuco compounds (Habermann; claims 1 and 3). The skilled artisan would recognize that the leuco compound of Acid Blue 1 (which reads on formulae IIa and IIb of instant claim 21) has the following structure, as evidenced by Gessner (Gessner; page 441, Col. 1 paragraphs 1-2, compound 59; page 431, Col. 1, examples of the reduced leuco form of triarylmethane dyes):
The skilled artisan would recognize that the molecular weight of leuco Acid Blue 1 is 546.70 g/mol, and therefore a 20% by weight aqueous solution of leuco Acid Blue 1 (as in Example 1 of Habermann) corresponds to a concentration of about 0.37 M, a value that reads directly on the range recited in the instant claim. MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”
Regarding claim 27 depending from claim 24, Example 1 of Habermann teaches that the process is conducted in an aqueous solution that further contains ~0.9% of free sulfate (Habermann; Col. 3, lines 10-11, 61-63, and 65-66; Example 1). The skilled artisan would recognize that the molecular weight of sulfate is about 96.07 g/mol, and therefore a 0.9% by weight aqueous solution of free sulfate corresponds to a concentration of about 0.09 M, a value that reads directly on the range recited in the instant claim. MPEP § 2144.05(I) states that “[i]n the case where the claimed ranges ‘overlap or lie inside ranges disclosed by the prior art’ a prima facie case of obviousness exists.”
Regarding claim 28 depending from claim 24, although Example 1 of Habermann teaches that the process is conducted in an aqueous solution that further contains ~0.9% of free sulfate (Habermann; Col. 3, lines 10-11, 61-63, and 65-66; Example 1), Habermann does not explicitly teach that the sulfate is an alkali or alkaline earth metal salt, as recited in instant claim 28.
However, Habermann teaches that when cation exchanger membranes are used, the catholyte used can be a solution of alkali metal hydroxide (Habermann; Col. 2, lines 52-56). Habermann further teaches that when anion exchanger membranes are used, aqueous alkali metal hydroxides, ammonia or alkali metal or ammonium carbonate or bicarbonate solutions are suitable as catholytes (Habermann; Col. 2, lines 60-63). Finally, Habermann teaches that in order to avoid damaging the membranes, primary, secondary or tertiary amines are advantageously added to the alkali metal hydroxides (Habermann; Col. 2, lines 63-68). Thus, the skilled artisan could arrive at wherein the electrolyte is an alkali carbonate or wherein the base is an amine based on the teachings of Habermann and therefore, as with claim 24, it would have been prima facie obvious to arrive at the claimed invention based on the teachings of Habermann and the supporting teachings of Gessner.
Regarding claim 30 depending from claim 24, Example 1 of Habermann teaches that a copper electrode is used as the cathode (Habermann; Example 1).
Regarding claim 32 depending from claim 21, Example 1 of Habermann teaches that electrolysis is carried out at a cell voltage of ~3.5 V (Habermann; Example 1). Although Habermann does not explicitly teach the claim limitation wherein a voltage is applied until a total charge equivalent greater than 0 to about 20 F (1 faraday) per mole of the compound of formula IIa or formula IIb has passed through the solution, this limitation is disclosed implicitly. The electrochemical oxidation of Acid Blue 9 from leuco Acid Blue 9 and its congeners Acid Blue 1 and Acid Blue 7 from their leuco starting materials (i.e., a compounds of formulae IIa and IIb of instant claim 21; Habermann; claims 1 and 3) consists of a two-electron oxidation process, as indicated by comparison of the leuco dye starting material and oxidized product structures, and therefore at least two moles of electrons per mole of leuco compound is required to pass through the solution, which corresponds to a total charge equivalent of 2 F and reads directly on the range recited in the instant claim. MPEP § 2144.01 states that “[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom.” In re Preda, 401 F.2d 825, 826, 159 USPQ 342, 344 (CCPA 1968).
Regarding claim 33 depending from claim 32, Example 1 of Habermann teaches that electrolysis is carried out at a cell voltage of ~3.5 V (Habermann; Example 1). This reads directly on the instantly claimed range of 0.5 V or greater and further corresponds with the electrochemical window of an aqueous solvent defined in the instant specification.
Regarding claim 34 depending from claim 21, Example 1 of Habermann teaches that after the electrolysis is terminated the electrolyte is worked up, and 99.9% pure Acid Blue 9 is obtained in virtually quantitative yield (Habermann; Example 1). The skilled artisan would deduce that the process of working up the electrolyte to obtain the pure product (i.e., a triaryl methane dye) necessarily comprises an isolation step, in a manner consistent with the instant claim.
Claim 29 is rejected under 35 U.S.C. 103 as being unpatentable over Habermann et al. (US 4,775,451 A; hereinafter “Habermann”), as evidenced by Gessner et al. (Ullman’s Encyclopedia of Industrial Chemistry, 2012, 37, 425-478; hereinafter “Gessner”) as applied to claims 21-25, 27-28, 30, and 32-34 above, and further in view of N.G. Anderson (Practical Process & Research Development, 2000, pages 117 and 168; PTO-892 of 05-29-2025; hereinafter “Anderson”).
Regarding claim 29, claim 28 is rendered obvious over Habermann and Gessner, as detailed above.
Habermann and Gessner fail to teach wherein the electrolyte of base is present at about 2 to about 4 molar equivalents per molar equivalent of the compound of formula IIa or formula IIb. Instead, Habermann teaches electrolyte concentrations higher or lower than the instantly claimed range, respectively ( Habermann; Example 1).
However, Anderson teaches practical process research and development, including the optimization of reaction conditions in chemical synthesis (Anderson; Title; page 117). Of particular note, Anderson teaches that the charges of reagents, starting materials, and solvents to reactions are minimized to decrease the cost of inputs and to optimize vessel throughput (Anderson; page 117, paragraph 3). Anderson further teaches that waste disposal charges are also decreased by minimizing charges of reaction components; thus, this consideration can have considerable impact on overall product cost and productivity (Anderson; page 117, paragraph 3). Finally, Anderson teaches that changing the proportion of reaction compounds (i.e., varying the equivalents of reagents) allows the chemist to select conditions that lead to complete reactions while generating minimal impurities (Anderson; page 168; paragraph 1; Figure 8.5; Table 8.2).
The prior art as taught by Habermann and Anderson reside in the overlapping technical field of synthetic organic chemistry, and are therefore deemed analogous art, as described in MPEP § 2141.01(a). As such, the skilled artisan would be sufficiently motivated to incorporate the teachings of Anderson into the process of Habermann and Gessner to pursue a process that decreases the cost of inputs and optimizes the vessel throughput with a reasonable expectation of success. Such an endeavor would result in combining prior art elements according to known methods to yield predictable results, as described in MPEP § 2143(I)(A). Furthermore, the teachings of Anderson indicates that the recited range of electrolyte or base concentration could be arrived at through routine optimization of synthetic processes by one of ordinary skill in the art. MPEP § 2144.05(II) states that “[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.”
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to have modified Habermann and Gessner to incorporate the teachings of Anderson to arrive at the claimed process through routine experimentation. The motivation to do so would permit the skilled artisan to pursue, with a reasonable expectation of success, an improved process that minimizes the charges of reagents to decrease the cost of inputs, optimize vessel throughput, decrease waste disposal charges, and minimize the generation of impurities, as described above.
Based on the combined teachings of the references, the Examiner submits that a person of ordinary skill in the art would have had a reasonable expectation of success of arriving at the instantly claimed method. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, before the effective filing date of the claimed invention, and absent a clear showing of evidence to the contrary.
Response to Arguments
Claim Rejections - 35 USC § 103
Applicant's arguments filed 19 September 2025, asserting that the Examiner has not met the burden of establishing that all elements of the invention are disclosed in the prior art, that the prior art relied upon, or knowledge generally available in the art at the time of the invention, must provide some suggestion or incentive that would have motivated the skilled artisan to modify a reference or combine references, have been fully considered but they are not persuasive.
Applicant argues the following:
“It is the Applicants' position that the combination of Kovi and Kern fail to teach or suggest each and every limitation of independent claim 1.
Kovi fails to teach or suggest preparing Isosulfan Blue by an electrochemical process as Kovi is entirely directed to the use of chemical oxidant silver oxide.
Taking Kern as a whole, one having ordinary skill in the art would not have a reasonable expectation of success in preparing the Isosulfan Blue of Kovi using an electrochemical process.
Furthermore, that artisan would not avoid using the particular electrode combination taught in Kern - a stainless steel c