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 .
Status of the Claims
Claims 1-8 and 10-12 are pending in the instant application and subject to examination herein.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 07/29/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections – Withdrawn
The prior rejection claims 1-5 and 11-12 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regards as the invention, has been overcome by Applicant’s amendment of claims 1-5 and 11, and is accordingly withdrawn. Specifically, Applicant’s amendment of claims 1-5 to indicate that the claims are drawn to a composition comprising Methylene Blue rather than being drawn to the specific compound Methylene Blue, and Applicant’s amendment of claim 11 to indicate that the presence of the (alleged) compound “N-nitroso-Azure B” in a sample is to be determined by liquid chromatography/tandem mass spectrometry (LC/MS/MS) have overcome the prior rejection.
The prior rejection claim 9 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or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention, is withdrawn in response to Applicant’s cancellation of the claim.
Claim Rejections - 35 USC § 112(a) - Maintained
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
The prior rejection of claims 1-5 and 10-12 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement, is maintained. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicant has traversed the rejection with the following assertions:
Conditions suitable for the formation of N-Nitroso-amine, as taught in the prior art by Lopez (Lopez-Rodriguez, R., et al.; Organic Process Research & Development, v24, pp1558-1585; 2020), are found in the prior synthesis of Methylene Blue by Colombo (U.S. Patent No. 10,723,710 B2, cited by Applicant as EP34585221), and since no purification is performed until the final product is formed, the compound instantly designated as “N-nitroso-Azure B (NnAB)”2 would be reasonably expected to be present;
The instantly claimed compound N-nitroso-Azure B has been officially classified as an impurity in methylene blue by the U.S. FDA in 2023;
The instantly claimed compound N-nitroso-Azure B is reportedly available for purchase from several chemical suppliers, with weblinks provided in Applicant’s response letter.
Applicant’s traverse has been considered, but is not found persuasive toward evidencing the possession of the claimed compound N-nitroso-Azure B at the effective time of filing, for the following reasons:
A person of ordinary skill in the art would not expect any N-nitroso impurity formed in the initial step of Colombo’s synthesis of Methylene Blue to persist in the reaction mixture and ultimately result in formation of the alleged compound N-nitroso-Azure B, because Colombo includes the reducing conditions of excess zinc powder after the initial para-nitrosation of dimethylaniline, which reduces the nitroso group to an amine and would be expected by a person of ordinary skill in the art to also reduce the N-nitroso group of any potential N-nitrosated impurity (paragraph [0045] in Applicant’s cited EP34585223, or Col. 6, lines 27-29 in Examiner’s cited U.S. Patent No.10,723,710 B2) ;
The cited reference Lopez does not provide any assertion that an N-nitroso group would survive reducing conditions of zinc powder;
Applicant provides an overall synthesis of Methylene Blue nearly identical to that of Colombo (instant Specification, page 8, line 17 to page 9, line 14), with the substitution of iron powder/HCl for the post-nitrosation reduction reaction, and Applicant asserts that the overall synthesis by this route provides a Methylene Blue product composition that is free of N-nitrosamines (page 9, lines 15-18). Applicant has not provided any evidence or prior art that would establish or reasonably suggest that the substitution of Fe/HCl for zinc powder would substantially alter the product composition compared to the synthesis prior disclosed by Colombo.
Thus, while Applicant has asserted a mechanism by which an N-nitroso-precursor of the alleged compound N-nitroso-Azure B would be formed, Applicant has failed to establish a mechanism for the formation of the final impurity N-nitroso-Azure B in the overall synthesis of Methylene Blue by Colombo, because a person of ordinary skill in the art would at once recognize that any potential N-nitroso precursor to the alleged compound would not survive the overall synthesis of Methylene Blue as reported by Colombo, which includes strongly reducing conditions in the form of excess zinc powder that would reduce any N-nitroso compound in the same manner as its intended effect of reducing the p-nitroso group of p-nitroso-dimethylaniline.
The FDA has not, contrary to Applicant’s assertion, established the alleged compound “N-nitroso-Azure B” as a known impurity of Methylene Blue. The link provided by Applicant provides an FDA webpage with guidelines of N-nitrosamine impurities and recommendations for their limit(s) in known compounds, and includes “N-nitroso-desmethyl-methylene blue” among the compounds listed with a recommended limit for any commercial production of Methylene Blue; however this inclusion does not establish any objective evidence that the compound has ever been prior synthesized or isolated. No analytical data or reference to prior synthesis or report of confirmed preparation of “N-nitroso-desmethyl-methylene blue” is provided by the FDA.
None of the commercial suppliers provided by Applicant reports any inventory or analytical data for the alleged compound. All cite “Custom Synthesis” or “Please Inquire” for the compound availability, indicating that they are willing to synthesize the compound if an order is placed. Moreover, there is no evidence that any such website was up prior to the effective filing date of the instant application.
As discussed in the prior rejection, there is no known reported direct synthesis of N-nitroso-Azure B, nor any prior art reporting any analytical data for the alleged compound N-nitroso-Azure B, and none of the references cited in Applicant’s traverse successfully challenge this prior assertion by the Examiner.
To overcome this rejection, Applicant must provide at least one valid prior art reference providing a report of the synthesis or isolation of the alleged compound N-nitroso-Azure B with objective, signature identifying analytical characteristics (i.e., 1H or 13C NMR, single-crystal X-ray diffraction, mass spectrometry, or comparable data) that establishes the prior known existence and structure of the alleged compound prior to the filing date of the instant application.
Reiterated Rejection:
The Invention in General:
Applicant has disclosed a process for preparing high purity Methylene Blue4, a compound with broad industrial use as a colorant, a diagnostic dye and a medicinal compound.
The Claimed Invention:
Applicant has claimed a process for the preparation of Methylene Blue (claims 6-9) as well as the product of this process, said product being Methylene Blue being “essentially free of” a named compound: N-nitroso-Azure B (claims 1-5), represented by the molecular formula below, as well as the use of this product in a method for treatment (claim 10). Applicant also provides an analytical method for the detection and quantification of this alleged compound (claims 11-12) shown below:
PNG
media_image1.png
138
480
media_image1.png
Greyscale
The Instant Disclosure:
The instant Specification does not assert any mechanism for the alleged formation of the compound named as “N-nitroso-Azure B” or otherwise assert that this alleged impurity is formed under any prior known process for the preparation of Methylene Blue. Applicant provides no spectroscopic or other signature data, for example 1H NMR, 13C NMR, mass spectrometry, UV-visible absorption, infra-red absorption, elemental analysis, crystallographic determination, etc., to identify any compound as “N-nitroso-Azure B” in the instant Specification. Applicant provides an analytical method for the detection and quantification of “N-nitroso-Azure B”, including instrumental parameters (page 11 – whole page, and page 12, lines 1-17), without any exemplary detection of this alleged compound. Applicant provides an exemplary preparation of Methylene Blue (Example 2 – page 19, line 20, through page 21, line 9) with the only documented attempt by Applicant to detect “N-nitroso-Azure B”, with the result that the compound was not detected (page 20, line 25).
Applicant cites a prior patented synthesis of Methylene Blue by Colombo (EP 3458522)5 and reports that no formation of the compound N-nitroso-Azure B is disclosed in that patent. Applicant provides an overall synthesis of Methylene Blue from dimethylaniline that includes a nitrosation step (instant Specification, page 8, line 17 to page 9, line 14), followed by strongly reducing conditions (iron powder/HCl). Applicant’s synthesis of Methylene Blue is nearly identical to the prior synthesis by Colombo, with the substitution of Fe/HCl reduction for Colombo’s zinc powder reduction (paragraph [0045]), and leading to Methylene Blue product that Applicant asserts as being free of Nitrosamine impurities (page 9, lines 15-18). Thus, Applicant has not provided any evidence of a prior synthesis of Methylene Blue nor even Applicant’s own synthesis of Methylene Blue wherein the alleged impurity N-nitroso-Azure B is confirmed to form.
The Field of Art and Predictability in the Art:
A search of the CAS database finds no prior report of any compound corresponding to Applicant’s asserted molecular structure for “N-nitroso-Azure B” or any other similar N-nitroso aminophenothiazinium compound, as either a commercially available compound, a reaction that would form such a compound, or any published report that has prior asserted the existence of such a compound. Additionally, as discussed above, the instant Specification does not assert any mechanism for the alleged formation of the compound named as “N-nitroso-Azure B”. A person of ordinary skill in the art would expect that a nitrosyl donor compound, such as nitrous acid, amyl nitrite, tert-butylnitrite, or similar, would be required for the formation of an N-nitroso compound, and so would not find it predictable that an N-nitroso byproduct would be formed in the absence of a nitrosyl donor. See, for example, Lopez-Rodriguez (Lopez-Rodriguez, et al.; Organic Process Research & Development, v24, pp1558-1585; 2020), who teaches that N-demethylation/nitrosation at secondary arylamines requires both an oxidant (e.g., TEMPO or O2) and a nitrosyl donor (e.g., tert-butylnitrite – see Schemes 28 and 29). Lopez-Rodriguez provides a mechanism for the demethylation/nitrosation at a dimethyl-anilinic nitrogen, showing that while demethylation is driven by radical oxidation, the N-nitrosation step still requires a neutral nitrosyl donor (Scheme 28, path b):
PNG
media_image2.png
330
976
media_image2.png
Greyscale
As discussed above, Applicant cites past overall synthesis of Methylene Blue by Colombo and Applicant’s own overall synthesis of Methylene Blue that both begin with nitrosation of dimethylaniline followed by strongly reducing conditions that a person of ordinary skill in the art would expect to also reduce any N-nitrosoamines. Applicant has not disclosed any conditions in the synthesis of Methylene Blue subsequent to such strongly-reducing conditions that would provide a mechanism for the nitrosation of Methylene Blue or the production of an N-nitroso precursor that a person of ordinary skill in the art would reasonably expect to persist throughout the overall synthesis of Methylene Blue and thereby produce the alleged compound N-nitroso-Azure B.
Applicant’s invention is predicated on the existence of an alleged compound that has never before been reportedly synthesized nor isolated, has not been directly prepared by Applicant or anyone else, has no mechanism for its formation under the conditions of preparing Methylene Blue as cited by Applicant in prior art nor Applicant’s own synthesis, has never been detected, including by Applicant, and has not been characterized for any signature identifying analytical characteristics, including by Applicant.
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.
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.
The prior rejection of claims 1-4 and 6-8 as being unpatentable over Colombo (U.S. Patent No. 10,723,710 B2) is maintained.
Applicant has traversed the rejection on the grounds that Colombo does not teach how to obtain a composition of Methylene Blue that is free of the impurity N-nitroso-Azure B, and the skilled person would have had no reason for modifying the teaching of Colombo to arrive at the presently claimed invention. Applicant’s traverse has been considered, but is not found persuasive, for the following reasons:
as noted in the 112(a) rejection above, Applicant has provided no evidence that the impurity N-nitroso-Azure B is a confirmed chemical species ever directly synthesized or isolated prior to the filing date of the instant application, therefore the claim limitation of comprising a unknown and unproven compound is not further limiting to a claim of a composition comprising Methylene Blue;
the composition of claim 1 is interpreted as the product of the method of claim 6 because the same method is disclosed in the instant Specification as being the method that produces such a composition of Methylene Blue;
a person of ordinary skill in the art would have a reasonable expectation of success in producing Methylene Blue by modifying the process of Colombo in each/all of the manners by which the method of instant claim 6 differs from the method of Colombo without affecting the yield or processability of the product(s) because none of these changes are significant.
Reiterated Rejection:
Claim 1 is drawn to a composition comprising Methylene Blue and also comprising ≤7ppm N-nitroso-Azure B (NnAB), to total mass of the combined composition, as measured by LC/MS/MS.
Claim 6 is drawn to a process of preparing Methylene Blue, which is the same process that is disclosed in the instant Specification as being the process that produces a composition of Methylene Blue comprising ≤7ppm N-nitroso-Azure B (NnAB) (page 3, line 1). Thus, the composition of claim 1 is the product of the process claimed in claim 6. The steps of the process of claim 6 are as follows:
providing a starting Methylene Blue selected from crude Methylene Blue, Methylene Blue double salt of zinc, and mixtures thereof;
adding a reducing agent, and subsequently a protective agent comprising a functional group “-Pr” to obtain a compound of formula III, wherein the protective agent is selected from a Markush group that includes benzoyl chloride:
PNG
media_image3.png
162
324
media_image3.png
Greyscale
;
isolating the compound of formula III, adding isopropyl alcohol (iPrOH) and heating at reflux, then cooling and filtering at 0-5°C, while washing with iPrOH;
oxidizing the compound of formula B by addition of a stable free radical agent in a 15-25% solution over a period of time of 2-2.5 hours at 30-35°C, then stirring for 40-50 minutes, to obtain raw Methylene Blue, wherein the stable free radical agent is selected from a Markush group that includes 4-hydroxyTEMPO (i.e., “TEMPOL”);
adding a water solution of NaCl, stirring for 2-4 hours at room temperature, filtering off the raw Methylene Blue and washing it with diluted HCl; and
triturating the raw Methylene Blue with iPrOH, filtering off, washing with iPrOH, and then crystallizing from a water solution of NaCl, wherein no sequestering agent is used in the process steps.
Colombo discloses a process for the preparation of diaminophenothiazinium compounds, which allows achieving quickly and effectively a high degree of purity thereof, and discloses that this family of compounds includes Methylene Blue (Col. 1, lines 6-30). Colombo discloses that the process for obtaining a diaminophenothiazinium compound of high purity includes the following steps (Col. 1, line 38, through Col. 4, line 4):
providing a crude diaminophenothiazinium compound of “formula A”, with substituents and limitations that include Methylene Blue within the scope:
PNG
media_image4.png
210
484
media_image4.png
Greyscale
;
synthesizing a compound of “formula B”, wherein the compound of formula B represents a reduced and N-protected derivative of the diaminophenothiazinium compound, wherein the N-protecting group is selected from a Markush group that includes benzoyl:
PNG
media_image5.png
218
438
media_image5.png
Greyscale
;
oxidizing the compound of formula B with a stable free radical agent, selected from a Markush group that includes 4-hydroxyTEMPO (i.e., “TEMPOL”), to obtain again a diaminophenothiazinium compound of formula A.
Colombo further discloses that, in a preferred embodiment, the “crude” diaminophenothiazinium compound of Formula A is selected from crude Methylene Blue, Methylene Blue double salt of zinc and mixtures thereof (Col. 4, lines 5-8), and additionally discloses that the oxidation step is preferably carried out at a temperature in the range of -10 to +20°C (Col. 4, lines 50-51), and that Methylene Blue can be recovered from the oxidation reaction by precipitation and washing, and is preferably crystallized from water, or more preferably, from acidified water (Col. 5, lines 56-58). Colombo specifically discloses an exemplary embodiment of the process as “Example 1”, wherein the Methylene Blue double salt of zinc is used as the crude Methylene Blue starting material, the oxidant in Colombo’s step 3, TEMPOL, is added from a 40% solution over 2 hours at -5°C, then the mixture is stirred for a total of an additional 3 hours, including 2 hours at room temperature, then filtered and washed with 0.1 N aq. HCl, then heated in water, cooled and diluted with more water, adjusted to pH 1 and stirred for 16 hours, then filtered again and washed again with 0.1 N aq. HCl, and dried under vacuum (Col. 7, lines 9-61). Colombo further discloses Example 5, wherein the synthesis is conducted similar to that of Example 1, but using crude Methylene Blue rather than the Methylene Blue double salt of zinc, and the oxidant is added as a 20% solution.
Colombo’s synthesis of Methylene Blue, Example 5, matches to that of the instant claim 6, with the following differences:
Colombo adds disodium EDTA during the initial reduction/acylation step, whereas claim 6 precludes any use of a “sequestering agent”;
Applicant’s process adds the oxidant at slightly higher temperature (30-35°C rather than Colombo’s range of -5 to +20°C);
Adding a water solution of NaCl to the post-oxidation reaction mixture and stirring for 2-4 hours at room temperature prior to filtration and washing with diluted HCl;
Triturating the filtered/acid-washed oxidation product with iPrOH, filtering and washing with iPrOH;
Recrystallizing Methylene Blue product from a water solution of NaCl (rather than simply water as disclosed by Colombo).
While Colombo’s process for making Methylene Blue by the two-stage reduction/acylation and re-oxidation methodology differs from that of instant claim 6 in the above parameters, a person of ordinary skill in the art would have a reasonable expectation of success in modifying the process of Colombo in each/all of these manners without affecting the yield or processability of the product(s) because none of these changes are significant. A person of ordinary skill in the art would recognize that disodium EDTA is added in Colombo’s Example 1 because the starting material is Methylene blue double salt of zinc, and would expect that Colombo’s process could readily be conducted without addition of disodium EDTA, particularly when the initial starting material is Methylene Blue that is not the double salt of zinc, because Colombo discloses that EDTA is added to remove metals from the initial reduction/acylation of starting material when the starting material is Methylene Blue double salt of zinc (Col. 5, lines 43-51). A person of ordinary skill in the art would not expect a difference of 10-15°C in oxidation reaction temperature, from Colombo’s upper temperature of 20°C to Applicant’s claimed range of 30-35°C, to adversely or favorably affect the reaction outcome, particularly when the temperature remains well below the boiling point of the reaction solvent (water) and none of the reactants are volatile. A person of ordinary skill in the art would not expect any adverse effect or advantage in the yield or processability of the reaction in adding a saline solution to the post-oxidation reaction mixture rather than Colombo’s step of adding simply water, as the desired product is insoluble in water already, and is not made soluble by the presence of NaCl in the water, therefore there is no difference in the outcome from such a change. A person of ordinary skill in the art would not expect any adverse effect or advantage in the yield or processability by treating the post-oxidation Methylene Blue product with iPrOH rather than 0.1 N aq HCl, because Methylene Blue (hydrate) is not significantly soluble in either of these solvents at room temperature. A person of ordinary skill in the art would not expect any adverse effect or advantage in the yield or processability by recrystallizing Methylene Blue in saline solution compared to water or acidified water, because a person of ordinary skill in the art would at once recognize that adding a low concentration of NaCl would not render Methylene Blue insoluble in water, as the solubility of Methylene Blue is an inherent property of the compound and is well known in the art – see, for example, the teaching of Samiey (Samiey, B., and Ashoori, F.; Chemistry Central Journal, v6, article 14, pp1-13; 2012), who teaches a study in the adsorption of Methylene Blue from solution onto agar surface, and teaches that Methylene Blue is soluble in aq NaCl (0.14 mM solutions prepared– see page 3) in solutions of 0.03 M and 0.1 M NaCl (page 6) and that “solubility of [Methylene Blue] decreases at higher NaCl concentration” (page 6). Finally, a person of ordinary skill in the art would at once recognize that the product of the process of Colombo would be the same product with any and/or all of the changes listed above to the instantly claimed process of claim 6, and thus, the composition of claim 1 is inherently the product of the process of Colombo.
Applicant’s invention is unpatentable over the disclosure of Colombo, because a person of ordinary skill in the art would have a reasonable expectation of success in modifying the method of Colombo in the manners that differentiate the instant process of claim 6 from Colombo’s method, including using a slightly higher temperature (10-15°C difference) in the oxidation reaction, washing the oxidation product with saline solution instead of mild acid, triturating the post-oxidation product with iPrOH instead of stirring in 0.1 N HCl, and recrystallizing in NaCl aqueous solution instead of in water or acidified water, because a person of ordinary skill in the art would not expect any adverse or advantageous effect from any of these mild changes in process, and because the product of this process is the same product with or without the modifications listed above.
Thus, the invention was prima facie obvious at the time of filing.
Claims 2-4 further limit the composition of claim 1 with regard to properties that are inherent to the process used to make the compound, namely absence of impurities, including the alleged impurity N-nitroso-Azure B (see 112(b) section above), N-nitrosamines, and potentially genotoxic compounds. As the composition of claim 1 is disclosed by the instant Specification to be the product of the process disclosed therein, and the process of Colombo is equivalent to the instant process, the limitations of claims 2-4 are met by the rejection above. Apparently, Applicant has discovered a new property or advantage of the composition(s) and/or method(s) that were already anticipated the disclosure of Colombo. MPEP 2112 I. states: “[T]he discovery of a previously unappreciated property of a prior art composition, or of a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer.” Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of a new use, new function or unknown property which is inherently present in the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 433 (CCPA 1977).”
Claim 7 further limits claim 6 to wherein the reducing agent used in the initial reduction of crude Methylene Blue is selected from a Markush group that includes sodium dithionite. Colombo discloses the reduction of Methylene Blue double salt of zinc with sodium dithionite in “Example 1” (Col. 7, lines 24-39).
Claim 8 further limits claim 6 to wherein the oxidant used in the oxidation step is TEMPOL, and is met by the reduction above.
Applicant’s invention is unpatentable over the disclosure of Colombo, because a person of ordinary skill in the art, at the effective time of filing, would have a reasonable expectation of success in modifying the process of Colombo of preparing high purity Methylene Blue with the mild changes evident in the instant application, because a person of ordinary skill in the art would not expect any adverse effect or advantage in any of the mild differences between the process of instant claim 6 and the process of Colombo, and because the product of the equivalent processes is the same product.
Thus, the invention was prima facie obvious at the time of filing.
Double Patenting – Maintained
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.
The prior rejection of claims 1-4 and 6-8 on the ground of nonstatutory double patenting as being unpatentable over claims 1-2, 6-7 and 9-10 of U.S. Patent No. 10,723,710 B2 (hereafter referred to as “Colombo”), is maintained. Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of Colombo describe all the critical aspects of the instant process.
Applicant has traversed the rejection on the grounds that Colombo does not teach how to obtain a composition of Methylene Blue that is free of the impurity N-nitroso-Azure B, and the skilled person would have had no reason for modifying the teaching of Colombo to arrive at the presently claimed invention. Applicant’s traverse has been considered, but is not found persuasive, because, for the following reasons:
as noted in the 112(a) rejection above, Applicant has provided no evidence that the impurity N-nitroso-Azure B is a confirmed chemical species ever directly synthesized or isolated prior to the filing date of the instant application, therefore the claim limitation of comprising a unknown and unproven compound is not further limiting to a claim of a composition comprising Methylene Blue;
the composition of claim 1 is interpreted as the product of the method of claim 6 because the same method is disclosed in the instant Specification as being the method that produces such a composition of Methylene Blue;
a person of ordinary skill in the art would have a reasonable expectation of success in producing Methylene Blue by modifying the process of Colombo in each/all of the manners by which the method of instant claim 6 differs from the method of Colombo without affecting the yield or processability of the product(s) because none of these changes are significant.
Reiterated Rejection:
The limitations of instant claims 1-4 and 6-8 and the disclosure of Colombo are discussed in the rejection above and hereby incorporated into the instant rejection.
Colombo’s claim 1 is drawn to a process for the preparation of diaminophenothiazinium compounds of formula A, a formula that includes Methylene Blue in its scope, comprising the following steps:
providing a crude diaminophenothiazinium compound of “formula A”, with substituents and limitations that include Methylene Blue within the scope:
PNG
media_image4.png
210
484
media_image4.png
Greyscale
;
synthesizing a compound of “formula B”, wherein the compound of formula B represents a reduced and N-protected derivative of the diaminophenothiazinium compound, wherein the N-protecting group is selected from a Markush group that includes benzoyl:
PNG
media_image5.png
218
438
media_image5.png
Greyscale
;
oxidizing the compound of formula B with a stable free radical agent, selected from a Markush group that includes 4-hydroxyTEMPO (i.e., “TEMPOL”), to obtain again a diaminophenothiazinium compound of formula A.
Colombo’s claim 2 further limits claim 1 to wherein the starting material is crude Methylene Blue, Methylene Blue zinc double salt or a mixture thereof.
Colombo’s claim 6 further limits claim 1 to wherein the stable free radical agent (oxidant) is selected from a small (3-member) Markush group that includes TEMPOL. Claim 7 further limits claim 6 to wherein the stable free radical agent is TEMPOL.
Colombo’s claim 9 further limits claim 1 to wherein the product of step 3 of the process of claim 1 is recovered from the reaction mixture by precipitation and washing.
Colombo’s claim 10 further limits claim 1 to wherein the stable free radical agent is added as an aqueous solution, preferably comprising 10-50% by weight of stable free radical agent.
The differences between the process claimed by Colombo and the process of instant claim 6 are as follows:
Applicant’s claimed process requires specific temperatures, reaction/processing times, specific solvents and specific workup/purification steps, all of which are within the scope of the process claimed by Colombo;
Applicant’s claimed process requires recrystallizing Methylene Blue product from a water solution of NaCl.
The claims of Colombo are not patentably distinct from the process of instant claim 6 because the specific temperatures, times, solvents and workup/purification steps are in scope of the process claimed by Colombo and are not critical to the process claimed by Colombo and a person of ordinary skill in the art would have a reasonable expectation of success in modifying the process of Colombo to include any/all of these specific parameters, and because recrystallization of Methylene Blue would be an obvious purification step as recrystallization is well known in the art and has been recommended, including by Colombo (Col. 5, lines 54-58).
Conclusion
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 W. JUSTIN YOUNGBLOOD whose telephone number is (703)756-5979. The examiner can normally be reached on Monday-Thursday from 8am to 5pm. The examiner can also be reached on alternate Fridays.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey S. Lundgren, can be reached at telephone number (571) 272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center to authorized users only. Should you have questions about access to the USPTO patent electronic filing system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via a variety of formats. See MPEP § 713.01. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/InterviewPractice.
/W.J.Y./Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
1 Cited in Applicant’s Specification, page 2, line 14, and in Applicant’s Information Disclosure Statement dated 03/26/2024)
2 3-(Dimethylamino)-7-(methyl (nitroso)amino)phenothiazin-5-ium
3 Cited in Specification on page 2, line 14, and cited in Applicant’s Information Disclosure Statement dated 03/26/2026.
4 3,7-bis(dimethylamino)-5-phenothiazinium chloride
5 Cited in Applicant’s Information Disclosure Statement dated 03/26/2024.
Prosecution Insights