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 .
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Status of Claims
Claims 1 – 30 are pending.
Claims 31 – 88 have been canceled.
Claims 9 – 11 and 24 – 27 are objected.
Claims 1 – 8, 12 – 23 and 28 – 30 are rejected.
Specification
The disclosure is objected to because of the following informalities: the body of the disclosure contains multiple formula structures. Certain of these structures contain lettering that was not reproducible in the published application (US 2025/0109158). Applicant is directed to the following publication page and paragraph:
page 11, [0098] formulas (V) – (IX);
page 21, [0145] synthesis scheme in the box;
page 22, [0151] General Reaction Scheme;
page 23, [0153] General Reaction Scheme;
page 25, top of page, General Reaction Scheme;
page 26, [0162] General Reaction Scheme;
page 27, [0166] General Reaction Scheme;
page 28, [0167] General Reaction Scheme;
page 29, [0172] General Reaction Scheme; and
page 32 [0215] formulas (V) – (VIII)
Appropriate correction is required.
The specification has not been checked to the extent necessary to determine thepresence of all possible minor errors, e.g., typographical, grammar, idiomatic, syntaxand etc. Applicants' cooperation is requested in correcting any errors of whichApplicant may become aware in the specification.
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.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1, 2, 3, 4, 6, 12, 13, 15, 18, 20, 21, 22 and 28 is/are rejected under 35 U.S.C. 102(a)(1) & (a)(2) as being anticipated by Slomczynska et al. (US 2004/0137638).
The rejected claims cover, inter alia, a process for preparing a pentaaza macrocyclic ring complex of formula (I)(a) or (I)(b) comprising: (A) in a cyclization stage reacting a tetraamine product of formula (III)(a)(i) or (III)(a)(ii) with a diacetyl pyridine compound of formula (III)(b) and a source of manganese (II) ion corresponding to Mn(X)(Y), in the presence of a tertiary amine base, to provide a cyclization stage product comprising bisimine compound of formula (II)(a) or (II)(b); and (B) in a reduction stage, performing a catalytic hydrogen reduction on the bisimine compound of formula (II)(a) or (II)(b) to form a reduction stage product comprising the pentaaza macrocyclic ring complex of formula (I)(a) or (I)(b).
In the process X and Y are independently neutral or negatively charged ligands.
However, Slomczynska discloses the synthesis of M40403 isomers in Part A or Example 12 Scheme 7. According to Slomczynska The various stereoisomers of M40403 are synthesized from the various isomers of 1,2-diaminocyclohexane which provides the chiral carbon centers in M40403. The reaction process for M40403 of Slomczynska is set out below:
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In the above X and Y are Cl, the base is triethylamine (a tertiary amine base)
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 2, 3, 5, 7, 8, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 24, 28, 29 and 30 are rejected under 35 U.S.C. 103 as being unpatentable over Slomczynska et al. (US 2004/0137638) in view of Riley et al. (US 6,214,817) and further in view of Beardsley et al. (US 2019/0151331).
The rejected claims cover, inter alia, a process for preparing a pentaaza macrocyclic ring complex of formula (I)(a) or (I)(b) comprising: (A) in a cyclization stage reacting a tetraamine product of formula (III)(a)(i) or (III)(a)(ii) with a diacetyl pyridine compound of formula (III)(b) and a source of manganese (II) ion corresponding to Mn(X)(Y), in the presence of a tertiary amine base, to provide a cyclization stage product comprising bisimine compound of formula (II)(a) or (II)(b); and (B) in a reduction stage, performing a catalytic hydrogen reduction on the bisimine compound of formula (II)(a) or (II)(b) to form a reduction stage product comprising the pentaaza macrocyclic ring complex of formula (I)(a) or (I)(b).
Dependent clam 2 limits the bisimine. Dependent claim 3 further limits the product pentaaza macrocyclic ring complex. Dependent claims 5, 7 and 8 further limit the process. Dependent clams 12, 13, 14, 15, 16, 17, 18 and 19 further limit substituents R1- 5, X and Y. Dependent claims 21 - 23 further limits the source of Mn. Dependent claims 28 – 30 further limit the product pentaaza macrocyclic ring complex
However, Slomczynska discloses the synthesis of M40403 isomers in Part A or Example 12 Scheme 7 below:
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The difference between the instantly claimed invention and Slomczynska is as follows: the definitions for substituents R1 – 5, X and Y; timing of the reduction stage (claim 5); isolating of the bisimine compound and removing impurities from the bisimine product prior to the reduction stage (claims 7 – 8); and optical purity of the reactants and products of the cyclization stage that the reduction stage.
With regard to the definitions for R1 – 5, X and Y, the Examiner turns to the prior art teachings of Riley and Beardsley. The prior art of Riley discloses a process for preparing a pentaaza macrocyclic ring complex corresponding to the below structure. (col. 35 & 36). The prior art of Riley discloses substituted pyridino pentaaza macrocycle complexes as follows:
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, with examples of the complexes set out in the Table of compounds. wherein X, Y, and Z represent suitable ligands or charge-neutralizing anions which are derived from any monodentate or polydentate coordinating ligand or ligand system or the corresponding anion thereof (for example benzoic acid or benzoate anion, phenol or phenoxide anion, alcohol or alkoxide anion). X, Y, and Z may be independently selected from the group consisting of halide, oxo, aquo, hydroxo, alcohol, phenol, dioxygen, peroxo, hydroperoxo, alkylperoxo, arylperoxo, ammonia, alkylamino, arylamino, heterocycloalkyl amino, heterocycloaryl amino, amine oxides, hydrazine, alkyl hydrazine, aryl hydrazine, nitric oxide, cyanide, cyanate, thiocyanate, isocyanate, isothiocyanate, alkyl nitrile, aryl nitrile, alkyl isonitrile, aryl isonitrile, nitrate, nitrite, azido, alkyl sulfonic acid, aryl sulfonic acid, alkyl sulfoxide, aryl sulfoxide, alkyl aryl sulfoxide, alkyl sulfenic acid, aryl sulfenic acid, alkyl sulfinic acid, aryl sulfinic acid, alkyl thiol carboxylic acid, aryl thiol carboxylic acid, alkyl thiol thiocarboxylic acid, aryl thiol thiocarboxylic acid, alkyl carboxylic acid (such as acetic acid, trifluoroacetic acid, oxalic acid), aryl carboxylic acid (such as benzoic acid, phthalic acid), urea, alkyl urea, aryl urea, alkyl aryl urea, thiourea, alkyl thiourea, aryl thiourea, alkyl aryl thiourea, sulfate, sulfite, bisulfate, bisulfite, thiosulfate, thiosulfite, hydrosulfite, alkyl phosphine, aryl phosphine, alkyl phosphine oxide, aryl phosphine oxide, alkyl aryl phosphine oxide, alkyl phosphine sulfide, aryl phosphine sulfide, alkyl aryl phosphine sulfide, alkyl phosphonic acid, aryl phosphonic acid, alkyl phosphinic acid, aryl phosphinic acid, alkyl phosphinous acid, aryl phosphinous acid, phosphate, thiophosphate, phosphite, pyrophosphite, triphosphate, hydrogen phosphate, dihydrogen phosphate, alkyl guanidino, aryl guanidino, alkyl aryl guanidino, alkyl carbamate, aryl carbamate, alkyl aryl carbamate, alkyl thiocarbamate aryl thiocarbamate, alkyl aryl thiocarbamate, alkyl dithiocarbamate, aryl dithiocarbamate, alkyl aryl dithiocarbamate, bicarbonate, carbonate, perchlorate, chlorate, chlorite, hypochlorite, perbromate, bromate, bromite, hypobromite, tetrahalomanganate, tetrafluoroborate, hexafluorophosphate, hexafluoroantimonate, hypophosphite, iodate, periodate, metaborate, tetraaryl borate, tetra alkyl borate, tartrate, salicylate, succinate, citrate, lactate, gluconate, ascorbate, saccharinate, amino acid, hydroxamic acid, thiotosylate, and anions of ion exchange resins. The preferred ligands from which X, Y and Z are selected include halide, organic acid, nitrate and bicarbonate anions.
W is a substituted pyridine, and U and V are trans-cyclohexano fused rings. Preferred substituents on W are those which increase the potency of the catalyst for pharmaceutical applications. For instance, lipophilic substituents are preferred when the target of the catalyst is a hydrophobic tissue of the patient. In addition to altering the catalytic activity or log P and the concomitant targeting/pharmokinetic effects. These preferred substituents include cyclohexyl, hydroxyl alkyl thio, alkyl (2-thioacetic acid) esters, benzyloxy, methoxyarylthio, alkoxycarbonylarylthio, and aryl (2-thioacetic acid) esters. (col. 10).
The prior art of Beardsley discloses the following pentaaza macrocyclic ring complex
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. Wherein W, together with the nitrogen of the macrocycle and the carbon atoms of the macrocycle to which it is attached, forms an aromatic or alicyclic, substituted or unsubstituted, saturated, partially saturated or unsaturated nitrogen-containing fused heterocycle having 2 to 20 ring carbon atoms, provided that when W is a fused aromatic heterocycle the hydrogen attached to the nitrogen which is both part of the heterocycle and the macrocycle and R.sub.5 and R.sub.6 attached to the carbon atoms which are both part of the heterocycle and the macrocycle are absent. In the above formula X and Y are other than Cl, and falling with the defining of applicant’s claim 12. With each X1 is independently substituted or unsubstituted phenyl or —C(—X2)(—X3)(—X4); and ach X.2 is independently substituted or unsubstituted phenyl or alkyl. (page 10). Also, see the below:
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(page 11).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the instantly claimed invention to prepare a pentaaza macrocyclic ring complex of M40403 (corresponding to formula (I)(a) or (I)(b) of claim 1) by the method set out in Slomcyznska, in view the process of Riley, and wherein the tetra-amine precursor and the pyridine tetraamine reactant of Scheme can be defined like the corresponding compounds with the substituent definitions of Riley and Beardsley, it would be within the purview of one skill in the art, to conduct a reaction wherein the tetraamine of Slomcyznska can be substituted and the substituents of Mn are not limited to Cl and produce various derivatives for the pentaaza macrocyclic ring complex.
Therefore, all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art before the effective filing date of the instantly claimed invention. KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (U.S. 2007).
With regard to the timing of the reduction stage (claim 5), the Examiner turns to the teaching of Slomczynska. According to the reaction scheme the cyclization stage takes 3 hours; and the reduction reaction take place after the formation of the bisimine compound. Based on this known reaction time for cyclization, one skill in the art desiring the best outcome for process in the synthesis of various isomer of M40403, would have tested the cyclization reaction products at various levels to determine the effects that would have downstream in the reduction reaction on the end product, as a matter of routine optimization of the process. It is a settled principle of law that a mere carrying forward of an original patented conception involving only change of form, proportions, or degree, or the substitution of equivalents doing the same thing as the original invention, by substantially the same means, is not such an invention as will sustain a patent, even though the changes of the kind may produce better results than prior inventions.". (In re Williams, 36 F.2d 436, 438, 4 USPQ 237 (CCPA 1929)).
With regard to isolating of the bisimine compound and removing impurities from the bisimine product prior to the reduction stage (claims 7 – 8), the Examiner turns to the teaching of Slomczynska. The process of Slomczynska seeks to quantitate the complexes of their process. Thus, removal of impurities would be a routine matter in order to obtain a product of the greatest purity for analysis. These limitations are deemed to be obvious absent a showing of unexpected results.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35USC 103.
With regard to optical purity of the reactants and products of the cyclization stage and the reduction stage, the Examiner turns to the teaching of Slomczynska. The prior art of Slomczynska discloses the processes and makes compounds of the claimed invention. From the standpoint of patent law, a compound and all its properties are inseparable. (In re Papesch, 315 F.2d 381,391, 137 USPQ 43, 51 (CCPA 1963)).
It is noted that a prima facie case of obviousness has been established in that the reference discloses all the limitations of a claim except for the property and the examiner cannot determine whether or not the reference inherently possesses properties that renders obvious the claimed invention but has a basis for shifting the burden of proof to applicant, as per (In re Fitzgerald, 619 F.2d 67,205 USPQ 594 (CCPA 1980)). See also In re Best, Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. (In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977)).
Art Made of Record
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. US 5,610,293 (Riley et al.) discloses methods of preparing manganese complexes of nitrogen-containing macrocyclic ligands. Aston et al. (Inorganic Chemistry, 2001, 40(8), pp. 1779 – 1789), discloses computer-aided design (CAD) of Mn(II) complexes. Kelso et al. (Chemistry & Biology, 2012, 19(10), ppl 1237 – 1236), discloses a mitochondria-targeted macrocyclic Mn(II) superoxide dismutase mimetic. Basharat, et al. (Reviews in inorganic chemistry, 2017, 37(3-4), pp. 105 – 130).
Allowable Subject Matter
Claims 9 – 11 and 24 – 27 are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: None of the prior art of record teaches or suggest a motivation for removing sulfur impurities from a pentaaza macrocyclic ring complex of formula (I)(a) or (I)(b). Further, none of the prior art of record teaches or suggest a motivation for, wherein the compound of Formula (II)(a) or (II)(b) comprises X and Y corresponding to a first ligand moiety, and wherein the process further comprises the intermediate step of reacting the compound of Formula (II)(a) or (II)(b) with a source of a second ligand moiety to provide a compound of Formula (II)(a) or (II)(b) having X and Y corresponding to the second ligand moiety, prior to performing the reduction stage (B).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to YATE' K. CUTLIFF whose telephone number is (571)272-9067. The examiner can normally be reached Monday-Friday (8:30 - 5:30).
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Scarlett Y. Goon can be reached at (571) 270-5241. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/YATE' K CUTLIFF/Primary Examiner, Art Unit 1692
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