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 1-10 are pending.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 04/02/2024, is in compliance with the provisions of 37 CFR 1.97. Accordingly, each of the information disclosure statement is being considered by the examiner.
Priority
This application, filed on 04/02/2024, is a 371 of PCT/IN2022/050843, filed on 09/12/2022, which claims priority to IN Application No. 202111045217, filed on 10/05/2021. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
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 1-10 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 2-10 depend from claim 1, and are therefore, also rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for reasons set forth below.
As per MPEP 2173.02, “[d]uring prosecution, applicant has an opportunity and a duty to amend ambiguous claims to clearly and precisely define the metes and bounds of the claimed invention. The claim places the public on notice of the scope of the patentee’s right to exclude. See, e.g., Johnson & Johnston Assoc. Inc. v. R.E. Serv. Co., 285 F.3d 1046, 1052, 62 USPQ2d 1225, 1228 (Fed. Cir. 2002) (en banc).”
If the language of the claim is such that a person of ordinary skill in the art could not interpret the metes and bounds of the claim so as to understand how to avoid infringement, a rejection of the claim under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph, is appropriate. See Morton Int’l, Inc. v. Cardinal Chem. Co., 5 F.3d 1464, 1470, 28 USPQ2d 1190, 1195 (Fed. Cir. 1993).
Claim 1 recites the phrase “a substantially pure Nitazoxanide”, however, one skilled in the art cannot reasonably determine the meets and bounds of this limitation in the claims. The term “substantially pure”, is a relative term which renders the claims indefinite because it is unclear to one skilled in the art as to the degree of purity that is considered as “substantially pure”, and the degree of purity that is not considered as “substantially pure”. The phrase “substantially pure”, is not defined by the claim and the specification does not provide a standard for ascertaining the requisite degree. Thus, one of ordinary skill in the art would not be able to draw a clear boundary between what is and is not covered by the claims. For the purpose of examination, any degree of nitazoxanide purity is included in the interpretation of “a substantially pure Nitazoxanide”. Appropriate correction is required.
Claim 10 is rendered indefinite for a requiring step d) and step e) to performed together. One skilled in the art cannot reasonably determine the meets and bounds of this limitation in the claim. Claim 10 depends from claim 1, which requires step e) to be optional.
This lack of clarity makes it impossible to ascertain with reasonable precision when that claim is infringed and when it is not. Lacking such clarity, the skilled artisan would not be reasonably apprised of the metes and bounds of the subject matter for which Applicants seek patent protection. Rather, a subjective interpretation of the claimed language would be required. However, as such is deemed inconsistent with the tenor and express language of 35 U.S.C. § 112, second paragraph, the claims are deemed properly rejected.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1 and 10 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Huang et al (hereinafter “Huang”, CN101007792A, published 08/01/2007, Machine Translation).
By way of a background, Applicants’ invention (see, e.g., ¶s 00010-00012 and 00021 and Examples 1-2 of the specification), is directed towards a method for preparing nitazoxanide (NTZ):
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, comprising the steps of reacting either 2-acetoxybenzoic acid:
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or 2-acetoxybenzoyl chloride:
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, with 2-amino-5-nitrothiazole:
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, wherein the 2-amino-5-nitrothiazole is prepared from readily available starting materials.
Under the broadest reasonable interpretation (BRI), consistent with the specification, independent claim 1 is being interpreted as a process for preparing NTZ comprising the steps of:
d) reacting 2-acetoxybenzoic acid with 2-amino-5-nitrothiazole to obtain NTZ, i.e.,
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; or
e) converting 2-acetoxybenzoic acid to 2-acetoxybenzoyl chloride, which is then reacted with 2-amino-5-nitrothiazole to obtain NTZ, i.e.,
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,
wherein, the step of preparing the 2-amino-5-nitrothiazole comprises:
a) reacting dimethylformamide-dimethylacetal with nitromethane to obtain N,N-dimethyl-2-nitroethenamine, i.e.,
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;
b) bromination of N,N-dimethyl-2-nitroethenamine to obtain 2-bromo-N,N-dimethyl-2-nitroethenamine, i.e.,
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; and
c) reacting 2-bromo-N,N-dimethyl-2-nitroethenamine with thiourea to obtain 2-amino-5-nitrothiazole, i.e.,
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.
Similar to the Applicants’ invention (see discussions above), Huang (see, e.g., ¶s 0011-00113), teaches a method comprising reacting 2-acetoxybenzoic acid with 2-amino-5-nitrothiazole in the presence of DCC, acetone and triethylamine to obtain NTZ with a purity of 98-99%. The 2-amino-5-nitrothiazole of Huang is identical to the 2-amino-5-nitrothiazole prepared from starting materials in steps a-c. Therefore, claim 1 is anticipated by Huang.
Regarding claim 10, Huang teaches precipitation without column chromatography (see ¶ 00113).
Claims 1 and 7-8 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Pullaguria et al (hereinafter “Pullaguria”, IN201841040410A, published 05/01/2020).
Similar to the Applicants’ invention (see discussions above), Pullaguria (see Examples 2-5), teaches a method comprising:
i) reacting 2-acetoxybenzoic acid with a reagent (oxalyl chloride) in an organic solvent (DCM) to obtain 2-acetoxybenzoyl chloride (see Example 2);
ii) reacting 2-acetoxybenzoyl chloride with 2-amino-5-nitrothiazole in the presence of THF and TEA, to obtain NTZ with a purity of 99.95-99.99% (see Examples 3-5). The 2-amino-5-nitrothiazole of Pullaguria is identical to the 2-amino-5-nitrothiazole prepared from starting materials in steps a-c. Therefore, claim 1 is anticipated by Pullaguria.
Regarding claim 7, Pullaguria teaches oxalyl chloride (see discussions above).
Regarding claim 8, Pullaguria teaches DCM (see discussions above).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-3, 5-8 and 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Jeankumar et al (hereinafter “Jeankumar”, Bioorg. Med. Chem. Lett., 2012, 22, 7414-7417) in view of: 1) Pullaguria (IN201841040410A, published 05/01/2020); 2) Huang (CN101007792A, published 08/01/2007, Machine Translation); 3) Ran et al (hereinafter “Ran”, CN111454231A, published 07/28/2020, Machine Translation); and 4) Astle et al (hereinafter “Astle”, U.S. Patent No. 2,725,383, issued 11/29/1955).
By way of a background, Applicants’ invention (see, e.g., ¶s 00010-00012 and 00021 of the specification and Examples 1-2), is directed towards a method for preparing nitazoxanide (NTZ):
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, comprising the steps of reacting either 2-acetoxybenzoic acid:
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or 2-acetoxybenzoyl chloride:
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, with 2-amino-5-nitrothiazole:
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, wherein the 2-amino-5-nitrothiazole is prepared from readily available starting materials.
Under the broadest reasonable interpretation (BRI), consistent with the specification, independent claim 1 is being interpreted as a process for preparing NTZ comprising the steps of:
d) reacting 2-acetoxybenzoic acid with 2-amino-5-nitrothiazole to obtain NTZ, i.e.,
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; or
e) converting 2-acetoxybenzoic acid to 2-acetoxybenzoyl chloride, which is then reacted with 2-amino-5-nitrothiazole to obtain NTZ, i.e.,
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,
wherein, the step of preparing the 2-amino-5-nitrothiazole comprises:
a) reacting dimethylformamide-dimethylacetal (DMF-DMA) with nitromethane to obtain N,N-dimethyl-2-nitroethenamine, i.e.,
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;
b) bromination of N,N-dimethyl-2-nitroethenamine to obtain 2-bromo-N,N-dimethyl-2-nitroethenamine, i.e.,;
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and
c) reacting 2-bromo-N,N-dimethyl-2-nitroethenamine with thiourea to obtain 2-amino-5-nitrothiazole, i.e.,
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.
Similar to Applicants’ invention (see discussions above), Jeankumar teaches a synthetic pathway for preparing NTZ and derivatives thereof (see page 7414, Figure 1-2, Schemes 1-2 and Table 1), comprising:
i) reacting 2-acetoxybenzoic acid with a reagent (oxalyl chloride) in an organic solvent (DM, DCM) to obtain 2-acetoxybenzoyl chloride (see Scheme 1bi); and
ii) reacting 2-acetoxybenzoyl chloride with 2-amino-5-nitrothiazole in the presence of DCM and DIPEA (a base), to obtain NTZ (see Scheme 1bii and Table 1),
wherein, the 2-amino-5-nitrothiazole prepared from nitromethane (see Scheme 2).
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Accordingly, at the time of the instant invention, a person skilled in the art would have envisaged a method for preparing NTZ from 2-acetoxybenzoyl chloride and 2-amino-5-nitrothiazole, wherein, the 2-amino-5-nitrothiazole prepared from nitromethane, in the disclosures of Jean Kumar.
Jeankumar differs from the claimed invention only insofar as Jeankumar is not explicit in teaching:
1) reacting 2-acetoxybenzoyl chloride with 2-amino-5-nitrothiazole in the presence of THF and TEA (a base), to obtain NTZ.
However, this aspect of the instant claims would have been obvious over Jeankumar because, similar to Jeankumar, Pullaguria (see Examples 2-5), teaches a method comprising:
i) reacting 2-acetoxybenzoic acid with a reagent (oxalyl chloride) in an organic solvent (DCM) to obtain 2-acetoxybenzoyl chloride (see Example 2);
ii) reacting 2-acetoxybenzoyl chloride with 2-amino-5-nitrothiazole in the presence of THF (an organic solvent) and TEA (a base), to obtain NTZ with a purity of 99.95-99.99% (see Examples 3-5).
2) reacting 2-acetoxybenzoic acid with 2-amino-5-nitrothiazole in the presence of DCC, acetone and triethylamine to obtain NTZ with a purity of 99.95-99.99%.
However, this aspect of the instant claims would have been obvious over Jeankumar because, similar to Jeankumar, Huang (see, e.g., ¶s 0011-00113), teaches a method comprising reacting 2-acetoxybenzoic acid with 2-amino-5-nitrothiazole in the presence of DCC, acetone and triethylamine to obtain NTZ with a purity of 98-99%.
3) a method for making 2-amino-5-nitrothiazole comprising specific steps a-c recited in instant claim 1.
However, this aspect of the instant claims would have been obvious over Jeankumar because, similar to Jeankumar, Ran teaches a method for making 2-amino-5-nitrothiazole (see ¶ 0008) comprising:
a) reacting DMF-DMA with nitromethane in solvent-free synthesis (neat), to obtain N,N-dimethyl-2-nitroethenamine (see ¶ 0010);
b-c) reacting N,N-dimethyl-2-nitroethenamine with bromine in an organic solvent (ethanol) to form 2-bromo- N,N-dimethyl-2-nitroethenamine, followed by addition of thiourea to form 2-amino-5-nitrothiazole (see ¶ 0011).
Although Ran is not explicit in employing an acid catalyst, this aspect of the instant claims would have been obvious over Jeankumar and Ran because, similar to Jeankumar and Ran, Astle teaches use of an acid catalyst in a cyclo addition reaction with thiourea for the synthesis of 2-aminothiazole compound (see columns 1-4 and Examples I-V).
Accordingly, at the time of the instant invention, one skilled in the art would have envisaged a method for preparing NTZ comprising the steps of reacting either 2-acetoxybenzoic acid: or 2-acetoxybenzoyl chloride, with 2-amino-5-nitrothiazole, wherein the 2-amino-5-nitrothiazole is prepared from the claimed starting materials, in the disclosures of Jeankumar, Pullaguria, Huang, Ran and Astle. Therefore, claim 1 is obvious over Jeankumar, Pullaguria, Huang, Ran and Astle.
Regarding claim 2, Ran teaches neat (see discussions above).
Regarding claim 3, Ran teaches bromine (see discussions above).
Regarding claim 5, Astle teaches that although it is preferred to use strong mineral acids (e.g., HCl), the catalyst employed may be any acid catalyst (see column 2, lines 55-63). Solvents such as DMF, DMSO, DMAc are well known solvents that have been routinely employed in the art of organic synthesis. As the selection of solvent would be within the knowledge of the person of ordinary skill in the art, there would be a reasonable expectation of success.
It is noted that no criticality has been demonstrated in the specification with regard to the selection of solvents for the synthesis of 2-amino-5-nitrothiazole from 2-bromo- N,N-dimethyl-2-nitroethenamine and thiourea.
Regarding claim 6, since Ran does not explicitly disclose the temperature at which the conversion of 2-bromo- N,N-dimethyl-2-nitroethenamine to 2-amino-5-nitrothiazole was carried out (see ¶ 0011), one skilled in the art would have reasonably assumed that the reaction was carried out at room temperature.
Regarding claim 7, Pullaguria teaches oxalyl chloride (see discussions above).
Regarding claim 8, Pullaguria teaches DCM (see discussions above).
Regarding claim 9, Ran teaches precipitation without column chromatography (see ¶s 0008 and 0010-0011).
Regarding claim 10, Huang teaches precipitation without column chromatography (see ¶ 00113), to the extent that step 1e) is optional.
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 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Thus, the claims fail to patentably distinguish over the state of the art as represented by the cited references.
Claims 1-8 and 9-10 are rejected under 35 U.S.C. 103 as being unpatentable over Jeankumar (Bioorg. Med. Chem. Lett., 2012) in view of: 1) Pullaguria (IN201841040410A, published 05/01/2020); 2) Huang (CN101007792A, published 08/01/2007, Machine Translation); 3) Ran (CN111454231A, published 07/28/2020, Machine Translation); and 4) Astle et al (hereinafter “Astle”, U.S. Patent No. 2,725,383, issued 11/29/1955) as applied to claims 1-3, 5-8 and 10 above, and further in view of Cheng et al (hereinafter “Cheng”, U.S. Patent No. 4,269,985, issued 05/26/1981).
The limitation of claims 1-3, 5-8 and 9-10 as well as the corresponding teachings of Jeankumar, Pullaguria, Huang, Ran and Astle are disclosed above, and are hereby incorporated into the instant rejections.
The invention of claim 4 is similar to claim 1, however, claim 4 differs slightly from claim 1 in that claim 4 requires that the organic solvent is selected from the group consisting of the list disclosed therein.
Jeankumar, Pullaguria, Huang, Ran and Astle differ from claim 4 only insofar as the cited references do not combine to explicitly teach a bromination solvent of claim 4.
However, this aspect of the claimed invention would have been obvious over Jeankumar, Pullaguria, Huang, Ran and Astle, because Cheng (see column 1, lines 52-65), teaches methanol, ethanol, THF, DCM and DCE among the organic solvents that can be employed in bromination reactions. Similar to Jeankumar and Ran (see discussions above), Cheng also teaches a method comprising reacting N,N-dimethyl-2-nitroethenamine with bromine in an organic solvent (ethanol) to form 2-bromo- N,N-dimethyl-2-nitroethenamine, followed by addition of thiourea to form 2-amino-5-nitrothiazole (see Examples 1-4). As the selection of solvent would be within the knowledge of the person of ordinary skill in the art, there would be a reasonable expectation of success.
It is noted that no criticality has been demonstrated in the specification with regard to the selection of solvents for bromination.
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 35 USC 103(a). From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Thus, the claims fail to patentably distinguish over the state of the art as represented by the cited references.
Conclusions
No claim is allowable.
If Applicants should amend the claims, a complete and responsive reply will clearly identify where support can be found in the disclosure for each amendment. Applicants should point to the page and line numbers of the application corresponding to each amendment, and provide any statements that might help to identify support for the claimed invention (e.g., if the amendment is not supported in ipsis verbis, clarification on the record may be helpful). Should the Applicants present new claims, Applicants should clearly identify where support can be found in the disclosure.
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Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to IBRAHIM D BORI whose telephone number is (571)270-7020. The examiner can normally be reached on Monday through Friday 8:00AM-5:00PM(EST).
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, JEFFREY S LUNDGREN can be reached on 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/IBRAHIM D BORI/
Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629
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