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 .
DETAILED ACTION
Claims 1-20 are pending in the instant application.
Claims 1-20 are examined herein.
Priority
The instant application claims benefit of foreign priority to IN202241027758, filed on 13 May 2022, and the benefit of priority to PCT/IB2023/054930, filed on 12 May 2023. The claims to the benefit of priority are acknowledged. As such, the effective filing date of the claims is 13 May 2022.
Information Disclosure Statement
The information disclosure statements (IDS), submitted on 01 November 2024 and 30 June 2025, are acknowledged and considered. The submissions are in compliance with the provisions of 37 CFR 1.97.
Claim Interpretation
Claim 1 recites the relative phrase “substantially free of 1-methyl-4-nitrosopiperazine (MeNP)” this phrase is defined on page 3 line 30 of the specification and therefore no 112(b) rejection has been made.
Claim 12 is directed to a compound; as such, the method of making does not alter the chemical structure(s) of composition and is therefore not further limiting. See MPEP 2113 I:
[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.
Claim 13 is directed to the compound of rifampicin. The chemical structure of rifampicin does not include MeNP and therefore the amount present is not further limiting. Should the claim be directed to a composition of rifampicin and MeNP then the amount of MeNP present would be limiting. Examiner suggests amending the claim to be directed to a composition comprising rifampicin and the byproduct, MeNP in an amount less than or equal to 0.16 ppm.
Claim Objections
Applicant is advised that should claim 12 be found allowable, claim 13 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m). The method of preparing the rifampicin of claim 12 is not limiting, and the MeNP is not a structural part of the claimed rifampicin of claim 13 and is therefore not limiting.
Claim Rejections - 35 USC § 112
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.
Claims 1-11 and 14-20 are rejected 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. 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.
See MPEP 2163 II. A. 3. (a) (ii) with regards to the requirements for descriptive support and for functional limitations of generically described entities:
“The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice (see i)(A) above), reduction to drawings (see i)(B) above), or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus (see i)(C) above). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406”
“A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.”
Claim 1 is directed to a method of preparing rifampicin comprising less than 0.16 ppm of MeNP. The process comprises several purification steps utilizing organic solvents, aqueous solutions, and antioxidants. The claim recites these broad genera of chemicals but provides an inadequate representative number of species in the demonstration of the claimed invention.
Examples 2 and 3 of the specification detail the purification process and both use the same solvents, aqueous solution, and antioxidants in the process. The crude rifampicin is dissolved in dichloromethane (DCM) and washed with acetic acid. Two antioxidants are added: butylhydroxytoluene and ascorbic acid. The DCM is distilled off, acetone is added and then distilled off, and then the product is recrystallized in acetone. The Applicant has failed to show that any organic solvent, aqueous solution, or antioxidant is interchangeable with another in the process.
The Applicant has also not related structure and function of the solvent within the claimed process. Solvent selection in purification is known in the art to be important. The solubility of the desired product must be balanced with the solubility profile of the impurities. The skilled artisan would be hesitant to believe any organic solvent would work in the claimed purification method. Rifampicin shows varying degrees of solubility in common organic solvents. While readily soluble in dimethylsulfoxide, dimethylformamide, chloroform, and ethyl acetate; rifampicin is sparingly soluble in methanol, acetone, and ethanol at room temperature (Sigma. Rifampicin Product Information Sheet. Page 1). Protic solvents are encompassed by claim 1 and yet rifampicin demonstrates limited solubility in protic solvents, suggesting these would not be solvents that could be used in the instant invention in the initial dissolution that is washed and left to cool to room temperature in the specification. This also suggests the aprotic solvent, acetone, could also not be used in this initial step as rifampicin precipitation would also be expected to occur as it cools. As the method requires washing with an aqueous solution, and not just water, water miscible organic solvents such as methanol, acetone, and ethanol, are not excluded from this step as an aqueous salt solution would lead to the desired separate organic and aqueous layers of claim 1.
Additionally, the Applicant does not seem to be in possession of the knowledge of going from steps c to f without additional dissolving and distilling steps with specific solvents as detailed in examples 2 and 3 of the specification. The specification recites distilling the organic solvent, as claimed, then dissolving the resulting residue in a different organic solvent and distilling again. There is no example provided where this additional dissolution and dissolving step is not present. Therefore, without a representative number of examples of the claimed invention, the skilled artisan is unable to determine whether this extra step is essential to the method or not, that is, if the process as claimed was carried out without the second distillation would the resulting rifampicin composition contain less than 0.16 ppm of MeNP.
The lack of structure-function correlation presented above also is a key factor within the absent dissolution and distilling steps. Solvent selection is paramount in a purification process. Ficklescherer et al. (AIChE J. 2021;67:e17169) stress that efficient recrystallizations must utilize a solvent in which the impurity has a high solubility in the solvent compared to the desired compound. In not presenting the structure-function correlation of the chosen solvents the skilled artisan is unable to determine the importance of the second dissolution and dissolving step. Is the first distillation or the second distillation required to selectively crystallize away from the antioxidant? Or are both needed? The same questions are presented regarding the main MeNP impurity. Does one step rid of the MeNP while another purifies out the antioxidant? The present written description is inadequate in determining if the process as claimed is possible, or if the additional steps supplied in the specification are essential to the process.
In Summary, failure to depict the claimed invention through a representative number of species or demonstration of structure and function suggests the applicant is not in the possession of the knowledge of which organic solvent, aqueous solution, or antioxidant leads to the reduction of the MeNP contaminant in the purified rifampicin, nor if it is possible to go from steps c to f without an additional dissolution and dissolving process.
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.
Claim 8 is 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.
The term “substantially” in claim 8 is a relative term which renders the claim indefinite. The term “substantially” 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 specification only defines the term substantially when referring to a composition substantially free of MeNP. A substantially nitrogen-saturated or argon-saturated atmosphere is not defined.
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.
Claim(s) 12 and 13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Sensi et. al (US3342810A).
Regarding claims 12 and 13 (as the compound rifampicin is the only limiting feature as described above), Sensi discloses 3-formyl-rifamycin SV derivatives of the following formula
PNG
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190
168
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where R is
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85
166
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(column 1 and column 3), which is the instant rifampicin. The MeNP byproduct is formed by the reaction of isoamyl nitrite and 1-amino-4-methylpiperazine. Sensi provides other oxidizing agents that would prevent this byproduct from forming (Example 1), and therefore the disclosed compound would have less than 0.16 ppm of MeNP.
Conclusion
Claims 1-20 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jerica K Wilson whose telephone number is (703)756-4690. The examiner can normally be reached Monday-Friday 9:00-5:00.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571)270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/J.K.W./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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