DETAILED ACTION
The Office Action is in response to the reply filed on October 24, 2024.
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 .
Priority
This Application filed on 10/24/2024 is a CON of 18/441,397 (ABN) filed on 02/14/2024 which is a CON of PAT 11931370 filed on 10/07/2022 which claims priority to INDIA 202141046000 filed on 10/08/2021.
Information Disclosure Statement
The information disclosure statement(s) (IDS) filed on 10/24/24 (2), is in compliance with the provisions of S7 CFR 1.97. Accordingly, the IDS is being considered by the Examiner.
The rejections are as below:
Claim Rejections - 35 USC § 103
The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-13 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Shaik et al. (US 20170143744 A1), as evidenced by Cremophor (Meyler's Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions (Fifteenth Edition), 2006).
Shaik et al. teaches a pharmaceutical formulation of cyclophosphamide comprising cyclophosphamide and at least one pharmaceutically acceptable excipient, wherein moisture content of the liquid formulation is less than about 2.0% by weight. Abstract and [0117] The reference teaches stability data with less than 0.49% impurities at 3 months [0366] [0369] . The reference shows the formulations are stable for 6 months. Sealed vials were charged on stability at 2-8° C. and 25° C./60% RH. (see i.e. Table 4 Example 3). The levels of impurity A in the formulation is less than about 1.5% by weight of label content of cyclophosphamide or its hydrate after storage at 2° C.-8° C. for at least 6 months. [0094] The reference teaches the use of non-aqueous solvents suitable for the formulations of the present invention include but not limited to alkyl alcohols, for example, ethanol/anhydrous ethanol/dehydrated alcohol/absolute alcohol, ethylene glycol, propylene glycol, butylene glycol, glycerin or glycerol, polysorbates, for example TWEEN 20, TWEEN 40, and TWEEN 80, and cyclodextrins (such as hydroxypropyl-.beta.-cyclodextrin), polyalkylene glycols, such as polyethylene glycol, polypropylene glycol, and polybutylene glycol, diemthyl acetamide, niacinamide, a diol such as a straight chain, branched or cyclic aliphatic diol, a triol such as straight chain, branched or cyclic aliphatic triol, a polyoxyethylene ether and a polyethylene glycol ether. [0306] The reference teaches stable liquid formulations of cyclophosphamide wherein excipient is at least one non-aqueous solvent selected from the group comprising ethanol, propylene glycol, polyethylene glycol, dimethyl acetamide, glycerol, polysorbate 80, polyethoxylated castor oil or combinations thereof. [0058] The liquid formulations of cyclophosphamide excipients are at least one non-aqueous solvent selected from the group comprising ethanol, propylene glycol, polyethylene glycol, dimethyl acetamide, glycerol, polysorbate 80, polyethoxylated castor oil or combinations thereof. [0208] The formulation is in a range between about pH 3 to about pH 9. [0253] The cyclophosphamide is at the pharmaceutically effective concentration in the range of about 0.1 mg/mL to about 5 g/mL [0217]. The ethanol is in the concentration of 10 to 100% by weight of the composition. [0162] The non-aqueous solvent system is combination of ethanol such as glycerol with ethanol or propylene glycol with ethanol or polyethylene glycol with ethanol or polysorbate with ethanol or cremophor with ethanol. [0163] Non aqueous solvent or combination of non-aqueous solvents are present in the formulation in a range from about 10 to 100% by weight. [0164] The formulations can be used as ready-to-use or ready-to-dilute compositions for oral or injections.
(Cremophor is a non-ionic solubilizer and emulsifier that is made by reacting ethylene oxide with castor oil (1). It is a pale yellow oily liquid consisting of a mixture of components, primarily polyethylene glycol conjugates. Fatty acid esters of polyethyleneglycol are also present, as well as hydrophilic polyethylene glycols and ethoxylated glycerol. Of note: Castor oil’s major fatty acid is the unsaturated, hydroxylated is ricinoleic acid).
While the reference teaches a non-aqueous lipid solvent which includes the claimed co-solvent combination, the reference fails to specify the co-solvent is in less than 10% by weight of the composition or the RC-A impurity of claim 2.
However, the prior art teaches the ethanol is in the concentration of 10 to 100% by weight of the composition. [0162] The non-aqueous solvent system is combination of ethanol such as glycerol with ethanol or propylene glycol with ethanol or polyethylene glycol with ethanol or polysorbate with ethanol or cremophor with ethanol. [0163] Non aqueous solvent or combination of non-aqueous solvents are present in the formulation in a range from about 10 to 100% by weight. [0164] The reference teaches stability data with less than 0.49% impurities at 3 months [0366] [0369] . The reference shows the formulations are stable for 6 months. Sealed vials were charged on stability at 2-8° C. and 25° C./60% RH. (see i.e. Table 4 Example 3). The levels of impurity A (Bis (2-Chloroethyl) amine hydrochloride ) in the formulation is less than about 1.5% by weight of label content of cyclophosphamide or its hydrate after storage at 2° C.-8° C. for at least 6 months. [0094]
It would have been obvious to one of ordinary skill in the art at the time of filing to use ethanol in 10% of the composition and has a RC-A impurity of less than about 1%w/w. The motivation to incorporate use ethanol in 10% of the composition and have a RC-A impurity of less than about 1%w/w is because the prior art teaches ethanol is in the concentration of 10 to 100% by weight of the composition. [0162]. Further, the levels of impurity A (Bis (2-Chloroethyl) amine hydrochloride ) in the formulation is less than about 1.5% by weight of label content of cyclophosphamide or its hydrate after storage at 2° C.-8° C. for at least 6 months. [0094]. Hence, a skilled artisan would have had reasonable expectation of successfully incorporating a vehicle such as glycerol monolinoleate to achieve liquid properties.
Relevant prior art:
Srivinivasan et al. (WO2017207719A1)
Shaik et al. (US10849916B2)
Shaik et al. (WO2016005962A2)
Double Patenting
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.
Claims 1-13 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 of U.S. Patent No. 11931370. Although the claims at issue are not identical, they are not patentably distinct from each other because the copending claims are drawn to table, ready-to-administer, liquid composition for oral administration comprising:(i) cyclophosphamide at a concentration of about 10 mg/ml;(ii) a non-aqueous lipid solvent is selected from a group consisting of phospholipids, medium-chain fatty acids, medium-chain fatty acid esters of glycerol, medium-chain fatty acid esters of polyethylene glycol, medium-chain fatty acid esters of propylene glycol, long-chain fatty acids, long-chain fatty acid esters of glycerol, long-chain fatty acid esters of polyethylene glycol, long-chain fatty acid esters of propylene glycol, or combinations thereof; and(iii) a co-solvent selected from ethanol and glycerin; wherein a concentration of the non-aqueous lipid solvent ranges from about 60% to 99% by weight of the composition; wherein a concentration of the co-solvent is less than 10% by weight of the composition; and wherein a level of total impurities in said liquid composition is less than 5% as determined by HPLC when stored at 2-8° C. for at least 3 months while the claims herein are generally drawn to a stable, ready-to-administer solution for oral administration comprising: (i) cyclophosphamide at a concentration of about 5 mg/ml to about 100 mg/ml; (il) a non-aqueous lipid solvent selected from phospholipids, medium- chain fatty acids, medium-chain fatty acid esters of glycerol, medium-chain fatty acid esters of polyethylene glycol, medium- chain fatty acid esters of propylene glycol, long-chain fatty acids, long-chain fatty acid esters of glycerol, long- chain fatty acid esters of polyethylene glycol, long-chain fatty acid esters of propylene glycol, or combinations thereof; and (ill) a co-solvent; wherein a concentration of the co-solvent is less than 10% by weight of the composition; and wherein a level of total impurities in said liquid composition is less than 5% as determined by HPLC when stored at 2-8° C for at least 3 months..
Conclusion
No claims allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Layla Soroush whose telephone number is (571)272-5008. The examiner can normally be reached on Monday through Friday from 8:30 a.m. to 5:00 p.m.
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/LAYLA SOROUSH/ Primary Examiner, Art Unit 1622
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