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 .
Applicant states that this application is a continuation application of the prior-filed application. A continuation application cannot include new matter. Applicant is required to delete the benefit claim or change the relationship (continuation) to continuation-in-part because this application contains the following matter not disclosed in the prior-filed application: In claims 35, 37 and 42, applicant recite “a buffer system comprising cyclodextrin”. The term “a buffer system” constitutes a new matter not supported by the parent application, 15/734,147 (the term is also not supported by any of the provisional applications).
Claim Objections
Claims 39 and 46 are objected to because of the following informalities: on the last lines of claims 39 and 46, applicant need to change “hydrochloric acid and orthophosphoric acid, or salt thereof.” to --- hydrochloric acid, orthophosphoric acid, and salt thereof. ---. Appropriate correction is required.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 35-40 and 42-47 are rejected under 35 U.S.C. 103 as being unpatentable over Back et al (US 2017/0360935 A1) in view of Phillips et al (5,298,410), Pitha (4,727,064), Bodor (4,983,586) and Redenti et al (“Drug/Cyclodextrin/Hydroxy Acid Multicomponent Systems. Properties and Pharmaceutical Application”, Mini-Review, Journal of Pharmaceutical Sciences, Vol.89(1) (2000), pg.1-8).
In its claim 1, Back teaches a pharmaceutical aqueous solution formulation comprising (i) 1-(4-{[4-(dimethylamino)piperidin-1-enyl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea (gedatolisib hereinafter) or its lactate salt, (ii) lactic acid (instant organic acid of claims 39, 40, 46 and 47) and (iii) water, wherein gedatolisib is present at a solution concentration of less than 6 mg/ml and sufficient lactic acid is present to provide a clear solution. Specifically, in its Example 2 ([0064]-[0067]; see also claim 19), Back teaches that such a pharmaceutical aqueous solution formulation was filled into 50 ml vials and then freeze-dried to form a lyophilized white solid. Back teaches ([0027]) that such (lyophilized) formulation is chemically stable on storage preferably for 2 years. Back further teaches (Example 3 in [0068]-[0069], claim 22, [0080]) that the vials of lyophilized solid composition obtained from its Example 2 were reconstituted with water to form a clear, colorless solution suitable for parenteral or intravenous administration.
As to instant buffer system comprising cyclodextrin, Back does not teach the use of such component. However, as evidenced by Phillips et al (col.3, lines 12-15, col.5, lines 6-11), it is already known in the art that cyclodextrins (such as -, -and -cyclodextrins) possess drug-solubilizing properties due to its ability to form inclusion complexes with the drug. Pitha teaches (abstract, col.2, lines 37-45) that the addition of a cyclodextrin-based mixture of -, -and -cyclodextrins to a pharmaceutical composition containing a drug with low water solubility improves the dissolution properties of the drug and thus its absorption by the body. Pitha furthermore teaches (col.2, lines 50-55) that such cyclodextrin-based mixture has very low toxicity when applied parenterally, and thus it is well suited as additives for parenteral preparations. Bodor teaches (abstract) that adding hydroxypropyl--cyclodextrin to an aqueous parenteral solutions of drugs which are sparingly soluble in water (and/or which are unstable in water) reduces problems of drug precipitation at the injection site following parenteral administration. Furthermore, Redenti teaches (pg.1, right-hand column, last three lines – pg.2, left-hand column, first seven lines) that although one of the most important application of cyclodextrins (CDs) is the possibility of increasing the aqueous solubility of sparingly soluble drugs, natural CDs are generally not very soluble in water because of the relatively strong binding of the molecules in the crystal state. Redenti, however, teaches (abstract, pg.2, right-hand column, 1st full paragraph and pg.3, right-hand column, 2nd full paragraph) multicomponent complexes made of a sparingly water-soluble amino-type drug, a cyclodextrin (such as -cyclodextrin, -cyclodextrin, -cyclodextrin, hydroxypropyl--cyclodextrin and sulfobutylether--cyclodextrin) and a hydroxy carboxylic acid (such as citric, malic, lactic or tartaric acid) where simultaneous complexation and salt formation with theses acids enhance the aqueous solubility of the hydrophobic drug by several orders of magnitude, while the aqueous solubility of CDs can be enhanced more than 10-fold. Based on the teachings of Phillips, Pitha, Bodor and Redenti, it would have been obvious to one skilled in the art to add cyclodextrins, such as -cyclodextrin, hydroxypropyl--cyclodextrin and/or sulfobutylether--cyclodextrin (SBECD), to Back’s pharmaceutical aqueous solution formulation comprising gedatolisib (an amino-type drug which is insufficiently soluble in water – see [0006] in Back) or its lactate salt (or its phosphate salt), lactic acid and water, with a reasonable expectation of enhancing the aqueous solubility of gedatolisib (by at least several orders of magnitude) and thus increasing its absorption by the body and reducing the problems of drug precipitation at the injection site following parenteral administration. Since Back in view of Phillips, Pitha, Bodor and Redenti teaches the use of instant cyclodextrin and instant lactic acid, the prior art teaches instant buffer system of claims 35 and 37.
As to instant solution concentration of gedatolisib (at least 6 mg/ml), as shown above, the solution concentration of gedatolisib in Back’s pharmaceutical aqueous solution formulation comprising gedatolisib or its lactate salt and lactic acid is less than 6 mg/ml. However, when cyclodextrins, such as -cyclodextrin, hydroxypropyl--cyclodextrin and/or sulfobutylether--cyclodextrin, are added (according to the teachings of Phillips, Pitha, Bodor and Redenti) to Back’s pharmaceutical aqueous solution formulations, it is the Examiner’s position that the solution concentration of gedatolisib in the formulation would be at least 6 mg/ml because Back already teaches (see claim 4) that the solution concentration of its gedatolisib (without the cyclodextrins) can be 2.5-5.5 mg/ml (when lactic acid is used) and because (i) the secondary prior arts cited above all indicate that addition of the cyclodextrins would increase the aqueous solubility of the drug due to their ability to form inclusion complexes with the drug and (ii) Redenti especially teaches that multicomponent complexes made of a sparingly water-soluble amino-type drug (Back’s gedatolisib is an insufficiently water-soluble amino-type drug), a cyclodextrin (such as -cyclodextrin, hydroxypropyl--cyclodextrin and sulfobutylether--cyclodextrin) and a hydroxy carboxylic acid (such as lactic acid) would enhance the aqueous solubility of the hydrophobic drug by several orders of magnitude (i.e., at least by 10-fold), which would give the solution concentration of gedatolisib to be at least about 25-55 mg/ml when lactic acid is used. Thus, Back in view of Phillips, Pitha, Bodor and Redenti teaches instant solution concentration (at least 6 mg/ml) of gedatolisib (when lactic acid is present) as claimed in claim 35.
As to instant limitation “a clear solution without chromonic liquid crystal formulation”, applicant state (see pg.4, lines 25-28 of present specification) that any opalescent hue may be caused by chromonic liquid crystal formation (pi-pi stacked aromatic sections of a molecule forming columns like stacks of dimers, trimers and low molecular weight oligomers) and further state (pg.7, lines 7-9) that by use of a pharmaceutically acceptable beta- or gamma-cyclodextrin it has been found that clear solutions may be achieved with no opalescence. Since Back in view of Phillips, Pitha, Bodor and Redenti teaches the use of -cyclodextrin, hydroxypropyl--cyclodextrin and/or sulfobutylether--cyclodextrin in Back’s pharmaceutical aqueous formulation, the result will be a clear solution without chromonic liquid crystal formulation (besides, Back’s aim is also to obtain a pharmaceutical aqueous formulation comprising gedatolisib that is a clear solution particularly suitable for intravenous or parenteral administration. Back also teaches (claim 1) that lactic acid is present in an amount sufficient to ensure that a clear solution is formed).
Thus, Back in view of Phillips, Pitha, Bodor and Redenti renders obvious instant claims 35-40 and 42-47 (Back’s lyophilized formulation of gedatolisib (as modified by the teachings of Phillips, Pitha, Bodor and Redenti to contain -cyclodextrin, hydroxypropyl--cyclodextrin and/or sulfobutylether--cyclodextrin), when reconstituted with water, teaches instant stable aqueous pharmaceutical formulation of claim 42).
Claim(s) 41 and 48 are rejected under 35 U.S.C. 103 as being unpatentable over Back et al (US 2017/0360935 A1) in view of Phillips et al (5,298,410), Pitha (4,727,064), Bodor (4,983,586) and Redenti et al (“Drug/Cyclodextrin/Hydroxy Acid Multicomponent Systems. Properties and Pharmaceutical Application”, Mini-Review, Journal of Pharmaceutical Sciences, Vol.89(1) (2000), pg.1-8) as applied to claims 35 and 42, respectively, and further in view of Carson et al (US 2013/0085280 A1).
With respect to instant claims 41 and 48, the Examiner established above that since Back in view of Phillips, Pitha, Bodor and Redenti teaches the use of -cyclodextrin, hydroxypropyl--cyclodextrin and/or sulfobutylether--cyclodextrin in Back’s pharmaceutical aqueous formulation, the result will be a clear solution without chromonic liquid crystal formulation. Furthermore, as evidenced by Carson ([0338]), it is known in the art that Polarized Optical Microscopy is used to confirm the formation of chromonic liquid crystalline phases. Thus, Back in view of Phillips, Pitha, Bodor and Redenti, and further in view of Carson renders obvious instant claims 41 and 48.
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 35-38, 41-45 and 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 8, 23 and 25 of U.S. Patent No. 11,541,058 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reason:
Claims 1, 7 and 8 of Pat.’058 teach a pharmaceutical aqueous solution formulation comprising (i) 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea (instant gedatolisib), (ii) methanesulfonic acid (instant organic acid), (iii) hydroxypropyl-b-cyclodextrin, sulphobutylether-b-cyclodextrin or gamma-cyclodextrin, and (iv) water, wherein 1-(4-{[4-(dimethylamino)piperidin-1-yl]carbonyl}phenyl)-3-[4-(4,6-dimorpholin-4-yl-1,3,5-triazin-2-yl)phenyl]urea is present at a solution concentration of less than 35 mg/ml. Claim 23 of Pat.’058 teaches a lyophilized formulation obtainable by freeze-drying the formulation of its claim 1, and claim 25 of Pat.’058 teaches a pharmaceutical aqueous solution formulation obtainable as a clear solution by reconstitution of the lyophilized formulation of claim 23 using water. The solution concentration of less than 35 mg/ml overlaps with instant concentration range of at least 6 mg/ml, thus rendering instant range prima facie obvious. In the case “where the [claimed] ranges overlap or lie inside ranges disclosed by the prior art,” a prima facie case of obviousness would exist which may be overcome by a showing of unexpected results, In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Since claims of Pat.’058 teach the use of -cyclodextrin, hydroxypropyl--cyclodextrin and/or sulfobutylether--cyclodextrin in the aqueous solution formulation of gedatolisib, the result will be a clear solution without chromonic liquid crystal formulation (according to present specification, pg.4, lines 25-28 and pg.7, lines 7-9). Thus, claims 1, 7, 8, 23 and 25 of Pat.’058 render obvious instant claims 35-38, 41-45 and 48 (instant claims 41 and 48 simply describes how the chromonic liquid crystal formation is assessed. Since instant claims 41 and 48 are product claims, and since claims of Pat.’058 already teach or render obvious instant clear solution without chromonic liquid crystal formation, the claims of Pat.’058 also teach or render obvious instant claims 41 and 48).
Claims 42-45 and 48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2 and 4-7 of Pat.’803 of U.S. Patent No. 11,541,058 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reason:
Claims 1, 2 and 4-7 of Pat.’803 teach a clear aqueous solution formulation comprising instant gedatolisib, methanesulphonic acid (instant organic acid) and water, wherein the gedatolisib is present at a solution concentration of from 6 to 30 mg/ml, and further comprising cyclodextrin, such as hydroxypropyl-b-cyclodextrin, sulphobutylether-b-cyclodextrin or gamma-cyclodextrin. Thus, claims 1, 2 and 4-7 of Pat.’803 render obvious instant claims 42-45 and 48 (instant claim 48 simply describes how the chromonic liquid crystal formation is assessed. Since instant claim 48 is a product claim, and since claims of Pat.’803 already teach or render obvious instant clear solution without chromonic liquid crystal formation, the claims of Pat.’803 also teach or render obvious instant claim 48.
Claims 35-48 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 9, 16 and 17 of U.S. Patent No. 12,109,308 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because of the following reason:
Claims 1, 3 and 9 of Pat.’308 teach an aqueous formulation comprising instant gedatolisib, lactic acid, cyclodextrin such as 2-hydroxypropyl-beta-cyclodextrin, sulphobutylether-b-cyclodextrin or gamma-cyclodextrin and water, wherein the gedatolisib is present at a solution concentration of from 6 to 30 mg/ml and wherein sufficient lactic acid and cyclodextrin are present to provide a clear solution. Claims 16 and 17 of Pat.’308 teach a lyophilized formulation obtainable by freeze drying the aqueous formulation of claim 1 and an aqueous formulation obtainable as a clear solution by reconstitution of a lyophilized formulation of claim 16 using water. Thus, claims 1, 3, 9, 16 and 17 of Pat.’308 render obvious instant claims 35-48 (instant claims 41 and 48 simply describes how the chromonic liquid crystal formation is assessed. Since instant claims 41 and 48 are product claims, and since claims of Pat.’308 already teach or render obvious instant clear solution without chromonic liquid crystal formation, the claims of Pat.’308 also teach or render obvious instant claims 41 and 48).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SIN J. LEE whose telephone number is (571)272-1333. The examiner can normally be reached on M-F 9 am-5:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Kwon can be reached on 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SIN J LEE/
Primary Examiner, Art Unit 1613
June 27, 2023
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