DETAILED ACTION
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 50-70 are pending and represent all claims currently under consideration.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 09/05/2025 has been entered.
Response to Arguments
Applicant's arguments regarding the rejection of claims 50-69 under 35 U.S.C. 103, filed 09/05/2025, have been fully considered but they are not persuasive.
Applicant argues that the claimed D50 range does not overlap with the range(s) disclosed in the prior art, because lot numbers 11122754 and 20140399 represent samples that were milled using conditions described by Brake and resulted in a dispersion with a D50 of 64 micrometers (Remarks, pages 6-7, point A). This argument is not persuasive, because the conditions of Brake cited by the Examiner include dispersions being screened through a 60 mesh (i.e., 250 micrometer as evidenced by Sigma Aldrich) screen in order to remove oversize material (Brake, page 12, paragraph 0154). In table 10 of the instant specification, lot number 11122754 uses milling conditions of a 500 micrometer screen at a milling speed 10,000 rpm (specification, page 37, table 10), which is a larger screen and a faster milling speed by 1,000 rpm (Brake, page 12, paragraph 0154) than the closest prior art previously cited. Further, it is not clear from the disclosure if a D50 for lot number 20140399 was measured, or what conditions from Brake were utilized.
Applicant argues that adjusting the D50 within the claimed range of 75-250 micrometers provides unexpected properties, namely an improved (i) dissolution profile and (ii) hardness profile (Remarks, pages 7-8, point B). This argument is not persuasive, because evidence of unexpected results must compare the claimed invention with the closest prior art. See MPEP 706.02(e)(III). The evidence regarding dissolution profile is comparing a dispersion with a D50 value of 45-75 micrometers with D50 values of 75-150 micrometers and 150-250 micrometers, not comparing the closest prior art, which as discussed previously would result in a dispersion with particle sizes of less than 250 micrometers and could potentially contain a mixture of particles from all three tested ranges, not limited to 45-75 micrometers as utilized in the comparative example. The comparative particles of size 45-75 micrometers show only about 10-40% dissolution within 60 minutes, while particles of size 75-150 micrometers show complete dissolution during the same time frame. Brake demonstrates a rapid dissolution of less than 10 minutes (Brake, page 4, paragraph 0055; page 14, paragraph 0198), suggesting the dissolution profile of the instant application is not unexpectedly greater and faster. Further, there is no comparison being made regarding the hardness profile and figure 7 appears to refer to a correlation between compression force applied and tablet hardness (specification, page 48, paragraph 0183).
Maintained 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 50-69 are rejected under 35 U.S.C. 103 as being unpatentable over Brake (US 20170173033 A1; IDS reference 09/06/2022), and as evidenced by Sigma Aldrich. The references were cited previously by the Examiner.
Regarding claim 50, Brake teaches a pharmaceutical composition comprising a solid dispersion, comprising one or more pharmaceutically acceptable excipients, (R)-2-(1-(6-amino-5-chloropyrimidine-4- carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyppyridin-2-yl)thiazole-5-carboxamide, and vinylpyrrolidinone-vinyl acetate copolymer (i.e., a polymer; Brake, claim 1), and exemplifies the dispersion contains about 30-50% of the carboxamide and 50-70% of the polymer (Brake, page 11, paragraph 0140), which lies within the claimed ranges of 10-70% and 30-90%, respectively. Brake does not specifically teach a D50 of about 75-250 micrometers for the solid dispersion, but does teach the dispersions can be screened through a suitable screen such as 60 mesh in order to remove oversize material (Brake, page 12, paragraph 0154). As evidenced by Sigma Aldrich, 60 mesh has a sieve opening of 250 micrometers, suggesting only particles of less than 250 micrometers will pass through the screen. A particle size of less than 250 micrometers overlaps the claimed range of 75-250 micrometers. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I).
Regarding claim 51, Brake teaches all the elements of the current invention as applied to claim 50. As above, Brake teaches vinylpyrrolidinone-vinyl acetate copolymer as the polymer (Brake, claim 1).
Regarding claim 52, Brake teaches all the elements of the current invention as applied to claim 51. Brake teaches the vinylpyrrolidinone-vinyl acetate copolymer is copovidone (Brake, page 4, paragraph 0058, “embodiment 14”).
Regarding claim 53, Brake teaches all the elements of the current invention as applied to claim 50. As above, Brake teaches vinylpyrrolidinone-vinyl acetate copolymer as the polymer (Brake, claim 1).
Regarding claim 54, Brake teaches all the elements of the current invention as applied to claim 50. As above, Brake teaches the dispersions can be screened through a suitable screen such as 60 mesh in order to remove oversize material (Brake, page 12, paragraph 0154). As evidenced by Sigma Aldrich, 60 mesh has a sieve opening of 250 micrometers, suggesting only particles of less than 250 micrometers will pass through the screen. A particle size of less than 250 micrometers overlaps the claimed range of 85-250 micrometers. It would have been prima facie obvious to one of ordinary skill in the art to optimize the particle size within the given range with a reasonable expectation for success using a particle size of 85-250 micrometers as claimed. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I).
Regarding claim 55, Brake teaches all the elements of the current invention as applied to claim 50. As above, Brake teaches the dispersions can be screened through a suitable screen such as 60 mesh in order to remove oversize material (Brake, page 12, paragraph 0154). As evidenced by Sigma Aldrich, 60 mesh has a sieve opening of 250 micrometers, suggesting only particles of less than 250 micrometers will pass through the screen. A particle size of less than 250 micrometers overlaps the claimed range of 95-150 micrometers. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I).
Regarding claim 56, Brake teaches all the elements of the current invention as applied to claim 50. Brake teaches (R)-2-(1-(6-amino-5-chloropyrimidine-4- carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyppyridin-2-yl)thiazole-5-carboxamide in 40% w/w (Brake, page 26, table A), which lies within the claimed range of 35-65%. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I).
Regarding claim 57, Brake teaches all the elements of the current invention as applied to claim 50. Brake further teaches pharmaceutically acceptable excipients comprising a filler, disintegrant, glidant and lubricant (Brake, page 4, paragraph 0045, “embodiment 2”).
Regarding claim 58, Brake teaches all the elements of the current invention as applied to claim 50. Brake teaches the filler comprises microcrystalline cellulose (Brake, page 7, paragraph 0098, “embodiment 52”) and teaches microcrystalline cellulose in an amount of 40-81% (Brake, page 7, paragraph 0099, “embodiment 53”), which lies within the claimed range of 40-90%. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I).
Regarding claim 59, Brake teaches all the elements of the current invention as applied to claim 50. Brake teaches the solid dispersion comprising the carboxamide is amorphous (Brake, page 5, paragraph 0059, “embodiment 15”).
Regarding claim 60, Brake teaches a process for the preparation of a pharmaceutical composition (Brake, page 2, paragraph 0014) comprising mixing of the carboxamide and copovidone (i.e., a vinylpyrrolidone-vinyl acetate copolymer) to give a powder mixture (Brake, page 11 paragraph 0152), followed by melt extrusion, milling, and blending with additional excipients (Brake, figure 1A). Brake further teaches the melt extrusion to be hot melt extrusion resulting in a solid dispersion extrudate (Brake, page 29, paragraph 0383) and the solid dispersion extrudate is milled and screened through a suitable screen such as 60 mesh in order to remove oversize material (Brake, page 12, paragraph 0154). As evidenced by Sigma Aldrich, 60 mesh has a sieve opening of 250 micrometers, suggesting only particles of less than 250 micrometers will pass through the screen. A particle size of less than 250 micrometers overlaps the claimed range of 75-250 micrometers. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I).
Regarding claim 61, Brake teaches all the elements of the current invention as applied to claim 60. As above, Brake teaches the vinylpyrrolidinone-vinyl acetate copolymer is copovidone (Brake, page 4, paragraph 0058, “embodiment 14”).
Regarding claim 62, Brake teaches all the elements of the current invention as applied to claim 60. As above, Brake teaches the dispersions can be screened through a suitable screen such as 60 mesh in order to remove oversize material (Brake, page 12, paragraph 0154). As evidenced by Sigma Aldrich, 60 mesh has a sieve opening of 250 micrometers, suggesting only particles of less than 250 micrometers will pass through the screen. A particle size of less than 250 micrometers overlaps the claimed range of 85-250 micrometers. It would have been prima facie obvious to one of ordinary skill in the art to optimize the particle size within the given range with a reasonable expectation for success using a particle size of 85-250 micrometers as claimed. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I).
Regarding claim 63, Brake teaches all the elements of the current invention as applied to claim 60. As above, Brake teaches the dispersions can be screened through a suitable screen such as 60 mesh in order to remove oversize material (Brake, page 12, paragraph 0154). As evidenced by Sigma Aldrich, 60 mesh has a sieve opening of 250 micrometers, suggesting only particles of less than 250 micrometers will pass through the screen. A particle size of less than 250 micrometers overlaps the claimed range of 95-150 micrometers. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I).
Regarding claim 64, Brake teaches all the elements of the current invention as applied to claim 60. As above, Brake teaches (R)-2-(1-(6-amino-5-chloropyrimidine-4- carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyppyridin-2-yl)thiazole-5-carboxamide in 40% w/w (Brake, page 26, table A), which lies within the claimed range of 35-65%. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I).
Regarding claim 65, Brake teaches all the elements of the current invention as applied to claim 60. As above, Brake further teaches pharmaceutically acceptable excipients comprising a filler, disintegrant, glidant and lubricant (Brake, page 4, paragraph 0045, “embodiment 2”).
Regarding claim 66, Brake teaches a method of treatment of cancer in a patient comprising administering an effective amount of the pharmaceutical composition (Brake, claim 20) comprising one or more pharmaceutically acceptable excipients, (R)-2-(1-(6-amino-5-chloropyrimidine-4- carboxamido)ethyl)-N-(5-chloro-4-(trifluoromethyppyridin-2-yl)thiazole-5-carboxamide, and vinylpyrrolidinone-vinyl acetate copolymer (i.e., a polymer; Brake, claim 1), and exemplifies the dispersion contains about 30-50% of the carboxamide and 50-70% of the polymer (Brake, page 11, paragraph 0140), which lies within the claimed ranges of 10-70% and 30-90%, respectively. Brake does not specifically teach a D50 of about 75-250 micrometers for the solid dispersion, but does teach the dispersions can be screened through a suitable screen such as 60 mesh in order to remove oversize material (Brake, page 12, paragraph 0154). As evidenced by Sigma Aldrich, 60 mesh has a sieve opening of 250 micrometers, suggesting only particles of less than 250 micrometers will pass through the screen. A particle size of less than 250 micrometers overlaps the claimed range of 75-250 micrometers. In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. See MPEP § 2144.05(I).
Regarding claim 67, Brake teaches all the elements of the current invention as applied to claim 66. Brake further teaches the cancer has one or more mutations in BRAF and/or NRAS (Brake, claim 22).
Regarding claim 68, Brake teaches all the elements of the current invention as applied to claim 66. Brake further teaches the cancer has a V600 BRAF mutation (Brake, claim 23).
Regarding claim 69, Brake teaches all the elements of the current invention as applied to claim 66. Brake further teaches the cancer is skin, ocular, gastrointestinal, thyroid, breast, ovarian, lung, brain, laryngeal, cervical, lymphatic, genitourinary, or bone cancer (Brake, claim 26).
New Claim Rejections - 35 USC § 103
Claim 70 is rejected under 35 U.S.C. 103 as being unpatentable over Brake (US 20170173033 A1; IDS reference 09/06/2022). The reference was cited previously by the Examiner.
Regarding claim 70, Brake teaches all the elements of the current invention as applied to claim 50. Brake teaches the pharmaceutical composition can be administered orally (i.e., an oral dosage form; Brake, page 2, paragraph 0025) and teaches a solid dispersion extrudate is compressed into tablets (i.e., the tablets are a solid; Brake, page 12, paragraph 0155).
Conclusion
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/C.P.J./Examiner, Art Unit 1613
/JENNIFER A BERRIOS/ Primary Examiner, Art Unit 1613