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.
Response to Amendment
The amendment filed 06/12/2026 has been entered.
Claim 65 was amended. No new material was added.
The rejections of claims 50-69 under 35 U.S.C. 103 have been maintained.
Response to Arguments
Applicant's arguments regarding the rejection of claims 50-69 under 35 U.S.C. 103, filed 06/12/2026, have been fully considered but they are not persuasive.
Applicant argues that a skilled artisan would not have a reasonable expectation of success to provide a pharmaceutical composition comprising a solid dispersion with any particular D50 based on Brake (Remarks, pages 6-8). This argument is not persuasive, because as previously stated, 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 a D50 75-250 micrometers. As defined by the instant specification, the D50 of a dispersion is the diameter at which 50% of the particles are larger and 50% of the particles of smaller (pages 22-23, paragraph 0107). It would be reasonable to expect that a dispersion of particles having a diameter of less than 250 micrometers would have a D50 that lies within the 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). Applicant argues that sieving through a 60 mesh does not govern the distribution of particles less than 250 micrometers, citing two examples which are passed through a 60 mesh and result in different particle size distributions as support for this assertion (Remarks, page 7, tables 8 and 3). This argument is not persuasive, because the differing amounts between the two examples of ~1% or ~30% of particles having a diameter of below 75 micrometers is not equivalent to the D50 of the particles. In each of the examples cited by the Applicant, the D50 of the particles falls within the claimed range of 75-250 micrometers (table 8 would result in a D50 of between 106-160 micrometers, and table 3 would result in a D50 of between 100-160 micrometers), further suggesting that the particles of Brake would be expected to also fall within the claimed range.
Applicant argues that the claimed particle size distribution leads to improved dissolution profiles, and specifically hardness (Remarks, pages 8-9). This argument is not persuasive, because as previously stated, 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 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.
Regarding the hardness, the data in figure 7 refers to a correlation between compression force applied and tablet hardness for particles having a D50 of 75-250 micrometers (specification, page 48, paragraph 0183). As discussed above, evidence of unexpected results must compare the claimed invention with the closest prior art. Brake further teaches tablets having a hardness values of approximately 10 kp (Brake, page 31, paragraph 0395), which would result in a hardness of approximately 98 N (1 kp is 9.81 N as evidenced by Bareiss Testing Solutions, page 2, “Units Used in Tablet Hardness Measurement”), which closely matches the hardness profiles of the tablets as claimed (instant specification, table 19). Therefore, the hardness of the claimed tablets is also not unexpected.
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 50-70 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).
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
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/C.P.J./Examiner, Art Unit 1613
/JENNIFER A BERRIOS/ Primary Examiner, Art Unit 1613
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