DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
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 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.
Previous Rejections
Applicant’s arguments, filed September 19, 2025, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Status
Claims 27-38 are cancelled.
Claims 1-26 are pending.
Claims 11-26 are withdrawn.
Claims 1-10 are examined on the merits in this prosecution.
CLAIM REJECTIONS
Obviousness Rejection
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 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 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.
1) Claims 1-10 are rejected under 35 U.S.C. 103 as being unpatentable over Amatangelo (WO 2017/146794 A1), in view of Dokou (US 2013/0224293 A1).
Amatangelo teaches a tablet or capsule comprising compound 1, known as enasidenib or 2-methyl-1-[(4-[6-(trifluoromethyl)pyridin-2-yl ]-6-{[2-(trifluoromethyl)pyridin-4-yl]amino}-1,3,5-triazin-2-yl)amino]propan-2-ol (structure below). See Abstract
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enasidenib
Amatangelo teaches the compound is useful in treating the hematologic malignancy acute myelogenous leukemia (AML) characterized by the presence of a mutant allele of IDH2 (pg 6, [0024]). Amatangelo teaches the compound is useful in treating AML regardless of the patients age (pg 56, [00188]).
Amatangelo teaches the formulation comprises 10 mg to 5000 mg of compound I (pgs 27-28, [0099]). Amatangelo teaches the following (pg 24, [081] to [087]):
In one embodiment, the diluent is a microcrystalline cellulose.
[082] In one embodiment, the binder is a hydroxypropyl cellulose.
[083] In one embodiment, the disintegrant is sodium starch glycolate.
[084] In one embodiment, the wetting agent is sodium lauryl sulfate.
[085] In one embodiment, the stabilizer is hypromellose acetate succinate.
[086] In one embodiment, the glidant is colloidal silicon dioxide.
[087] In one embodiment, the lubricant is magnesium stearate.
For the percentage of Compound 1A in the claimed minitablet, routine optimization of would have led to the claimed range based on the amount of drug effective in the subject. The person of ordinary skill in the art would have found it obvious to optimize within the claimed range because Amatangelo teaches a range that treats the disease in a subject of at least 10 years of age ([00188]) and methods of determining a safe range for subjects younger than this age are well-known to practitioners of the pharmaceutical arts.
Amatangelo teaches microcrystalline cellulose as a binder in an amount of 42 or 44% (pg 32, [00107]); mannitol as a diluent in an amount of 26 or 28% ([00108]); the binder in an amount of 2% (pg 32, [00107]); the disintegrant in an amount of about 6%, about 8%, or about 10% (pg 34, [00110]); the sodium lauryl sulfate in an amount of about 2% (pgs 33-34, [00109]); the stabilizer in an amount of about 1% (pg 35, [00111]); the glidant in an amount of about 1%, about 2%, or about 3% (pg 36, [00112]); and a lubricant in an amount of about 1.4% or 1.6% (pg 34, [00109]).
For claims 1, 2, and 7 (for the amount of Compound 1A), Amatangelo teaches an amount that overlaps the claimed range of each component taught by Amatangelo as discussed above. Because the claimed range overlaps with the range disclosed by the prior art, a prima facie case of obviousness exists.
Amatangelo does not teach the presence of 3.5% to 5% sucralose in the dosage form. Amatangelo also does not teach a minitablet formulation or the dimensions of the minitablet.
Dokou teaches the missing elements of Amatangelo.
Dokou teaches pharmaceutical compositions, including mini-tablets, that may comprise sucralose in an amount of 10% or less (Abstract; pg 4, [0049]), overlapping the claimed range. Dokou teaches the mini-tablets may also contain microcrystalline cellulose or mannitol as a filler (pg 9, [0100]); hydroxypropyl methylcellulose (pg 4, [0045]); sodium starch glycolate as a disintegrant (pg 4, [0049]); sodium lauryl sulfate as a wetting agent (pg 4, [0047]); colloidal silicon dioxide as a glidant (pg 4, [0049]); hypromellose acetate succinate (pg 84, [1693]); and magnesium stearate as a lubricant ([0049]). Dokou exemplifies the composition in a drug for pediatric cystic fibrosis (pg 2, [0014]).
Dokou teaches the compositions are useful in pediatric patients since the minitablet formulation is readily added to foods or liquids such as pudding or applesauce for ingestion (pg 5, [0056]; pg 48, [1246]; pg 49, [1259]).
For claim 3, routine optimization of Dokou’s minitablet would have led to the claimed range of a weight of about 1.67 mg because Dokou teaches that the minitablet in any dimension is from about 1 mm to 5 mm (pg 6, [0054]). For example, a cubic minitablet having dimensions of 1.17 mm on a side and a density of 1 gm/cm3 would have a mass of 1.6 gm, reading on the limitation of “about 1.67 mg”.
For claims 4, 5 and 8, Dokou teaches minitablet that can be formulated into capsules. The minitablets range in size from about 1 mm to about 5 mm in any dimension (pg 6, [0054]), overlapping the ranges recited in claims 4 and 5.
For claim 6, Dokou teaches an average tensile strength of between about 0.5 MPa and about 4 MPa (pg 5, [0054]), overlapping the claimed range. For the limitation of the mini-tablet having a solid fraction of about 0.9 to 0.95, it is known in the pharmaceutical arts that one of ordinary skill can optimize the solid fraction by manipulating tableting parameters such as compaction pressure, powder properties such as particle size, and use of an appropriate tableting machine
For claims 9 and 10, Dokou teaches the composition comprises over 60 minitablets, including 65, 78, 91, 104, 117, 130, or 336 mini-tablets. (pgs 4-5, [0053]), overlapping the claimed range.
It is further noted that the tablet components taught by Amatangelo are likewise taught by Dokou as the components useful in preparing minitablets also comprising sucrose.
The skilled artisan would have expected success in adding the claimed amount of sucralose to the composition Amatangelo, and formulating the capsules taught by Amatangelo in the dosage form of minitablets or minitablets comprised within a capsule, since Amatangelo teaches dosage forms for children wherein the addition of sucralose would make the medication more palatable, and Amatangelo further teaches minitablets of the claimed size, weight, and tensile strength are useful for pediatric dosing since the minitablets are readily dispersed in foods such as applesauce or pudding that may increase the compliance of children.
Examiner’s Reply to Attorney Arguments dated 9/19/2025
1. Rejection of claims 1-10 under 35 U.S.C. § 103 over Amatangelo and Dokou.
For clarification, this rejection is an obviousness rejection under 35 U.S.C. § 103.
The applicant argues that Amatangelo does not teach or suggest any minitablet compositions, and no reason has been provided by the Examiner as to why one of ordinary skill in the art would consider modifying the formulations described in Amatangelo.
The Examiner acknowledges the arguments presented, but does not consider them persuasive. The rejection recites two references, Amatangelo and Dokou. As set forth in MPEP 2145(IV),
One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., Inc., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Where a rejection of a claim is based on two or more references, a reply that is limited to what a subset of the applied references teaches or fails to teach, or that fails to address the combined teaching of the applied references may be considered to be an argument that attacks the reference(s) individually.
The prior art of Dokou teaches the motivation for providing the formulation of Amatangelo in the form of a mini-tablet, since such formulations are useful in pediatric patients since the minitablet formulation is readily added to foods or liquids such as pudding or applesauce for ingestion.
Furthermore, as set for the in MPEP 2144.04(IV)(A), rescaling the size of a device where the performance of the device has not changed does not patentably distinguish the claimed device. In the instant case, the resulting increase in dissolution rate from down-sizing the tablet is predictable and well-known in the art, as discussed by the evidentiary teachings of Markl (“A Review of Disintegration Mechanisms and Measurement Techniques,” Pharm Res. 2017 May; 34(5):890-917; note that this reference is evidentiary and not cited in the instant rejection, but cited herein for the purpose of the response to applicant’s arguments). Markl teaches “The total surface area of the sample exposed in the solvent is one of the main aspects that influences the dissolution rate. In fact the dissolution process can be accelerated by increasing surface area and decreasing the particle size.” See page 910, left column).
The applicant argues that Dokou does not teach specifically using about 3.5% to 5% sucralose, much less using a specific combination of about 42% to about 45% microcrystalline cellulose, about 26.5% to about 28.5% mannitol, about 1% to about 3% hydroxypropyl cellulose, about 6% to about 10% sodium starch glycolate, about 0.5% to about 1.5% sodium lauryl sulfate, about 1% to about 3% colloidal silicon dioxide, about 0.5% to about 2% hypromellose acetate succinate, about 3.5% to 5% sucralose, and about 1% to about 3% magnesium stearate in the minitablets taught therein. The applicant further argues that Dokou does not specifically mention Compound 1A. For a proper prima facie case, suggestion of a claimed subject matter as a whole must be found in the combination of the cited references.
The Examiner acknowledges the arguments presented, but does not consider them persuasive. As discussed above, the rejection recites a combination of two references and it is improper to attack references individually where the rejections are based on combinations of references. See MPEP 2145(IV). In the above rejection, the Examiner acknowledges Amatangelo does not teach the presence of 3.5% to 5% sucralose in the dosage form, and that Dokou teaches an amount of sucralose overlapping the claimed range.
The obviousness of ranges is discussed in MPEP 2144.05(I): ” In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.” Dokou teaches a range of 10% or less of sucralose in the mini-tablet, and that range overlaps the claimed range. Such a disclosure can be overcome by unexpected showing the criticality of the claimed range. See MPEP 2145. Such a showing has not been submitted to the record in this application.
The applicant alleges the Examiner used “hindsight reconstruction to pick and choose among isolated disclosures in the prior art.”
The Examiner acknowledges the arguments presented, but does not consider them persuasive. As discussed in MPEP 2145(X)(A), “"[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In the instant rejection, the Examiner relied only on the teachings of the prior art of Amatangelo and Dokou, and both of these references were public before the instant application was filed.
The applicant argues on page 8 of the Remarks that “The PTO is reminded that prior art must collectively, although not explicitly, guide an artisan of ordinary skill towards a particular solution.” Unigene Laboratories, Inc. v. Apotex, Inc., 655 F.3d 1352, 1361 (Fed. Cir. 2011) (Emphasis added). The Federal Circuit has held that there must be some reason to modify the prior art in the manner necessary to arrive at the claimed invention, wherein a lack of recognition of the flaws in the prior art that would prompt such modification weighs against a finding of obviousness (even though the possibility of certain modifications were known, there were no undue technical hurdles to overcome and there was no lack of a reasonable expectation of success).”
The Examiner acknowledges the arguments presented, but does not consider them persuasive. As discussed above, the motivation to prefer minitablets over an adult dosage size, as taught by Dokou, is that the minitablets are the preferred tableted dosage form for pediatric patients.
The applicant argues that:
Example 5 in the application describes that the claimed specific combination of components was required to overcome the problems linked with compaction and stickiness in the manufacturing process of the claimed minitablets. Applicant further submits that data provided in the application demonstrate that claimed minitablets have beneficial release profile, see Example 6, Figure 12; good chemical stability, see Example 7, that Example 5 in the application describes that the claimed specific combination of components was required to overcome the problems linked with compaction and stickiness in the manufacturing process of the claimed minitablets. Applicant further submits that data provided in the application demonstrate that claimed minitablets have beneficial release profile, see Example 6, Figure 12; good chemical stability, see Example 7, Table 7; good dissolution rate, see Example 7, Figure 13; and food compatibility with different food products, see Example 8. As described in Example 5, paragraph [0240], a taste assessment evaluation was conducted with an exemplary formulation within the scope of the instant claims as described in Table 10. The results, presented in Figure 7, showed that the formulation containing sucralose as sweetener reduced the bitterness of solid form 3 of 2-methyl-1-[(4-[6-(trifluoromethy]) pyridin-2-yl]-6-{[2-(trifluoromethyl) pyridin-4-yl- amino}-1,3,5-triazin-2- yl)amino]propan-2-ol methanesulfonate to a very slight intensity, below the level of patient perception (1.0). As further described in paragraph [0240], this result is a significant improvement when compared against granules prepared according to the adult formulation.
The Examiner acknowledges the arguments and evidence presented, but does not consider them persuasive. Regarding the applicant’s allegation that “Example 5 in the application describes that the claimed specific combination of components was required to overcome the problems linked with compaction and stickiness in the manufacturing process of the claimed minitablets,” the applicant compared the instant minitablet with the tablets described in US 2018/0064715 A1 (reference not cited in the rejection). It is noted that this publication is not the closest art determined by the Examiner. As set forth in MPEP 716.02(e), to demonstrate unexpected results, the applicant must compare the claimed subject matter with the closest prior art.
Secondly, the compositions in the ‘715 publication differ markedly with the claimed composition. Specifically, the ‘715 publication, as disclosed in Table 2, comprise an amount of drug of 20-30%, 2- to 3-fold more than the claimed amount. Also, the ‘715 composition comprises an amount of microcrystalline cellulose outside of the claimed range, and does not contain sucralose in any amount. As such, one of ordinary skill in the art would not expect the ‘715 composition to have the same physical characteristics as the claimed minitablet composition.
The applicant argues that data provided in Example 7 and Figure 13 of the application demonstrate that claimed minitablets have an unexpected beneficial release profile. The Examiner disagrees. As discussed above, it is well-known in the art, as evidenced by the Markl evidentiary reference cited above, that reducing the size of a dosage form increases the surface area, and increasing surface area increases the rate of dissolution.
Regarding the argument of an unexpected taste improvement of the claimed composition as described in Example 5, it is well-known in the art that sucralose acts as a bitter blocker, as disclosed by evidentiary prior art of Hutchings (Food Quality and Preference 50 (2016) 157-162; reference not cited in the rejection, but cited herein for the purpose of the response to applicant’s arguments).
The Examiner also disagrees with applicant’s argument that the instant composition yields an unexpected ease in tableting by reducing stickiness. As discussed by the evidentiary prior art of Chaudari (Drug Development and Delivery, October 2017; reference not cited in the rejection, but cited herein for the purpose of the response to applicant’s arguments), the combination of mannitol, microcrystalline cellulose, and 1% magnesium stearate decreased the sticking propensity of the tablet ingredients (9th paragraph).
The applicant argues on page 9 or the Remarks that “a finding of obviousness requires not only a hope that a potential formulation could be prepared, but a reasonable expectation that such formulation would be palatable, have good chemical stability, dissolution rate and food compatibility….Therefore, even if the combination of prior art had taught the claimed invention, a showing of reasonable expectation of success would still be required for a finding of obviousness. As discussed above, none of the prior art references, alone or in combination, provides such a reasonable expectation of success for the claimed invention.”
The Examiner acknowledges the arguments presented, but does not consider them persuasive. Since the combination of references teaches the claimed composition in the form of a minitablet, and the alleged unexpected advantages cited by the applicant appear to have been previously known in the art, the prior art of Amatangelo as modified by Dokou provide composition having a reasonable expectation of success.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MICHAEL P COHEN whose telephone number is (571)270-7402. The examiner can normally be reached on M-Th 8:30-5:30; F 9-4.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sahana S. Kaup, can be reached on (571)272-6897. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/MICHAEL P COHEN/Primary Examiner, Art Unit 1612
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