FINAL 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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted 05/13/2025 has been considered by the examiner and initialed copies of the IDS are included with the mailing of this office action.
Status of the Claims
This action is in response to papers filed 03/19/2025 in which claims 2-8, 11-13, 15-22, 25-26, 28-35, 39-41, 43, and 45-46 were canceled; claim 27 was withdrawn; claims 1, 9, 10, 14, 23-24, 38, 42, and 44 were amended; and claims 47-55 were newly added. All the amendments have been thoroughly reviewed and entered.
Claims 1, 9-10, 14, 23-24, 36-38, 42, 44, and 47-55 are under examination.
Withdrawn Rejections
The Examiner has re-weighted all the evidence of record. Any rejection and/or objection not specifically addressed below is hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
Modified Rejection
Necessitated by Applicant’s Claim Amendments
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 9-10, 14, 23-24, 36-38, 42, 44, and 47-55 is/are rejected under 35 U.S.C. 103 as being unpatentable over Martino et al (US 2006/0257476 A1) in view of Chen et al (WO 2017/161937 A1; English translation and citation via US 2019/0077791), Murpani et al (WO 2016/096999 A1), Miyamoto (KONA Powder and Particle Journal, 2018, 26: 142-152), and Ibrahim et al (US 2018/0207100 A1).
Regarding claim 1, Martino teaches a compressed tablet formulation comprising an active ingredient, and pharmaceutically acceptable excipients including filler/diluent such as microcrystalline cellulose and lactose; a disintegrant selected from croscarmellose sodium, sodium starch glycolate (carboxymethyl starch sodium) and L-hydroxypropyl cellulose; and lubricant, wherein the compressed tablet improve the dissolution of the active ingredient (Abstract; [0001], [0012]-[0015], [0017], [0019]-[0022], [0024], [0026]; Example 1; claims 1-16). Martino teaches the disintegrant is most preferably present in an amount of about 10% to about 30% by weight ([0019] and [0021]; claims 6 and 8). Martino teaches microcrystalline cellulose and lactose as the preferred filler ([0013]-[0014] and [0036]-[0037]; Example 1). Martino teaches microcrystalline cellulose is present in the tablet in an amount from 10-50% by weight and lactose is present in the tablet in an amount of 5 to 20% by weight (Martino: [0012]-[0014], [0021]-[0022]; claims 9 and 16).
Martino further teaches microcrystalline cellulose is present in the tablet in an amount from 10-50% by weight and lactose is present in the tablet in an amount of 5 to 20% by weight (Martino: [0012]-[0014], [0021]-[0022]; claims 9 and 16). Martino teaches the tablet comprises 30% by weight of microcrystalline and 10.7% by weight of lactose (Martino: Example 1). The ranges for microcrystalline cellulose and lactose as taught in Martino overlaps the claimed ranges weight ratio of microcrystalline cellulose to lactose is 1:3 to 3:1, as recited in claim 1. Martino further teaches the optimal amount of disintegrant such as carboxymethyl starch in the compressed tablet to achieve a desired compressed tablet with improved dissolution is preferably from about 10% to about 30% by weight, which is a range that substantially overlaps the claimed range of “the disintegrant is present in an amount of 14% to 16% by weight” as recited in claim 1. Thus, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists (see In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990); Titanium Metals Corp. of America v. Banner, 778 F2d 775. 227 USPQ 773 (Fed. Cir. 1985). Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the weight ratio of microcrystalline cellulose to lactose, as well as, the amount of disintegrant in the composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
However, Martino does not teach the active ingredient is N-(5-((4-(1-cyclopropyl- 1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxyphenyl)acrylamide of claim 1; and the microcrystalline cellulose is KG802 of claim 1; and the lubricants are sodium stearyl fumarate and magnesium stearate of claim 1.
Regarding the active ingredient of claim 1, Chen teaches a pharmaceutical composition comprising an EGFR inhibitor such as N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxyphenyl)acrylamide as an active ingredient, and at least one pharmaceutically acceptable excipient, wherein the active ingredient is in its salt form of mesylate salt (Abstract; [0001]-[0006], [0009], [0046], [0051], [0112]-[0113] and [0116]; Examples 10-15; claims 1-5, 13, 16 and 22).
It would have been obvious to one of ordinary skill in the art to incorporate a mesylate salt of N-(5-((4-(1-cyclopropyl- 1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide as the active ingredient the compressed tablet of Martino, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Murpani provided the guidance to do so by teaching that active ingredient such as EGFR inhibitor are suitable for formulating in an immediate release formulation such as a compressed tablet containing filler/diluent such as microcrystalline cellulose and lactose and disintegrant such as sodium starch glycolate (carboxymethyl starch sodium) so as to improve dissolution properties (Murpani: Abstract; page 1, lines 5-17; page 4, lines 5-20; page 5, lines 19-end; page 6, lines 17-end; pages 7-8; Example 7-8), and per Chen, mesylate salt of N-(5-((4-(1-cyclopropyl- 1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxyphenyl)acrylamide is an EGFR inhibitor (Chen: Abstract; [0001]-[0009]). Thus, ordinary artisan seeking to formulate an EGFR inhibitor such as mesylate salt of N-(5-((4-(1-cyclopropyl- 1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxyphenyl)acrylamide in an immediate release dosage form which has improved dissolution properties would have looked to including the mesylate salt of N-(5-((4-(1-cyclopropyl- 1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4- methoxyphenyl)acrylamide as the active ingredient in the compressed tablet of Martino, and achieve Applicant’s claimed invention with reasonable expectation of success.
Regarding the microcrystalline cellulose is KG802 of claim 1. Miyamoto teaches microcrystalline cellulose KG-802 is a high compactibility grade microcrystalline cellulose that functions as a high performance filler-binder of direct compression (Abstract; pages 142-144, and 146-151). Miyamoto teaches microcrystalline cellulose KG-802 is superior to standard microcrystalline celluloses such as PH-101 and PH102 in compactibility, friability, and tablet hardness, as well as, in tablet formulation that contain high content of active ingredient (pages 146-151).
I would have been obvious to one of ordinary skill in the art to incorporate microcrystalline cellulose KG-802 as the microcrystalline cellulose in the tablet of Martino, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Miyamoto provided the guidance to do by teaching that microcrystalline cellulose KG-802 is preferably suitable as the filler in a compressed tablet that has high content of active ingredient, as it is considered a high compactibility grade microcrystalline cellulose that is superior to standard grades such as PH-101 and PH102, as provide microcrystalline cellulose KG-802 increased hardness and reduced friability to the tablet, as well as, it is preferred to be the microcrystalline cellulose used when formulating a tablet contain high content of active ingredient. One of ordinary skill in the art would have reasonable expectation of success incorporate microcrystalline cellulose KG-802 as the microcrystalline cellulose in the tablet of Martino because Martino’s tablet contains high amount of active ingredient (upward to 60% by weight of active ingredient) (Martino: Abstract; [0012]-[0015], [0017] and claim 1) and Martino also indicated the preferred microcrystalline cellulose is selected from microcrystalline coarse powder and microcrystalline medium powder (Martino: [0021]; Example 1), in which microcrystalline cellulose KG-802 is within the scope of the preferred microcrystalline cellulose.
Regarding the lubricants are sodium stearyl fumarate and magnesium stearate of claim 1, Ibrahim teaches a compressed tablet with improved dissolution properties comprising an active ingredient, fillers such as lactose and microcrystalline cellulose, a disintegrant such as sodium starch glycolate (carboxymethyl starch sodium), and one or more lubricants such as a mixture of magnesium sulfate and sodium stearyl fumarate (Abstract; [0023]-[0028], [0043]-[0044], [0048]-[0049], [0094]-[0096], [0100]-[0104]; claims 1 and 3-9). Ibrahim teaches that lubricants are preferably present in the solid dosage form in an amount from about 0.5 wt% to about 6 wt% ([0025], [0096], [0100]-[0101])
It would have been obvious to one of ordinary skill in the art to include magnesium sulfate and sodium stearyl fumarate as the lubricant in the compressed tablet of Martino, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because Ibrahim provided the direct guidance to do by teaching that solid dosage form such as a compressed tablet, frequently contain one or more lubricants selected from magnesium stearate, sodium stearyl fumarate, and mixture of magnesium stearate and sodium stearyl fumarate. Thus, an ordinary artisan would have looked to select and use a mixture of magnesium stearate and sodium stearyl fumarate as the lubricant in the compressed tablet of Martino so as to achieve a desired compressed tablet with improved dissolution properties, as [t]he selection of a known material based on its suitability for its intended use supported a prima facie obviousness determination in Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). "Reading a list and selecting a known compound to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle." 325 U.S. at 335, 65 USPQ at 301.).
Regarding claim 9, as discussed above, Martino teaches microcrystalline cellulose is present in the tablet in an amount from 10-50% by weight and lactose is present in the tablet in an amount of 5 to 20% by weight (Martino: [0012]-[0014], [0021]-[0022]; claims 9 and 16), and Miyamoto provided the guidance for incorporating microcrystalline cellulose KG-802 as the microcrystalline cellulose in the tablet of Martino (Miyamoto: Abstract; pages 142-144, and 146-151). It is noted that weight amount ranges for microcrystalline cellulose and lactose overlap the claimed ranges for microcrystalline cellulose and lactose of claim 9, respectively. Thus, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the weight amounts of microcrystalline cellulose and lactose in the composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 10, as discussed above, Martino teaches microcrystalline cellulose is present in the tablet in an amount from 10-50% by weight and lactose is present in the tablet in an amount of 5 to 20% by weight (Martino: [0012]-[0014], [0021]-[0022]; claims 9 and 16), and Miyamoto provided the guidance for incorporating microcrystalline cellulose KG-802 as the microcrystalline cellulose in the tablet of Martino (Miyamoto: Abstract; pages 142-144, and 146-151). Martino teaches the tablet comprises 30% by weight of microcrystalline and 10.7% by weight of lactose (Martino: Example 1). The ranges for microcrystalline cellulose and lactose as taught in Martino overlaps the claimed ranges weight ratio of microcrystalline cellulose to lactose is 2-3:1. Thus, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the weight ratio of microcrystalline cellulose to lactose in the composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 14, Martino teaches microcrystalline cellulose is present in the tablet in an amount from 10-50% by weight and lactose is present in the tablet in an amount of 5 to 20% by weight (Martino: [0012]-[0014], [0021]-[0022]; claims 9 and 16), and Miyamoto provided the guidance for incorporating microcrystalline cellulose KG-802 as the microcrystalline cellulose in the tablet of Martino (Miyamoto: Abstract; pages 142-144, and 146-151). The ranges for microcrystalline cellulose and lactose as taught in Martino overlap the claimed range of filler is present in an amount of 20% to 80%. Thus, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the weight ratio of filler in the composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claims 23 and 24, Murpani teaches the EGFR inhibitor is present in the compressed tablet in an amount of 45-60% by weight (Murpani: page 4, lines 5-20; page 5, lines 19-end). Martino teaches microcrystalline cellulose is present in the tablet in an amount from 10-50% by weight and lactose is present in the tablet in an amount of 5 to 20% by weight (Martino: [0012]-[0014], [0021]-[0022]; claims 9 and 16), and Miyamoto provided the guidance for incorporating microcrystalline cellulose KG-802 as the microcrystalline cellulose in the tablet of Martino (Miyamoto: Abstract; pages 142-144, and 146-151) . Martino teaches disintegrant (carboxymethyl starch sodium) is present in the tablet in an amount from about 6% to about 40% by weight (Martino: [0012]-[0014], [0019]; claims 1 and 6). Martino teaches lubricant is present in the tablet in an amount of about 0.25% to about 5% (Martino: [0012]-[0014], [0024]; claim 23). It is noted that the amounts of active ingredient, lactose, microcrystalline cellulose, carboxymethylcellulose starch sodium and lubricant as taught by Martino and Murpani, respectively, overlap or fall within the claimed ranges/amounts for active ingredient, lactose, microcrystalline cellulose, carboxymethylcellulose starch sodium and lubricant. Thus, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the weight amounts of the active ingredient, lactose, microcrystalline cellulose, carboxymethylcellulose starch sodium and lubricant in the composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 36, as discussed above, Murpani provide the guidance for optimizing the EGFR inhibitor in the compressed tablet in an amount of 45-60% by weight (Murpani: page 4, lines 5-20; page 5, lines 19-end), which falls within the claimed range of “1% to 60% by weight.” Thus, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the weight amount of the active ingredient in the composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 37, Murpani teaches the tablet comprises from 50 to 500 mg of EGFR inhibitor (Murpani: page 5, lines 2-5; page 7, lines 12-14), which overlap the claimed range of 10 to 200 mg. Thus, it is noted that the Courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the dosage amount of the active ingredient in the composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 38, as discussed above, Martino teaches the filler contains microcrystalline cellulose and lactose ([0013]-[0014] and [0036]-[0037]; Example 1), and Miyamoto provided the guidance for incorporating microcrystalline cellulose KG-802 as the microcrystalline cellulose in the tablet of Martino (Miyamoto: Abstract; pages 142-144, and 146-151).
Regarding claim 42, as discussed above, Martino teaches the compressed tablet formulation contain lubricant. Martino teaches the lubricant is selected from magnesium stearate and stearic acid (Martino: [0024]). As discussed above, Ibrahim provided the guidance for including magnesium sulfate and sodium stearyl fumarate as the lubricant in the compressed tablet of Martino (Ibrahim: Abstract; [0023]-[0028], [0043]-[0044], [0048]-[0049], [0094]-[0096], [0100]-[0104]; claims 1 and 3-9), and said lubricants are preferably present in the solid dosage form in an amount from about 0.5 wt% to about 6 wt% (Ibrahim: [0025], [0096], [0100]-[0101]). Martino also teaches the lubricant is present in the tablet in an amount of about 0.25% to about 5% (Martino: [0012]-[0014], [0024]; claim 23). The weight amount ranges of lubricants as taught in Martino and Ibrahim overlap or fall within the claimed range of 0.1% to 10% by weight.” Thus, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the weight amount of lubricant in the composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 44, as discussed above, Ibrahim teaches that lubricants are preferably present in the solid dosage form in an amount from about 0.5 wt% to about 6 wt% ([0025], [0096], [0100]-[0101]). It would also have been obvious to one of ordinary skill in the art to optimize the amounts of magnesium sulfate and sodium stearyl fumarate as the lubricant in the compressed tablet of Martino to an amount as claimed in claim 44, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because as discussed above, Ibrahim teaches that lubricants are preferably present in the solid dosage form in an amount from about 0.5 wt% to about 6 wt% ([0025], [0096], [0100]-[0101]), which overlaps “the sodium stearyl fumarate is present in an amount of 0.1% to 5% by weight and the magnesium stearate is present in an amount of 0.1% to 5% by weight” of claim 44. Thus, the Courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the amounts of lubricant and respectively of magnesium sulfate and sodium stearyl fumarate in the pharmaceutical composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 47, as discussed above, Murpani teaches and provide the guidance for optimizing the EGFR inhibitor in the compressed tablet to an amount of 45-60% by weight (Murpani: page 4, lines 5-20; page 5, lines 19-end), which overlaps the claimed amount of 35% to 50% by weight. Thus, the Courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the amount of active ingredient in the pharmaceutical composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 48, as discussed above, Murpani teaches the tablet comprises from 50 to 500 mg of EGFR inhibitor (Murpani: page 5, lines 2-5; page 7, lines 12-14), which overlap the claimed range of 55 mg to 110 mg. Thus, it is noted that the Courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the dosage amount of the active ingredient in the composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claims 49 and 50, as discussed above, Martino teaches microcrystalline cellulose is present in the tablet in an amount from 10-50% by weight and lactose is present in the tablet in an amount of 5 to 20% by weight (Martino: [0012]-[0014], [0021]-[0022]; claims 9 and 16), and Miyamoto provided the guidance for incorporating microcrystalline cellulose KG-802 as the microcrystalline cellulose in the tablet of Martino (Miyamoto: Abstract; pages 142-144, and 146-151). It is noted that weight amount ranges for microcrystalline cellulose and lactose overlap the claimed ranges for microcrystalline cellulose and lactose of claims 49 and 50, respectively. Thus, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the weight amounts of microcrystalline cellulose and lactose in the composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 51, as discussed above, Martino teaches microcrystalline cellulose is present in the tablet in an amount from 10-50% by weight and lactose is present in the tablet in an amount of 5 to 20% by weight (Martino: [0012]-[0014], [0021]-[0022]; claims 9 and 16), and Miyamoto provided the guidance for incorporating microcrystalline cellulose KG-802 as the microcrystalline cellulose in the tablet of Martino (Miyamoto: Abstract; pages 142-144, and 146-151). The ranges for microcrystalline cellulose and lactose as taught in Martino overlap the claimed range of filler is present in an amount of 30% to 50% by weight Thus, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the weight ratio of filler in the composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 52, as discussed above, as discussed above, Martino teaches the compressed tablet formulation contain lubricant. Martino teaches the lubricant is selected from magnesium stearate and stearic acid (Martino: [0024]). As discussed above, Ibrahim provided the guidance for including magnesium sulfate and sodium stearyl fumarate as the lubricant in the compressed tablet of Martino (Ibrahim: Abstract; [0023]-[0028], [0043]-[0044], [0048]-[0049], [0094]-[0096], [0100]-[0104]; claims 1 and 3-9), and said lubricants are preferably present in the solid dosage form in an amount from about 0.5 wt% to about 6 wt% (Ibrahim: [0025], [0096], [0100]-[0101]). Martino also teaches the lubricant is present in the tablet in an amount of about 0.25% to about 5% (Martino: [0012]-[0014], [0024]; claim 23). The weight amount ranges of lubricants as taught in Martino and Ibrahim overlap or fall within the claimed range of 0.2% to 5% by weight.” Thus, it is noted that the courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the weight amount of lubricant in the composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 53, as discussed above, Ibrahim teaches that lubricants (sodium stearyl fumarate and magnesium stearate) are preferably present in the solid dosage form in an amount from about 0.5 wt% to about 6 wt% ([0025], [0096], [0100]-[0101]). It would also have been obvious to one of ordinary skill in the art to optimize the amounts of magnesium sulfate and sodium stearyl fumarate as the lubricant in the compressed tablet of Martino to an amount as claimed in claim 53, and produce the claimed invention. One of ordinary skill in the art would have been motivated to do so because as discussed above, Ibrahim teaches that lubricants are preferably present in the solid dosage form in an amount from about 0.5 wt% to about 6 wt% ([0025], [0096], [0100]-[0101]), which overlaps “the sodium stearyl fumarate is present in an amount of 0.3% to 3% by weight and the magnesium stearate is present in an amount of 0.2% to 2% by weight” of claim 53. Thus, the Courts have stated where the claimed ranges “overlap or lie inside the ranges disclosed by the prior art” and even when the claimed ranges and prior art ranges do not overlap but are close enough that one skilled in the art would have expected them to have similar properties, a prima facie case of obviousness exists. Absent some demonstration of unexpected results showing criticality from the claimed parameters, the optimization of the amounts of lubricant and respectively of magnesium sulfate and sodium stearyl fumarate in the pharmaceutical composition would have been obvious before the effective filing date of Applicant’s invention. See MPEP §2144.05 (I)-(II).
Regarding claim 54, Martino teaches the compressed tablet is film coated ([0025]-[0026], [0037]).
Regarding claim 55, Ibrahim teaches and provide guidance for formulating the compressed tablet of Martino to be an immediate release film-coated tablet (Ibrahim: [0027], [0048], [0090]; Example 16; and claim 10).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the in art the before the effective filing date of Applicant’s invention, as evidenced by the references, especially in the absence of evidence to the contrary.
Response to Arguments
Applicant's arguments filed 03/19/2025 have been fully considered but they are not persuasive.
Applicant argues that there is no motivation to combine and modify the five cited references and that the obviousness analysis in the 103 rejection was based on impermissible hindsight. (Remarks, page 9).
In response, the Examiner disagrees. The obviousness analysis in the 103 rejection are proper, as there is a motivation to combine or modify the cited prior arts as combined, and a reasonable expectation of success in doing so have been provided in the pending 103 rejection supra (see 103 rejection, page 4-9 of this office action). Applicant is noted that "[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 re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971). Applicant is further noted that “there is no requirement that an "express, written motivation to combine must appear in prior art references before a finding of obviousness." Ruiz v. A.B. Chance Co., 357 F.3d 1270, 1276, 69 USPQ2d 1686, 1690 (Fed. Cir. 2004). See KSR, 550 U.S. at 402, 82 USPQ2d at 1389.” Thus, the pending 103 rejection is not based on impermissible hindsight because the obviousness analysis provided in the 103 rejection gleaned only from the teachings of the cited prior art and such reconstruction using the teachings and guidance of the cited prior art is proper to render obvious Applicant’s claimed invention.
Applicant argues that “a person of skill in the art would have had no reason or motivation to combine the disclosure of Martino, which relates to pharmaceutical compositions suitable for preventing precipitation for rapidly precipitating drugs, with the disclosure of Chen related to the active ingredient of the instant claims as amended, namely a mesylate salt of N-(5-((4-(1-cyclopropyl-IH-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamtino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide. There is nothing in the disclosure of Chen to suggest that the mesylate salt of N-(5-((4-(1-cy clopropyl-1IH-indol-3-yl1)pyrimnidin-2-yl1)amnino)-2-((2-(dimeothylaino)ethyl)(methyl)amino)-4- methoxyphenyl)acrylamide disclosed therein is a rapidly precipitating drug.” Applicant goes on to alleges that “[b]ecause the active ingredient of instant claim 1 is not a rapidly precipitating compound as used in Martino, without impermissible hindsight, a person of skill in the art looking to provide a formulation for the highly soluble active ingredient of claim 1 would have no reason to look at Martino, which discloses formulations that would prevent precipitation of rapidly precipitating drugs and combine it with the disclosure of Chen.” (Remarks, pages 10-12).
In response, the Examiner disagrees. As previously discussed, it is maintained that Applicant’s argument and evidence drawn to N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) is not a rapidly precipitating drug, is not persuasive. This is because the evidence in the Chen Declaration from Table S2 is drawn to mesylate salt of N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl). Thus, obviously the mesylate salt form of the claimed parent drug of N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) would be a soluble form of the parent drug, as making a parent drug to a salt form would be expected to improve solubility of the parent drug.
As previously discussed, the cited prior arts have established that the parent drug of N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) is an EGFR inhibitor that is known to be poorly soluble, and to improve the solubility, it is made to a salt form. As previously discussed, it is reiterated that Martino defines “a rapidly precipitating drug” as a fairly soluble or highly soluble salt form of a poorly soluble free base or free acid drug (Martino: [0015]). It is noted that Chen describes that acid salt polymorphs of the compound of N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl) amino)-4-methoxyphenyl)acrylamide), an EGFR inhibitor, has improved solubility (Chen: [0005]), thereby the parent drug of N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl) amino)-4-methoxyphenyl)acrylamide), is a poorly soluble drug. This is in line with Murpani, which also teaches an EGFR inhibitor that is a poorly soluble drug (Murpani, pages 1-2). Thus, the EGFR inhibitors of Chen and Murpani are within the scope of a poorly soluble free base or free acid drug of Martino, as well as, mesylate salt of N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl) amino)-4-methoxyphenyl)acrylamide) of Chen is within the scope of “a fairly soluble or highly soluble salt form of a poorly soluble free base or free acid drug” of Martino. Accordingly, it is maintained that that obviousness analysis in the pending 103 rejection is not based on impermissible hindsight, as Martino, Chen, and Murpani were properly combined in the pending 103 rejection to render obvious Applicant’s claimed invention.
Applicant argues “a person of skill in the art would combine Martino and Chen, neither of the references provide any reason to further modify the formulations disclosed in Martino teaches away from the preferred and indeed, only exemplary embodiments. Paragraph 0019 of the specification of Martino discloses that "[t]he super disintegrant is selected from the group consisting of croscarmellose sodium, sodium starch glycolate, L-hydroxypropyl cellulose; it is more preferred that the super disintegrant be croscarmellose" and the sole example of Martino also uses croscarmellose as the disintegrant.” (Remarks, page 12, last paragraph to page 13).
In response, the Examiner disagrees. Applicant is noted that the 103 rejection was over the prior art’s (Martino) broader disclosure. Thus, [d]isclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004). As discussed above in the pending 103 rejection, not only does paragraph [0019] of Martino teaches carboxymethyl starch sodium (sodium starch glycolate) as the suitable superdisintegrant for selection, but claim 6 also particularly indicate that sodium starch glycolate is one of the preferred superdisintegrant. Thus, contrary to Applicant’s allegation, Martino does not teach away from using sodium starch glycolate. Rather, as discussed above, the disclosure from Martino provide the direct teaching to use carboxymethyl starch sodium (sodium starch glycolate) as the disintegrant, thereby teaches towards the use of carboxymethyl starch sodium as the disintegrant.
Applicant argues “unlike the compound of Murpani the active ingredient recited in the instant claims is not a poorly soluble drug, and therefore a person of skill in the art would not look at Murpani for teachings regarding its formulation.” (Remarks, page 13).
In response, the Examiner disagrees. As discussed above, it is reiterated the cited prior arts have established that the parent drug of N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2- (dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl) is an EGFR inhibitor that is known to be poorly soluble, and to improve the solubility, it is made to a salt form. As previously discussed, it is reiterated that Martino defines “a rapidly precipitating drug” as a fairly soluble or highly soluble salt form of a poorly soluble free base or free acid drug (Martino: [0015]). It is noted that Chen describes that acid salt polymorphs of the compound of N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl) amino)-4-methoxyphenyl)acrylamide), an EGFR inhibitor, has improved solubility (Chen: [0005]), thereby the parent drug of N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl) amino)-4-methoxyphenyl)acrylamide), is a poorly soluble drug. This is in line with Murpani, which also teaches an EGFR inhibitor that is a poorly soluble drug (Murpani, pages 1-2). Thus, the EGFR inhibitors of Chen and Murpani are within the scope of a poorly soluble free base or free acid drug of Martino, as well as, mesylate salt of N-(5-((4-(1-cyclopropyl-1H-indol-3-yl)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl) amino)-4-methoxyphenyl)acrylamide) of Chen is within the scope of “a fairly soluble or highly soluble salt form of a poorly soluble free base or free acid drug” of Martino. Accordingly, it is maintained that that obviousness analysis in the pending 103 rejection is not based on impermissible hindsight, as Martino, Chen, and Murpani were properly combined in the pending 103 rejection to render obvious Applicant’s claimed invention.
Applicant argues that “there is no teaching in Murpani of a formulation containing 14-16% by weight of carboxymethvl starch as a disintegrant.” Applicant alleges that the Office “articulated no rationale that would prompt a person of skill in the art to select, specifically, Martino, and not any one of the other compressible tablet formulation available in the art (such as, for example, one of the exemplar formulations in Ibrahim which contains carboxymethyl starch sodium, in an amount of 5%, which is well below the recited range 14-16% of claim 1 and which does not contain lactose) as a starting point. The Office has further provided no rationale to combine the disclosure of Martino specifically with the disclosure of Chen, and not any one of the other disclosures of EGFR inhibitors present in the art.” (Remarks, page 13, last paragraph to page 14).
In response, the Examiner disagrees. As discussed above and in the 103 rejection, the claimed 14-16% by weight of carboxymethvl starch as a disintegrant was taught in render obvious by the teaching from Martino. See 103 rejection, pages 4-5 of this office action.
Applicant argues that “the sole example in Miyamoto where KG802 is used to improve the compressibility of a high-API load formulation uses a formulation that contains 80% API. In contrast, the formulations of the instant disclosure only contain ~43% and are therefore nowhere near the very high API load disclosed in Miyamoto where KG802 was shown to be beneficial.” Applicant further argues “Miyamoto highlights some of the drawbacks of KG802: "CeolusKG-802 is bulkier than standard grade, and it is relatively poor flowability of powder" (Page 148). Thus, without a specific need to use a high-compressibility microcrystalline cellulose (such as a pressure sensitive API or very high API loads), there would be no motivation to replace the microcrystalline cellulose in the disclosures of Martino and Murpani with the KG802 of Miyamoto and risk introducing drawbacks such as poor flowability.” (Remarks, page 15).
In response, the Examiner disagrees. Contrary to Applicant’s allegation, per Miyamoto, the drawback of poor flowability of CeolusKG-802 is not always true, as it was shown in Miyamoto that CeolusKG-802 was stabilized at high speed tableting (see page 148 of Miyamoto). Furthermore, 80% API loading as disclosed in Miyamoto is only an exemplary model of a high content of active ingredient, because other loading content lower than 80% can still be considered “high loading content”. This is because, as defined by the instant specification, a high content of active ingredient or high loading of the active ingredient encompassed a drug loading capacity that reach more than 40% (Specification: page 4, lines 18-21). As discussed in the pending 103 rejection (pages 7-8 of this office action), Miyamoto teaches that microcrystalline cellulose KG-802 is preferably suitable as the filler in a compressed tablet that has high content of active ingredient, as it is considered a high compactibility grade microcrystalline cellulose that is superior to standard grades such as PH-101 and PH102, as provide microcrystalline cellulose KG-802 increased hardness and reduced friability to the tablet, as well as, it is preferred to be the microcrystalline cellulose used when formulating a tablet contain high content of active ingredient. One of ordinary skill in the art would have reasonable expectation of success incorporate microcrystalline cellulose KG-802 as the microcrystalline cellulose in the tablet of Martino because Martino’s tablet contains high amount of active ingredient (upward to 60% by weight of active ingredient) (Martino: Abstract; [0012]-[0015], [0017] and claim 1) and Martino also indicated the preferred microcrystalline cellulose is selected from microcrystalline coarse powder and microcrystalline medium powder (Martino: [0021]; Example 1), in which microcrystalline cellulose KG-802 is within the scope of the preferred microcrystalline cellulose. As such, contrary to Applicant’s allegation, there is clear guidance and motivation from Miyamoto for incorporating microcrystalline cellulose KG-802 as the microcrystalline cellulose in the tablet of Martino to do the fact that KG-802 is preferably suitable as the filler in a compressed tablet that has high content of active ingredient, as it is considered a high compactibility grade microcrystalline cellulose that is superior to standard grades such as PH-101 and PH102, as provide microcrystalline cellulose KG-802 increased hardness and reduced friability to the tablet, as well as, it is preferred to be the microcrystalline cellulose used when formulating a tablet contain high content of active ingredient, which is consistent with Martino, as Martino’s tablet contains high amount of active ingredient (upward to 60% by weight of active ingredient) (Martino: Abstract; [0012]-[0015], [0017] and claim 1) and Martino also indicated the preferred microcrystalline cellulose is selected from microcrystalline coarse powder and microcrystalline medium powder (Martino: [0021]; Example 1), in which microcrystalline cellulose KG-802 is within the scope of the preferred microcrystalline cellulose.
Applicant argues “the results described in the specification as filed for the KG802 formulation, combined with the results described in table S1 of the Chen declaration (submitted with the August 22 2024 response) show that replacement of microcrystalline cellulose PH102 with KG802 results in tablets with better dissolution at the same hardness. Good compressibility as described in Miyamoto can only be expected to yield tablets with higher hardness, but it cannot be expected to yield higher dissolution at the same hardness. Additionally, none of the cited prior art documents indicate that use of the formulations disclosed therein (using conventional grades of microcrystalline cellulose) would result in formulations with inadequate dissolution profiles at higher hardness levels.” Applicant alleges “the inadequate dissolution rate for formulations containing microcrystalline cellulose PH102 was not known or suggested in the prior art, and thus the solution to this previously unrecognized problem is inventive under the framework set forth in In re Omeprazole. Further, even if, contrary to reality, the problem had been known, nothing in the cited prior art suggests that microcrystalline cellulose KG802 would be able to solve that problem.” (Remarks, page 15, last paragraph to page 16).
In response, the Examiner disagrees. The prior art of Miyamoto have already recognized the superior properties of KG802 over standard PH102. As discussed above, Miyamoto teaches that microcrystalline cellulose KG-802 is preferably suitable as the filler in a compressed tablet that has high content of active ingredient, as it is considered a high compatibility grade microcrystalline cellulose that is superior to standard grades such as PH-101 and PH102, as provide microcrystalline cellulose KG-802 increased hardness and reduced friability to the tablet, as well as, it is preferred to be the microcrystalline cellulose used when formulating a tablet contain high content of active ingredient. Furthermore, Martino also indicated the preferred microcrystalline cellulose is selected from microcrystalline coarse powder and microcrystalline medium powder (Martino: [0021]; Example 1) and that such tablet formulation containing microcrystalline coarse powder and microcrystalline medium powder is expected to provide improved dissolution. As discussed above, it is reiterated that microcrystalline cellulose KG-802 of Miyamoto is within the scope of the preferred microcrystalline ce