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 .
DETAILED ACTION
The amendment dated 13 November 2025, in which claim 22 has been amended, and claim 17 has been cancelled, is acknowledged.
Claims 1, 13-16, 22-23, 29 are pending in the instant application.
Claims 1, 13-16, 22-23, 29 are being examined herewith.
Response to arguments of 13 November 2025
In view of Applicant’s amendment of 13 November 2025, all the objections and rejections to claim 17 are herein withdrawn. Claim 17 has been cancelled.
In view of Applicant’s amendment of 13 November 2025, the objection to claims 23, 24 is herein withdrawn. Applicant has corrected the claim number.
In view of Applicant’s amendment of 13 November 2025, the objection to claim 22 is herein withdrawn. Applicant has clarified the claim language.
Applicant’s arguments (Remarks of 13 November 2025, pages 6-8) against the rejection of claims 1, 13-17, 22-23, 29 under AIA 35 U.S.C. 103 over Furet, in view of Mendizabal and Fielden, have been considered.
Applicant argues (page 7, second paragraph) that Furet does not teach MCC or dissolution time of 3 minutes or less; that Mendizabal (page 7, third paragraph) is directed to a dispersible tablet containing a low loading of a different drug (fluoxetine), Mendizabal does not teach alpelisib, and Mendizabal does not teach high drug loading that is recited in the present claims. Applicant argues (page 7, fourth paragraph) that Fielden does not teach alpelisib.
In response, the rejection uses the combined teachings of Mendizabal and Fielden, where Mendizabal teaches disintegrants, binders and lubricants such as the very ones of the instant claims, used in dispersible tablets with low drug loading, and Fielden teaches that rapid dispersal of tablets is accomplished with high drug loading, and disintegrants, binders and lubricants present in the composition.
Applicant’s argument (page 7, third paragraph) that there is no expectation of success for taking a low load drug formulation and applying it to a high load formulation is not persuasive, because the ingredients in the oro-dispersible tablets with low drug loading (Mendizabal) and in the oro-dispersible tablets with high drug loading (Fielden) are similar or the same, and are the same ingredients in the instant claims. Therefore, Mendizabal and Fielden cannot be regarded as non-analogous art.
Mendizabal teaches (claim 1) sodium starch glycolate as one out the three disintegrants to be used in dispersible tablets. Mendizabal teaches (column 3, lines 18-19) that sodium starch glycolate is a particularly preferred disintegrant, to be used in concentrations exceeding 5% wt. in relation to the total weight of the formulation, which is within the instant range of 5% to 10% wt. Mendizabal explains that below 5%, the volume increase caused by the swelling of sodium starch glycolate is relatively large and causes rapid but insufficient disintegration (column 3, lines 15-23).
The instant claims recite microcrystalline cellulose and Mendizabal teaches microcrystalline cellulose present at 46% to 58% by weight of the tablet, which is encompassed by the 30% to 60% wt. range (MCC + mannitol) in instant claims. Moreover, Mendizabal explains (column 4, lines 8-26) why MCC is preferred. Mendizabal teaches (column 4, lines 13-18) that microcrystalline cellulose enables tablets to be manufactured with a high degree of purity using the direct compression technique, while also acting as a binder, to give strong tablets a suitable hardness, while its swelling capacity provides short disintegration times.
Mendizabal clearly teaches that (b) sodium starch glycolate at over 5% is particularly preferred disintegrant (one of preferred 3); (c) low-substituted hydroxypropyl cellulose is preferred binder (one of preferred 5);
(d) sodium stearyl fumarate is preferred lubricant (one of preferred 2),
mannitol as sweetener and
microcrystalline cellulose at 46% to 58% by weight as preferred diluent in dispersible tablets.
The point of the rejection is that it is obvious to use ingredients commonly used in dispersible tablets (Mendizabal, Fielden), namely sodium starch glycolate, low-substituted hydroxypropryl cellulose, sodium stearyl fumarate, and microcrystalline cellulose, mannitol, to prepare a dispersible tablet of alpelisib. As such, the rejection combines the teachings of several prior art references, which are not limited to alpelisib. Mendizabal teaches the very ingredients of the instant claims, namely sodium starch glycolate, low-substituted hydroxypropryl cellulose, sodium stearyl fumarate, and microcrystalline cellulose, mannitol, in low drug loading dispersible tablets, and Fielden teaches the same ingredients present in high drug loading tablets.
Oro-dispersible tablets are common and many small molecule drugs have been formulated in this dosage form. The examiner maintains that it would be obvious to apply the general teachings related to common ingredients in oro-dispersible tablets (Mendizabal and Fielden), to prepare an oro-dispersible tablet of alpelisib.
For all these reasons, the rejection to claims 1, 13-17, 22-23, 29 under AIA 35 U.S.C. 103 over Furet, in view of Mendizabal and Fielden, is herein maintained and a modified rejection is made below, based on Applicant’s amendment of 13 November 2025.
Applicant has put forth no arguments (page 8) against the rejections of claims 1, 13-17, 22-23, 29 on the ground of nonstatutory obviousness-type double patenting over claims of US patent 8,227,462, in view of Mendizabal and Fielden; and over claims of US patent 8,476,268, in view of Mendizabal and Fielden. As a result, these rejections are herein maintained and modified rejections are made below, based on Applicant’s amendment of 13 November 2025.
Claim Rejections- 35 USC 103
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.
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.
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.
Claims 1, 13-16, 22-23, 29 are rejected under AIA 35 U.S.C. 103 as being unpatentable over Furet et al. (WO 2013/144249, published 3 October 2013, cited in IDS), in view of Mendizabal (US 5,747,068 of 5 May 1998, cited in IDS) and Fielden K. (US 5,698,226 of 16 December 1997, cited in IDS).
Furet discloses (page 26, last paragraph) pharmaceutical compositions in the form of tablets comprising (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) or a pharmaceutically acceptable salt thereof as the active ingredient, together with a) diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine: b) lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; c) binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and or polyvinylpyrrolidone; d) disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or e) absorbents, colorants, flavors and sweeteners as excipients.
Furet teaches (page 26, first paragraph, last 3 lines) unit dosage forms for oral administration comprising about 1 mg to 500 mg of the compound (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) or a pharmaceutically acceptable salt thereof, which encompasses the range in instant claim 13, and the amounts in instant claims 14, 15.
Furet teaches a method of treating cancer (Abstract), as in instant claim 29, comprising administering to a subject in need thereof a pharmaceutical composition in the form of tablets comprising (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) or a pharmaceutically acceptable salt thereof as the active ingredient.
Furet does not disclose the concentration of each of the ingredients in the tablet.
While Furet broadly teaches starches as disintegrants in the tablets, Furet does not specifically teach sodium starch glycolate as disintegrant in said tablets.
Furet does not specifically teach low-substituted hydroxypropyl cellulose as binder in said tablets.
Furet does not teach sodium stearyl fumarate as lubricant in said tablets.
Furet does not teach specifically teach microcrystalline cellulose as pharmaceutically acceptable excipient in said tablets, as in instant claims.
Furet does not teach that the disintegration time of the tablet is 3 minutes or less, as in instant claims.
Furet does not specifically teach that the tablet comprises 50 mg of active ingredient (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) or a pharmaceutically acceptable salt thereof, as in instant claims 13, 14, or 200 mg of active ingredient (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) or a pharmaceutically acceptable salt thereof, as in instant claims 13, 15.
Furet does not teach the force used to compress the tablets, nor does he teach the hardness of the tablets, as in instant claims 14, 15.
Mendizabal (US 5,747,068) teaches a dispersible tablet manufactured by direct compression, dispersible in water in less than 3 minutes (as in instant claims), consisting of an active ingredient, along with:
(b) a disintegrant which is sodium starch glycolate (claim 1 and 2);
(c) a diluent which is microcrystalline cellulose (claims 1 and 8) or low-substituted hydroxypropyl cellulose (L-HPC) (claims 1, 5, 6), or mixtures thereof (claim 1);
(d) a lubricant which is stearyl sodium fumarate (claims 1 and 10);
(e) additional excipients sweeteners, flavoring, colorant.
Mendizabal teaches (claim 2) that the concentration of sodium starch glycolate disintegrant (b) in the formulation is 9.5% to 17% by weight, which overlaps with the instantly claimed range.
Mendizabal teaches (claim 5) that the formulation contains low-substituted hydroxypropyl cellulose (L-HPC) as diluent in an amount 5% to 25% by weight in relation to the total weight of the formulation.
Mendizabal teaches (column 4, line 32) microcrystalline cellulose in the formulation, in an amount of 46% to 58% by weight to the total weight of the formulation, which is within the range in instant claim 1.
Mendizabal specifically teaches (Example 3, column 8) a dispersible tablet containing an active compound, and ingredients
(b) sodium starch glycolate (10% wt., within the range in instant claim 1),
(c) low-substituted hydroxypropyl cellulose L-HPC,
(d) sodium stearyl fumarate, which are the very ingredients in instant claim 1, and
( e) microcrystalline cellulose, the ingredient in instant claims, present in an amount within the range in instant claim 1. Mendizabal also teaches sweeteners (column 5, lines 8-10), and, for example, mannitol (column 5, lines 48) as excipients in dispersible tablets.
Thus, Mendizabal teaches the very ingredients used in a dispersible tablet of the instant claims, in combination.
Mendizabal teaches (Example 3, column 8) that the hardness of the tablet is measured, as in instant claims 14, 15, and that the disintegration time of the tablet is less than 3 minutes, as in instant claims.
Importantly, Mendizabal presents a number of general teachings about the importance and the rationale behind selecting ingredients/excipients in dispersible tablets
Mendizabal teaches (column 2, lines 46-58) that the properties and qualities of the dispersible tablet depend largely on the coadjuvants it incorporates, making the selection of such coadjuvants of the greatest importance.
Mendizabal teaches (column 3, lines 9-11) that, because the dispersible tablet’s critical parameter is its rate of disintegration in water, the selection of the appropriate disintegrant is one of the most important phases.
Mendizabal teaches that sodium starch glycolate is a particularly preferred disintegrant, to be used in concentrations exceeding 5% wt. in relation to the total weight of the formulation, preferably at concentration between 9.5% and 17%, which overlaps with the instantly claimed range. Mendizabal teaches that below 5%, the volume increase caused by the swelling of sodium srtarch glycolate is relatively large and causes rapid but insufficient disintegration (column 3, lines 15-23).
Mendizabal teaches that most suitable “diluents” (defined as excipients which facilitate the compression of powdery materials and give the tablets strength, column 3, lines 44-46) are hydroxypropyl cellulose (column 3, lines 50-67, column 4, lines 1-7), microcrystalline cellulose (column 4, lines 8-26). Mendizabal teaches that hydroxypropyl cellulose (HPC) not only facilitates compression, but also accelerates disintegration of the tablet and acts as an exfoliant (column 3, lines 55-57). Mendizabal teaches that, of the existing HPCs, L-HPC low-substituted hydroxypropyl cellulose is preferred, which is differentiated from classical HPCs by its low substitution rate and weak solubility in water (column 3, lines 57-61).
Mendizabal teaches (column 4, lines 40-45) stearyl sodium fumarate, a hydrophilic lubricant, as preferred lubricant, better than stearates such as magnesium stearate (column 4, lines 53-58), and the role of lubricants to reduce inter-particle friction inside the tablet, reducing the reaction forces appearing on the walls of the matrix (column 4, lines 40-44).
Mendizabal teaches (column 4, lines 13-18) that microcrystalline cellulose enables tablets to be manufactured with a high degree of purity using the direct compression technique, while also acting as a binder, to give strong tablets a suitable hardness, while its swelling capacity provides short disintegration times.
Mendizabal also teaches the importance of selecting sweeteners (column 5, lines 8-10), and incorporating mannitol, sorbitol (column 5, lines 48) as excipients in dispersible tablets.
Mendizabal does not teach (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) or a pharmaceutically acceptable salt thereof as active ingredient in a dispersible tablet.
Mendizabal does not teach high drug loading tablets, where the active compound is present in an amount of 35% to 45% in weight based on the total weight of the tablet, as in the instant claims.
Fielden (US 5,698,226) teaches high drug loading water dispersible tablets, capable of dispersing in water within 3 minutes (Abstract), having 40 mg to 800 mg (column 7, lines 40-50) active ingredient and comprising:
(a) 20 to 90%, or 25% to 80%, or 10-40% w/w active ingredient (column 8, lines 1-18),
(b) disintegrants such as, for example, sodium starch glycolate 0 to 10% (column 8, lines 38-40)
(c) binders such as, for example, hydroxypropyl cellulose up to 5% wt., preferably 2 to 4% wt. (column 9, lines 17-18)
(d) lubricants such as, for example, magnesium stearate 0.2% to 5% w/w (column 10, lines 14-15),
( e) fillers / water-soluble fillers, for example, mannitol sorbitol, xylitol (column 9, lines 60-62, column 10, lines 4-9), present at 0 to 95% (column 9, lines 58-60).
The ranges of concentrations for active ingredient, disintegrant, binder, lubricant, filler in Fielden overlap with the instant claimed ranges.
Fielden specifically teaches high drug loading water dispersible tablets, capable of dispersing in water within 3 minutes (Abstract), having 25 mg to 200 mg active ingredient and comprising (claim 13):
(a) 30% to 50% w/w active ingredient,
(b) 0 to 8% w/w sodium starch glycolate as disintegrant,
(c) 5% to 15% w/w low-substituted hydroxypropyl cellulose or microcrystalline cellulose as diluent,
(d) a lubricant which is magnesium stearate 0.25% to 2% w/w.
Thus, Fielden teaches the very disintegrant (b) and binder (c) as instantly claimed in water-dispersible tablets having high load of active ingredient.
Fielden also teaches (column 10, lines 4-10) that inclusion of a filler having a negative heat of solution in water, for example, mannitol, (or sorbitol or xylitol), which is an excipient in instant claims, provides tablets which, in addition to being water-dispersible (dispersible in an ingestible liquid, as in instant claims 22, 23), are especially suitable for chewing in the mouth (which is relevant to claim 22), the dissolving of such an excipient in the saliva producing a cool, pleasant sensation.
Fielden also teaches (column 10, lines 57-58) sorbitol, as a sweetening agent in the tablets of the invention at 25 to 90% w/w.
Fielden teaches that the tablets of the invention are capable of dispersing in water within 3 minutes, as in instant claims.
Fielden teaches (column 7, lines 34-37) that the tablets of the invention contain a pre-determined amount of the active compound, depending on the identity of the compound, the desired dosage and the total weight of the tablet.
Fielden measures tablet hardness (column 11, lines 40-52), as in instant claims 14, 15.
Fielden teaches wet granulation (column 20, lines 61-67, columns 21, 22), as in instant claims 16, 17, as a step in the preparation of dispersible tablets.
Fielden does not teach (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) or a pharmaceutically acceptable salt thereof as active ingredient in a dispersible tablet.
Fielden does not teach sodium stearyl fumarate as lubricant (d) in the tablets.
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of Furet, Mendizabal and Fielden to arrive at the instantly claimed invention.
The person of ordinary skill in the art would have been motivated to formulate (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) or a pharmaceutically acceptable salt thereof as a dispersible tablet, because Furet teaches tablets for oral administration comprising Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide), and Mendizabal and Fielden teach the advantages of dispersible tablets in terms of rapid disintegration rate.
The person of ordinary skill in the art would have formulated a dispersible tablet of Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) comprising sodium starch glycolate, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate, and microcrystalline cellulose and mannitol, of the instant invention, because Mendizabal and Fielden teach dispersible tablets containing an active compound and sodium starch glycolate as super disintegrant, low-substituted hydroxypropyl cellulose as binder, lubricants, and sweeteners such as mannitol, sorbitol, as common excipients, and Mendizabal clearly explains the reasons for choosing sodium starch glycolate as super disintegrant, low-substituted hydroxypropyl cellulose as binder, sodium stearyl fumarate as lubricant, and microcrystalline cellulose as diluent, as critical ingredients in a dispersible tablet.
Further, the person of ordinary skill in the art would have been motivated to prepare a high drug loading tablet comprising 35% to 45% in weight active ingredient (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) or a pharmaceutically acceptable salt thereof, based on the weight of the tablet, and comprising
(b) sodium starch glycolate (disintegrant),
(c) low-substituted hydroxypropyl cellulose (binder),
(d) sodium stearyl fumarate lubricant,
because Fielden teaches dispersible tablets containing an active compound and super disintegrants such as sodium starch glycolate, binders such as low-substituted hydroxypropyl cellulose, lubricants such as stearates, and sweeteners such as mannitol, sorbitol, as common excipients, and Mendizabal clearly explains the reasons for choosing sodium starch glycolate as super disintegrant, low-substituted hydroxypropyl cellulose as binder, sodium stearyl fumarate as lubricant, and microcrystalline cellulose as diluent, as critical ingredients in a dispersible tablet. Thus, based on the teachings of Mendizabal, the person of ordinary skill in the art would have been motivated to specifically choose sodium starch glycolate as super disintegrant from the list of disintegrants in Fielden, low-substituted hydroxypropyl cellulose as binder from the list of binders in Fielden, sodium stearyl fumarate as lubricant as a preferred lubricant to the stearates in Fielden, and microcrystalline cellulose as diluent from the list in Fielden, as ingredients in a dispersible tablet, with the expectation that such a combination of ingredients added to drug alpelisib will result in a dispersible tablet of alpelisib.
It is acknowledged that the content/concentration of active ingredient and excipients sodium starch glycolate, low-substituted hydroxypropyl cellulose, lubricant in a dispersible tablet, as disclosed by Fielden is overlapping in scope relative to that range which is claimed. MPEP §2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" aprimafacie case of obviousness exists." 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) and "a prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish aprimafacie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003). In the instant case, the Fielden reference discloses a concentration of active ingredient, disintegrant such as sodium starch glycolate, binder such as low-substituted hydroxypropyl cellulose, and lubricant such as stearates in a dispersible tablet which demonstrates clear and significant overlap with the ratio as instantly claimed and as such the Examiner advances that a person of ordinary skill in the art (e.g., Applicants) would have been motivated to employ routine experimentation in arriving at the claimed ratio range, absent a clear showing of criticality for the instantly claimed range.
Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of ranges in which known/common excipients are being combined would have been obvious at the time of Applicant's invention.
As such, claims 1, 13-16, 22-23, 29 are rejected as prima facie obvious.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1, 13-16, 22-23, 29 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable at least over claims 1, 3-4 of US patent 8,227,462 (cited in IDS), in view of Mendizabal (US 5,747,068 of 5 May 1998, cited in IDS) and Fielden K. (US 5,698,226 of 16 December 1997, cited in IDS).
Claims 1, 4 of US patent 8,227,462 are drawn to the instant (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) or to a pharmaceutical composition comprising (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide and one or more pharmaceutically acceptable excipients; claim 3 is drawn to a method of treating for example cancer of the breast (as in instant claim 29) with (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide).
Mendizabal and Fielden are as above.
It would be obvious to prepare a dispersible tablet of (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) using the ingredients (and the relative concentrations of ingredients) taught by Mendizabal and Fielden to be of importance in dispersible tablets.
The person of ordinary skill in the art would have formulated a dispersible tablet of Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) comprising sodium starch glycolate, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate, and microcrystalline cellulose, because Mendizabal and Fielden teach dispersible tablets containing an active compound and sodium starch glycolate as super disintegrant, low-substituted hydroxypropyl cellulose as binder, lubricants, and sweeteners such as mannitol, sorbitol, as common excipients, and Mendizabal clearly explains the reasons for choosing sodium starch glycolate as super disintegrant, low-substituted hydroxypropyl cellulose as binder, sodium stearyl fumarate as lubricant, and microcrystalline cellulose as diluent, as critical ingredients in a dispersible tablet.
Further, the person of ordinary skill in the art would have been motivated to prepare a high drug loading tablet comprising 35% to 45% in weight active ingredient (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) or a pharmaceutically acceptable salt thereof, based on the weight of the tablet, and comprising (b) sodium starch glycolate (disintegrant), (c) low-substituted hydroxypropyl cellulose (binder), (d) sodium stearyl fumarate lubricant, because Fielden teaches dispersible tablets containing an active compound and super disintegrants such as sodium starch glycolate, binders such as low-substituted hydroxypropyl cellulose, lubricants such as stearates, and sweeteners such as mannitol, sorbitol, as common excipients, and Mendizabal clearly explains the reasons for choosing sodium starch glycolate as super disintegrant, low-substituted hydroxypropyl cellulose as binder, sodium stearyl fumarate as lubricant, and microcrystalline cellulose as diluent, as critical ingredients in a dispersible tablet. Thus, based on the teachings of Mendizabal, the person of ordinary skill in the art would have been motivated to specifically choose sodium starch glycolate as super disintegrant from the list of disintegrants in Fielden, low-substituted hydroxypropyl cellulose as binder from the list of binders in Fielden, sodium stearyl fumarate as lubricant as a preferred lubricant to the stearates in Fielden, and microcrystalline cellulose as diluent from the list in Fielden, as ingredients in a dispersible tablet, with the expectation that such a combination of ingredients added to drug alpelisib will result in a dispersible tablet of alpelisib.
It is acknowledged that the content/concentration of active ingredient and excipients sodium starch glycolate, low-substituted hydroxypropyl cellulose, lubricant in a dispersible tablet, as disclosed by Fielden is overlapping in scope relative to that range which is claimed. MPEP §2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" aprimafacie case of obviousness exists." 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) and "a prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish aprimafacie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003). In the instant case, the Fielden reference discloses a concentration of active ingredient, disintegrant such as sodium starch glycolate, binder such as low-substituted hydroxypropyl cellulose, and lubricant such as stearates in a dispersible tablet which demonstrates clear and significant overlap with the ratio as instantly claimed and as such the Examiner advances that a person of ordinary skill in the art (e.g., Applicants) would have been motivated to employ routine experimentation in arriving at the claimed ratio range, absent a clear showing of criticality for the instantly claimed range.
Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of ranges in which known/common excipients are being combined would have been obvious at the time of Applicant's invention.
Claims 1, 13-16, 22-23, 29 are rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable at least over claims 1-5 of US patent 8,476,268 (cited in IDS), in view of Mendizabal (US 5,747,068 of 5 May 1998, cited in IDS) and Fielden K. (US 5,698,226 of 16 December 1997, cited in IDS).
Claims 1-3 of US patent 8,476,268 are drawn to a genus of compounds encompassing the instant (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) (compound listed in claim 3); claim 4 is drawn to a method of treating a proliferative disease such as cancer of the breast (as in instant claim 29) with a compound of claim 3; claim 5 is drawn to a pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable carrier.
Mendizabal and Fielden are as above.
It would be obvious to prepare a dispersible tablet of (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) using the ingredients (and the relative concentrations of ingredients) taught by Mendizabal and Fielden to be of importance in dispersible tablets.
The person of ordinary skill in the art would have formulated a dispersible tablet of Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) comprising sodium starch glycolate, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate, and microcrystalline cellulose, because Mendizabal and Fielden teach dispersible tablets containing an active compound and sodium starch glycolate as super disintegrant, low-substituted hydroxypropyl cellulose as binder, lubricants, and sweeteners such as mannitol, sorbitol, as common excipients, and Mendizabal clearly explains the reasons for choosing sodium starch glycolate as super disintegrant, low-substituted hydroxypropyl cellulose as binder, sodium stearyl fumarate as lubricant, and microcrystalline cellulose as diluent, as critical ingredients in a dispersible tablet.
Further, the person of ordinary skill in the art would have been motivated to prepare a high drug loading tablet comprising 35% to 45% in weight active ingredient (S)-Pyrrolidine-1,2-dicarboxylic acid 2-amide 1-({4-methyl-5-[2-(2,2,2-trifluoro-l, l-dimethyl-ethyl)-pyridin-4-yl]-thiazol-2-yl}-amide) or a pharmaceutically acceptable salt thereof, based on the weight of the tablet, and comprising (b) sodium starch glycolate (disintegrant), (c) low-substituted hydroxypropyl cellulose (binder), (d) sodium stearyl fumarate lubricant, because Fielden teaches dispersible tablets containing an active compound and super disintegrants such as sodium starch glycolate, binders such as low-substituted hydroxypropyl cellulose, lubricants such as stearates, and sweeteners such as mannitol, sorbitol, as common excipients, and Mendizabal clearly explains the reasons for choosing sodium starch glycolate as super disintegrant, low-substituted hydroxypropyl cellulose as binder, sodium stearyl fumarate as lubricant, and microcrystalline cellulose as diluent, as critical ingredients in a dispersible tablet. Thus, based on the teachings of Mendizabal, the person of ordinary skill in the art would have been motivated to specifically choose sodium starch glycolate as super disintegrant from the list of disintegrants in Fielden, low-substituted hydroxypropyl cellulose as binder from the list of binders in Fielden, sodium stearyl fumarate as lubricant as a preferred lubricant to the stearates in Fielden, and microcrystalline cellulose as diluent from the list in Fielden, as ingredients in a dispersible tablet, with the expectation that such a combination of ingredients added to drug alpelisib will result in a dispersible tablet of alpelisib.
It is acknowledged that the content/concentration of active ingredient and excipients sodium starch glycolate, low-substituted hydroxypropyl cellulose, lubricant in a dispersible tablet, as disclosed by Fielden is overlapping in scope relative to that range which is claimed. MPEP §2144.05(I) states that "[i]n the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" aprimafacie case of obviousness exists." 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) and "a prior art reference that discloses a range encompassing a somewhat narrower claimed range is sufficient to establish aprimafacie case of obviousness." In re Peterson, 315 F.3d 1325, 1330, 65 USPQ2d 1379, 1382-83 (Fed. Cir. 2003). In the instant case, the Fielden reference discloses a concentration of active ingredient, disintegrant such as sodium starch glycolate, binder such as low-substituted hydroxypropyl cellulose, and lubricant such as stearates in a dispersible tablet which demonstrates clear and significant overlap with the ratio as instantly claimed and as such the Examiner advances that a person of ordinary skill in the art (e.g., Applicants) would have been motivated to employ routine experimentation in arriving at the claimed ratio range, absent a clear showing of criticality for the instantly claimed range.
Thus, absent some demonstration of unexpected results from the claimed parameters, this optimization of ranges in which known/common excipients are being combined would have been obvious at the time of Applicant's invention.
Conclusion
Claims 1, 13-16, 22-23, 29 are rejected.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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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/IRINA NEAGU/Primary Examiner, Art Unit 1629