DETAILED 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 .
Status of the Claims
Claims 1-12 and 16-32 are pending.
Claims 9-12 and 19-23 are withdrawn from consideration as directed to non-elected inventions.
Claims 1-8, 16-18, and 24-32 are presented for examination and rejected as set forth below.
Claim Interpretation
Applicants Claims are directed to pharmaceutical compositions comprising amorphous solid dispersions of the 5-fluoro-1-( 4-fluoro-3-( 4-(pyrimidin-2-yl)piperazine- l-carbonyl)benzyl)quinazoline-2,4(1 H,3H)-dione (“the active”) combined with fillers including mannitol having at least 70% of the particles with a size greater than 75 microns, disintegrants, glidants, and lubricants, where the agent is present in less than 10% having a crystalline form. Dependent claims specify the solid dispersion is one which contains hydroxypropyl methylcellulose phthalate and, optionally, a poloxamer. Claim 3 specifies a particular HPMCP is to be used; review of applicants own specification indicates that the HPMCP available as “HP-55” addresses these limitations. Additional dependent claims narrow the identity and amounts of each of the fillers, disintegrants, glidants, and lubricants to be employed in the compositions claimed, with further dependent claims specifying concentrations of each, or particular properties the excipients are to possess. Claim 7 places the compositions into capsules, more particularly gelatin capsules.
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 1-5, 7, 16-18, 24-26, 28, 29, 31, and 32 are rejected under 35 U.S.C. 103 as being unpatentable over Cai (U.S. PGPub. 2018/0071290), in view of Xu (WO2019/152798).
Cai describes a solid dispersion powder including 5-fluoro-1-( 4-fluoro-3-( 4-(pyrimidin-2-yl)piperazine- l-carbonyl)benzyl)quinazoline-2,4(1 H,3H)-dione and polymers, wherein the content of polymers is from about 50 wt % to about 80 wt %, and wherein less than 10 wt % of 5-fluoro-1-( 4- fluoro-3-( 4-(pyrimidin-2-yl)piperazine-l-carbonyl)benzyl) quinazoline-2,4(1H,3H)-dione is in crystalline form, ranges overlapping and therefore rendering obvious the limitations of present claims 1, 6, 8, 24, 29, and 30. (Abs.), see In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) (“A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.”). In fact, Cai describes compositions with nearly no crystalline agent. [0007]. The HPMCP of the instant claims is identified as a preferred polymer for inclusion in the solid dispersions in concentrations of between about 40-80%, while the agent is present in concentrations of about 10-40% by weight of the solid dispersion, defining ranges which encompass the agent concentrations as well as agent to polymer weight ratios of present claims 1, 2, 5, 6, 8, 16, 25, and 29-32. [0009]. Cai indicates that the HPMCP HP-55 applicants indicate address the limitations of Claim 3 represents an exemplary HPMCP polymer to be used. [0034]. Cai indicates that a poloxamer may optionally be included in the solid dispersion in concentrations of about 1-10%, addressing limitations of Claims 2, 16, and 32. [0010]. As no additional components are identified by Cai as necessary for inclusion in the solid dispersion, the claim limitations indicating that the solid dispersion is to consist of the agent and HPMCP, or of the agent, HPMCP, and optional surfactant such as poloxamer, are necessarily addressed. Taken together, Cai therefore suggests agent, polymer, and optional surfactant ranges overlapping and therefore rendering obvious the ranges of the present claims. See Peterson, supra. Cai indicates that these solid dispersions may be incorporated into oral unit dosage forms containing between about 0.01-50mg, a range overlapping and therefore rendering obvious the solid dispersion weights of the present claims 8, 30. [0045-46]. Gelatin capsules of Claim 7 are identified as a particular oral dosage form, which may be formulated to contain fillers, binders, lubricants such as magnesium stearate of the present claims, and stabilizers, while indicating that parameters normally encountered in and therefore obvious to those of skill in the art fall within the scope of the compositions described.
Despite suggesting a solid dispersion of amorphous agent containing nearly zero crystalline agent in combination with HPMCP and optionally poloxamer in concentrations encompassing those of the instant claims, then incorporating such a dispersion in combination with fillers, binders, lubricants such as magnesium stearate of the present claims, stabilizers, and components ordinarily encountered in the pharmaceutical arts to be placed in a gelatin capsule, the particular use of microcrystalline cellulose and mannitol as a filler, crospovidone as a disintegrant, colloidal silicon dioxide as glidant, and magnesium stearate as lubricant in the concentrations claimed is not described by Cai.
However, Xu indicates that microcrystalline cellulose and polyols used as filler excipients, crospovidone (described as crosslinked polyvinylpyrrolidone) as a disintegrant, binders and combinations thereof are commonly employed in the pharmaceutical formulation arts. [0004; 0032-33; 0035]. Colloidal silicon dioxide of Claims 4, 6, 8, 17, 29, and 30 is identified as a suitable glidant, and mannitol an exemplary polyol to be used as a filler. [0036-38; 0173]. As regards the particular size of mannitol particles to be used as fillers, Xu indicates that mannitol used as fillers may suitably have a particle size falling within the range of 100-500, or 100-200 microns, ranges addressing the newly added limitations of Claims 1, 17, 28, 29, and 30. [0164]. Xu indicates that fillers may be present in pharmaceutical formulations in concentrations from about 10-90% of the composition, overlapping the microcrystalline cellulose and mannitol concentration ranges and ratios of Claims 4, 5, 6, 8, 17, 18, 25, 26, 29, and 30. [0165]. Disintegrants are described as being included in concentrations between about 0.5-30% by weight, overlapping the crospovidone ranges recited in Claims 4, 5, 6, 8, 17, 25, 29, and 30. [0166-67]. Lubricants such as magnesium stearate are described as includable in concentrations of between 0.1-5% by weight of the composition, overlapping and rendering obvious the ranges recited by claims 4-6, 8, 17, 25, 26, 29, and 30. [0170-71]. While not particularly limited, exemplary embodiments of oral dosage forms containing silicon dioxide contain this component in concentrations of 1%, addressing limitations of Claims 4-6, 8, 17, 25, 29, and 30. [0455].
It therefore would have been prima facie obvious at the time the present application was filed to have combined the solid agent dispersion of Cai with the various fillers, disintegrants, glidants, and lubricants recited by the claims in the amounts claimed and placed such a composition into a gelatin capsule. This is because Cai suggests a solid dispersion of amorphous agent containing nearly zero crystalline agent in combination with HPMCP and optionally poloxamer in concentrations encompassing those of the instant claims to be combined with various elements known to be useful in the pharmaceutical arts to provide oral unit dosage forms including gelatin capsules. Xu indicates that each of the microcrystalline cellulose and polyols such as mannitol are used as filler excipients, crospovidone as a disintegrant, colloidal silicon dioxide is identified as a suitable glidant, and magnesium stearate as a lubricant. This suggests that the claimed combination amounts to little more than the predictable use of prior art elements according to their established functions, and obvious thereby. KSR v. Teleflex, 127 S.Ct. 1727, 1740 (2007) (quoting Sakraida v. A.G. Pro, 425 U.S. 273, 282 (1976)).
Claims 1-8, 16-18, and 24-32 are rejected under 35 U.S.C. 103 as being unpatentable over Cai and Xu as applied to claims 1-5, 7, 16-18, 24-26, 28, 29, 31, and 32 above, and further in view of Zhang (WO2020/011257)(U.S. PGPub. 2021/0186909, the National Stage entry of Zhang, relied on as English translation: all references are to the U.S. PGPub.), and Serpelloni (U.S. 5,573,777).
Cai and Xu, discussed in greater detail above, suggest pharmaceutical gelatin capsules combining a solid dispersion of amorphous agent containing nearly zero crystalline agent in combination with HPMCP and optionally poloxamer in concentrations and amounts encompassing those of the instant claims with each of the microcrystalline cellulose and mannitol filler excipients, crospovidone as a disintegrant, colloidal silicon dioxide as a glidant, and magnesium stearate as a lubricant.
Neither Cai nor Xu describe microcrystalline cellulose with the size ranges recited by the claims.
Zhang also describes combinations of microcrystalline cellulose and mannitol used as pharmaceutical fillers. [0071]. Zhang indicates that one particular microcrystalline cellulose available as a pharmaceutical excipient possesses a D90 of 270-450 microns, a range overlapping and therefore rendering obvious that of the instant claims 6, 8, 17, 27, 29, and 30. [0079], see Peterson, supra.
Serpelloni indicates that particulate mannitol having less than 30% of the particles smaller than 75 microns provides remarkable functional properties for use in pharmaceuticals, further addressing the limitations of Claims 1, 17, 28, 29, and 30. (Abs).
It therefore would have been prima facie obvious to have used a microcrystalline cellulose with a D90 of 270-450 microns as the microcrystalline cellulose of the composition of Cai and Xu, owing to the fact that such MCC was known to be useful as a pharmaceutical filler, and it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945). A similar rationale holds true for the obviousness of using as the mannitol filler of the compositions of Cai and Xu particulate mannitol having less than 30% of the particles smaller than 75 microns, and in fact falling within the range of, for example, 100-200 microns.
Response to Amendment
Applicant’s arguments with respect to the rejection of previously presented claims 1-8 and 16-18 as being indefinite under 35 U.S.C. 112(b) have been fully considered and, in view of the amendments presented, are persuasive. The rejection of Claims 1-8 and 16-18 as being indefinite has been withdrawn.
Response to Arguments
Applicant's arguments filed 21 May 2026 have been fully considered.
Applicants assert that the newly added limitations concerning the mannitol particle size are not taught by Cai, Zhang, or Serpelloni. This is unpersuasive for the reason that the Examiner has not asserted that it does. See In re Keller, 642 F.2d 413, 426 (C.C.P.A. 1981) (citing Application of Young, 403 F.2d 754, 757 (C.C.P.A. 1968) (indicating that "[O]ne cannot show non-obviousness by attacking references individually where ... the rejections are based on combinations of references"); In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000)(the proper test for obviousness is what the combined teachings would have suggested to a person of ordinary skill in the art). The mannitol particle sizes of the instant claims are rendered obvious not only by the teachings of Xu, but are in fact further motivated by the teachings of Serpelloni. Not only does Xu indicate that mannitol filler particles having a size falling within the range of 100-200 microns, a range well in excess of the requirements of the present claims, were at the time known to be useful fillers in pharmaceutical dosage forms, but Serpelloni indicates that there was an art-recognized advantage to utilizing mannitol particles whereby less than 30% of the particles fell below 75 microns. See In re Sernaker, 702 F.2d 989, 994-95 (Fed. Cir. 1983) (“The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination.”).
Applicants allusion to some long-standing problem in the art is devoid of objective evidence and therefore per se unpersuasive. Applicants are reminded that establishing long-felt need requires objective evidence that an art recognized problem existed in the art for a long period of time without solution. The relevance of long-felt need and the failure of others to the issue of obviousness depends on several factors. First, the need must have been a persistent one that was recognized by those of ordinary skill in the art. In re Gershon, 372 F.2d 535, 539, 152 USPQ 602, 605 (CCPA 1967). Second, the long-felt need must not have been satisfied by another before the invention by applicant. Newell Companies v. Kenney Mfg. Co., 864 F.2d 757, 768, 9 USPQ2d 1417, 1426 (Fed. Cir. 1988). Third, the invention must, in fact, actually satisfy the long-felt need. In re Cavanagh, 436 F.2d 491, 168 USPQ 466 (CCPA 1971).
That Xu lists mannitol as a filler among many alternatives is immaterial to the question of obviousness, for it is long-settled that it is a matter of obviousness for one of ordinary skill in the art to select a particular component from among many disclosed by the prior art as long as it is taught that the selection will result in the disclosed effect, even when the possible selections number 1200 or in the thousands. Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807 (Fed. Cir. 1989); In re Corkill, 771 F.2d 1496, 1500 (Fed. Cir. 1985).
That Zhang uses mannitol and MCC as fillers for a different active agent is, again, immaterial to the matter of obviousness, as Zhang establishes that these components, as taught not only by Zhang but Xu as well, were recognized as fillers for pharmaceutical dosage forms, thereby rendering their use as pharmaceutical dosage form fillers prima facie obvious to a skilled artisan. This is because it has long been held that it is prima facie obvious to select a known material for incorporation into a composition, based on its recognized suitability for its intended use. See Sinclair & Carroll Co. v. Interchemical Corp., 325 U.S. 327, 65 USPQ 297 (1945) (indicating that "Reading a list and selecting a known component to meet known requirements is no more ingenious than selecting the last piece to put in the last opening in a jig-saw puzzle. It is not invention.”).
That Serpelloni advocates the use of mannitol addressing the instant claim limitations for a different reason than that utilized by the applicants is, again, immaterial to the question of obviousness of the composition being claimed. That is because the reason or motivation to modify a prior art reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006) (motivation question arises in the context of the general problem confronting the inventor rather than the specific problem solved by the invention).
Applicants discussion of various alleged benefits associated with the composition claimed fail to overcome the prima facie case of obviousness for at least the reason that applicants fail to compare the invention claimed with the closest prior art. Once a prima facie case of obviousness is established, the burden shifts to the applicant to come forward with arguments and/or evidence to rebut the prima facie case. In re Dillon, 919 F.2d 688, 692, 16 USPQ2d 1897, 1901 (Fed. Cir. 1990); see In re Burckel, 592 F.2d 1175, 201 USPQ 67 (CCPA 1979)( Evidence of unexpected results must compare the claimed subject matter with the closest prior art to be effective to rebut a prima facie case of obviousness).
For at least these reasons, applicants arguments are unpersuasive.
Conclusion
No Claims are allowable.
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 SEAN M BASQUILL whose telephone number is (571)270-5862. The examiner can normally be reached Monday through Thursday, 5:30 AM to 4 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Ali Soroush can be reached at (571) 272-9925. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SEAN M BASQUILL/Primary Examiner, Art Unit 1614
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