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 .
Election/Restrictions
Applicant’s election without traverse of the composition of Claims 1-8 and 16-18 in the reply filed on 29 December 2025 is acknowledged.
Status of the Claims
Claims 1-23 are pending.
Claims 9-15 and 19-23 are withdrawn from consideration as directed to non-elected inventions.
Claims 1-8 and 16-18 are presented for examination and rejected as set forth below.
Priority
The instant application is a National Stage entry of International application PCT/CN2022/08/3127 filed 25 March 2022.
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55 pertaining to Chinese national application 202110327776.4 filed 26 March 2021. The Examiner notes that no English language translation has been provided.
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, 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 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 § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-8 and 16-18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, Claim 1 specifies multiple ranges of crystalline agent concentrations, each of Claims 5, 6, 8, 16 and 18 identifies multiple concentration ranges for each listed composition component, while each of Claims 6, 8, and 17 recite alternative overlapping particle size distribution ranges. The claims are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
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 (i.e., changing from AIA to pre-AIA ) 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.
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, and 18 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 the present claims. (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 to polymer weight ratios of the present claims. [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%. [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, Cia 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 fomes containing between about 0.01-50mg, a range overlapping and therefore rendering obvious the solid dispersion weights of the present claims. [0045-46]. Gelatin capsules 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 is identified as a suitable glidant, and mannitol an exemplary polyol to be used as a filler. [0036-38; 0173]. 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 claimed. [0165]. Disintegrants are described as being included in concentrations between about 0.5-30% by weight, overlapping the crospovidone ranges claimed. [0167]. Lubricants such as magnesium stearate are described as includable in concentrations of between 0.1-5% by weight of the composition, overlapping the ranges recited by the claims. [0170-71]. While not particularly limited, exemplary embodiments of oral dosage forms containing silicon dioxide contain this component in concentrations of 1%. [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 and 16-18 are rejected under 35 U.S.C. 103 as being unpatentable over Cai and Xu as applied to claims 1-5, 7, 16, and 18 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, nor a mannitol whereby at least 70% of which has a particle size of greater than 75 microns.
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. [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. (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.
Conclusion
No Claims are allowable.
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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/SEAN M BASQUILL/Primary Examiner, Art Unit 1614