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 .
Claim Status
Claims 17 and 22 are cancelled.
Claims 1-16 and 18-21 are pending.
Priority
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Information Disclosure Statement
The information disclosure statements (IDSs) submitted on 10/16/24, 3/24/25 and 10/23/25 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3, 5 and 14 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kirkorian (EP2444064).
Regarding claims 1-3 and 5, Kirkorian disclose a process of producing a tablet and the tablet made (Claims 1, 2 and 12-14) comprising thioguanine (Claim 10) and a polyethylene oxide with a molecular weight of at least 1000000 (Claim 6). The term “at least” is properly interpreted to mean one or more of the claimed limitation and thus the disclosure of “at least 1000000” means 1000000 or more and falls within and embraces the claimed range of about 900000 and 9000000 g/mol and the range of greater than about 900000 and less than 7000000 g/mol and in one interpretation is substantially a single approximate molecular weight of 1000000. Performing the process of Kirkorian produces the instantly claimed pharmaceutical composition. Regarding claim 14, since the components are the same as claimed, then the oral dosage form tablet of Kirkorian is also formulated to provide approximately zero-order kinetics of 6-TG release. See MPEP 2112.01 II.COMPOSITION CLAIMS — IF THE COMPOSITION IS PHYSICALLY THE SAME, IT MUST HAVE THE SAME PROPERTIES
“Products of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).”
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 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 1-16 and 18-21 are rejected under 35 U.S.C. 103 as being unpatentable over Florin et al. (CA3038602) in view of Gold et al. (US20070020331) and Parker et al. (Abstract of Curr. Opin. Investig. Drugs 2004;5(6): 592-6; 1 page) as evidenced by Shojaee et al. (Pharmaceutical Development and Technology 2016; 21:2: 189-195).
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103, the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103.
Applicant claims, for example:
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Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a pharmaceutical research scientist, as is the case here, then one can assume comfortably that such an educated artisan will draw conventional ideas from pharmaceutical formulation including active agent and excipient selection for the desired dosage form— without being told to do so. For example, the ordinary pharmaceutical formulation artisan understands controlled release tablet systems1 and that tablets are made with core components including diluents, fillers, disintegrants, binders and lubricants and may be enteric coated with known polymeric materials with functional additives to allow for intestinal release of the active agent. In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 1 and 21, Florin et al. teach pharmaceutical compositions comprising 6-thioguanine formulated for release in the distal intestine and methods of treating a disease or condition of the distal ileum (Abstract; [0085-0087]; claims 1 and 74-75). Florin et al. teach that the pharmaceutical composition comprises an erodible hydrophilic polymer matrix (Claim 1) that comprises polyethylene oxide (Claims 4, 6, 20, 33; [00207, 00219] for example) and the method comprises administering the 6-TG to an individual [0022, 0066-0067, 0085].
Regarding claims 2, 7, 11-12, Florin et al. teach enteric coated tablets with Eudragit S100 ([00219]; Figure 12; claim 14), which is formulated for oral administration, and provides a tablet core with an enteric coating. Florin et al. teach that enteric coating may be applied to a tablet using conventional techniques known in the art [00139]. Florin et al. teach using suitable enteric coatings include cellulose coatings such as cellulose acetate phthalate polymers or hydroxypropyl methylcellulose phthalate polymers or co-polymers of acrylic acids and their esters or methacrylic acids or their esters, such as those sold under the trade mark Eudragit® including Ll00, Ll00-55 and Sl00. [00137]. The enteric coating may comprise lubricants, plasticizers and anti-tacking agents [00138].
Regarding claim 8, Florin et al. teach: “In some embodiments the tablet comprises about 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 40 mg or 50 mg of 6-TG.” [00121], the 6-TG can be present from 10-30% w/w of the tablet [00127] and the tablet can weigh about 100-200 mg [00122].
Regarding claims 13, 15-16 and 19-20, Florin et al. claim: “wherein the composition is formulated for oral administration and provides release of at least 35% of the 6-TG in vitro at about pH 6 to about pH 7.5 after approximately 12 hours” (Claim 1); and teach that: “the composition provides for extended release over a period extending from 8 hours, 10 hours or 12 hours up to, for example, 18, 24, 30, 36, 40 or 48 hours following oral administration…at a pH range to 6 to 7.5” [0062], thus being capable of dissolving at a pH of at least 5.5; and “an oral formulation of the invention releases 6-TG in a controlled manner and attains release of about 80% of 6-TG content by the end of 24 hours from oral administration.” [0063]. Florin et al. also teach: “wherein the composition provides release of at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, or at least 95% of the 6-TG in vitro at about pH 6 to about pH 7.5 after approximately 12 hours.” (Claims 25, 38; see also claims 1, 8 and 9). Thus, Florin et al. reasonably teach embodiments where the pharmaceutical compositions provides release of: at least about 30% of the 6-TG in vitro at about pH 5.5 to about pH 7.5 by approximately 10 hours; at least
70% of the 6-TG in vitro at about pH 5.5 to about pH 7.5 by approximately 20 hours; less than 80% of the 6-TG in vitro at about pH 5.5 to about pH 7.5 by approximately 10 hours; and at least 85% of the 6-TG in vitro at about pH 5.5 to about pH 7.5 by
approximately 30 hours, and less than 80% of the 6-TG in vitro at about pH 5.5 to about pH 7.5 by approximately 10 hours.
Regarding claim 14, Florin et al. teach: “In preferred embodiments, the extended-release formulation provides approximately zero order kinetics of 6-TG release (i.e., a linear delivery with respect to the time of extended release).” ([0090]; see also claim 15).
Regarding claim 18, Florin et al. demonstrated wherein the pharmaceutical composition provides release of less than about 10% of the 6-TG in vitro at less than about pH 5.5 by approximately 2 hours by showing cumulative release of enteric coated formulation 12 [0036] in simulated gastric fluid [00219], a pH less than about 5.5, in Figure 12.
Regarding claims 1-4, Gold et al. teach: “Tablets for the controlled release of an active ingredient in a zero-order or near zero-order fashion are provided. The
tablet includes a core and a coating. The core includes at least one active pharmaceutical agent and a polyethylene oxide with a molecular weight of between about 1,000,000 and 10,000,000, preferably between about 4,000,000 and
8,000,000.” (Abstract; see also claims 1-23). The molecular weight range of between about 1000000 and 10000000 overlaps the claimed ranges of between about 900000 and 9000000; greater than about 9000000 and less than about 7000000 and about 2000000 g/mol. Gold et al. teach the purine analogs cladibrine and fludarabine as representative therapeutic agents [0034]. Parker et al. teach that the ordinary artisan is aware that that thioguanine, fludarabine and cladribine are purine analogs used in the treatment of cancer (Abstract). Tablets are formulated for oral administration.
Regarding claim 5, Gold et al. teach specific polyethylene oxides such as polyethylene oxide N3032 (Claims 3 and 14), which would comprise substantially a single approximate molecular weight.
Regarding claim 7, Gold et al. teach a film coating (Claims 22-23) such as ethyl cellulose [0061-0062], which provides an enteric coating on the core.
Regarding claims 9-10, Gold et al. teach a hydrophilic or hydrophobic drug present in a range between about 1-10% by weight of the tablet (Claims 9 and 19), which means the remainder of about 90-99% can be the polyethylene oxide.
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
The difference between the instant application and Florin et al. is that Florin et al. do not expressly teach a polyethylene oxide polymer having a molecular weight between about 900000 and 9000000; greater than about 9000000 and less than about 7000000 and about 2000000 g/mol and wherein the polyethylene oxide polymer comprises a substantially a single approximate molecular weight and is present from about 60-98% of the pharmaceutical composition or about 70 to 99% w/w of the core of the tablet or that the 6-TG and the polyethylene oxide polymer are in a ratio of about 1:20 to 1:50. This deficiency in Florin et al. is cured by the teachings of Gold et al. and Parker et al.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to employ a polyethylene oxide polymer having a molecular weight between about 900000 and 9000000; greater than about 9000000 and less than about 7000000 and about 2000000 g/mol and wherein the polyethylene oxide polymer comprises a substantially a single approximate molecular weight, as suggested by Gold et al. and Parker et al., for the polyethylene oxide polymer in the pharmaceutical composition of Florin et al. and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because Florin et al. expressly teach using a polyethylene oxide polymer but does not teach the molecular weight to select. As stated above, Gold et al. teach: “Tablets for the controlled release of an active ingredient in a zero-order or near zero-order fashion are provided. The tablet includes a core and a coating. The core includes at least one active pharmaceutical agent and a polyethylene oxide with a molecular weight of between about 1,000,000 and 10,000,000, preferably between about 4,000,000 and 8,000,000.” (Abstract; see also claims 1-23). The molecular weight range of between about 1000000 and 10000000 overlaps the claimed ranges of between about 900000 and 9000000; greater than about 9000000 and less than about 7000000 and about 2000000 g/mol. MPEP 2144.05(I): In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Furthermore, Gold et al. teach specific polyethylene oxides (Claims 3 and 14), which would comprise substantially a single approximate molecular weight and such species as obvious choices. Moreover, Gold et al. also teach the purine analogs cladibrine and fludarabine as representative therapeutic agents [0034]. Parker et al. teach that the ordinary artisan is aware that that thioguanine, fludarabine and cladribine are purine analogs used in the treatment of cancer (Abstract). Consequently, the molecular weights of polyethylene oxide taught by Gold et al. for other purine analogs would also be suitable for use with 6-TG.
Regarding the limitations of wherein the polyethylene oxide polymer is present from about 60-98% of the pharmaceutical composition or about 70 to 99% w/w of the core of the tablet or that the 6-TG and the polyethylene oxide polymer are in a ratio of about 1:20 to 1:50, the Examiner notes that Florin et al. teach: “In some embodiments the tablet comprises about 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 40 mg or 50 mg of 6-TG.” [00121], the 6-TG can be present from 10-30% w/w of the tablet [00127] and the tablet can weigh about 100-200 mg [00122]. Consequently, in one embodiment where the 6-TG is present from 10-30% w/w, that means there can be from 70-90% polyethylene oxide in the core of the tablet pharmaceutical composition, which overlaps the claimed ranges. In another interpretation, a 100 mg tablet with 1 mg of 6-GT can have 99% polyethylene oxide polymer or a 200 mg tablet with 5 mg of 6-GT and 195 mg polyethylene oxide polymer provides a ratio of 5:195 or 1:39, which is within the range of about 1:30 to 1:50. MPEP 2144.05(I): In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Accordingly, it is merely routine optimization of the dosage form to arrive at wherein the polyethylene oxide polymer is present from about 60-98% of the pharmaceutical composition or about 70 to 99% w/w of the core of the tablet or that the 6-TG and the polyethylene oxide polymer are in a ratio of about 1:20 to 1:50. From MPEP 2144.05 (II) (A): “[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the combined 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 art at the time the invention was made, as evidenced by the combined references, especially in the absence of evidence to the contrary.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNST V ARNOLD whose telephone number is (571)272-8509. The examiner can normally be reached M-F 7-3:30.
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/ERNST V ARNOLD/ Primary Examiner, Art Unit 1613
1 See for example Ma et al. (Drug Dev Ind Pharm, 2014; 40(7): 845–851) teaching applications of PEO in controlled release tablets and commercial sources of POLYOX™ of various molecular weights (Table 1).
2 This appears to be referencing the PEO POLYOX™ WSR N303 with a MW of about 7000000 as evidenced by Shojaee et al. (Pharmaceutical Development and Technology, 21:2,
189-195; page 190, left column materials).
Prosecution Insights