Ex Parte Uchida et al

Patent Trial and Appeal BoardMar 8, 2019

10515204 (P.T.A.B. Mar. 8, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 10/515,204 11/22/2004 5514 7590 03/11/2019 VenableLLP 1290 A venue of the Americas NEW YORK, NY 10104-3800 FIRST NAMED INVENTOR Akihiro Uchida UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www .uspto.gov ATTORNEY DOCKET NO. CONFIRMATION NO. 00005.001250. 4305 EXAMINER BREDEFELD, RACHAEL EV A ART UNIT PAPER NUMBER 1611 MAIL DATE DELIVERY MODE 03/11/2019 PAPER Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte AKIHIRO UCHIDA, Y ASUHIRO ISHIKAWA, Y ASUHIKO UENO, KIICHIRO KAJI, and TSUNEAKI TOTTORI Appeal2018-003965 Application 10/515,204 1 Technology Center 1600 Before DONALD E. ADAMS, JOHN E. SCHNEIDER, and RACHEL H. TOWNSEND, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL This Appeal under 35 U.S.C. Â§ 134(a) involves claims 5-19, 21, 30, 32--41, and 43-53 (App. Br. l; Final Act. 2 2). Examiner entered a rejection under 35 U.S.C. Â§ 103(a). We have jurisdiction under 35 U.S.C. Â§ 6(b). We AFFIRM. 1 Appellants identify "Kyowa Hakko Kirin Co., Ltd." as the real party in interest (Appellants' September 7, 2017 Appeal Brief (App. Br.) 1). 2 Examiner's September 13, 2016 Final Office Action. Appeal2018-003965 Application 10/515,204 STATEMENT OF THE CASE Appellants' disclosure "relates to a solid formulation comprising xanthine derivative or a pharmaceutically acceptable salt thereof' (Spec. 1: 5-7). Claims 5-7 are representative and reproduced below: 5. A tablet comprising (E)-8-(3,4-dimethoxystyryl)-1,3- diethyl-7-methyl-3, 7-dihydro-lH-purine-2,6-dione represented by formula (IA) 0 FH3 f-bC....-._. N=r~r-0Â·Â·. 0 .. -CHa OAN N ' Â·~ A <\ j . . ... CH:, H:iC- . or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, wherein the proportion of the (E)-8-(3 ,4-dimethoxystyryl)-1,3-diethyl-7- methyl-3, 7-dihydro-1 H-purine-2,6-dione or the pharmaceutically acceptable salt thereof in the tablet is 2 to 30% of the total weight of the tablet, and the microcrystalline cellulose content in the tablet is 10 to 3 0% of the total weight of the tablet. (App. Br. 16.) (Id.) 6. The tablet according to claim 5, further comprising a sugar. 7. The tablet according to claim 6, wherein the sugar comprises 1.0 to 9.0 parts by weight per 1.0 part by weight of microcrystalline cellulose. (Id. at 17). 2 Appeal2018-003965 Application 10/515,204 Grounds of rejection before this Panel for review: Claims 5-19, 21, 30, 32--41, and 43-53 stand rejected under 35 U.S.C. Â§ I03(a) as unpatentable over the combination of Shimada, 3 Oren, 4 and Reier. 5 ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? FACTUAL FINDINGS (FF) We adopt Examiner's findings concerning the scope and content of the prior art (see Final Act. 4--7) and provide the following findings for emphasis. FF 1. Shimada discloses "therapeutic agents for neurodegenerative disorders," which include "Compound 1: (E)-1,3-diethyl-8-(3,4- dimethoxystyryl)-7-methylxanthine" (Shimada 1:6-7; id. at 4:34--35; see Final Act. 4 (Examiner finds that Shimada discloses "compound 1, which is identical to ... [Appellant's] claimed[, trans- or E- isomeric form of 1,3- diethyl-8-(3 ,4-dimethoxystyryl)-7-methylxanthine, which is] compound IA)"). FF 2. Shimada discloses that "[t]he pharmaceutical compositions ... [ within the scope of its disclosure] can be prepared by uniformly mixing an effective amount of compound [1] or a pharmaceutically acceptable salt 3 Shimada et al., US 6,727,259 B2, issued Apr. 27, 2004. 4 Oren et al., US 4,753,801, issued June 28, 1988. 5 George E. Reier et al., Microcrystalline Cellulose in Tableting, 55 J. PHARMA. SCI. 510-514 (1966). 3 Appeal2018-003965 Application 10/515,204 thereof as an active ingredient with pharmaceutically acceptable carriers" (Shimada 6:51-55; see Final Act. 4). FF 3. Shimada discloses that pharmaceutical compositions comprising compound 1 in the form of "[p ]owder, pills, capsules and tablets can be prepared using excipients such as lactose ... ; disintegrating agents such as starch ... ; lubricants such as magnesium stearate ... ; binders such as ... hydroxypropyl cellulose ... ; surfactants ... ; [and] plasticizers" (Shimada 7:3-10; id. at 7:7-9 ("Tablets and capsules are the most useful oral unit dosage because of the readiness of administration"); see Final Act. 4--5). FF 4. Shimada exemplifies a tablet comprising: (Shimada 7:47-55.) TABLE:; EÂ·iy,.i,-:',:-.:J''P ~Â·:::-p~Â·J (\.:lfoJ,:-~:1:: ~'\:fo~:s1;::.:~Â·~:.:.u~ .S;-i:~::~Â·::il-:~ FF 5. Shimada exemplifies a capsule comprising 20 mg Compound 1, 99.5 mg Avicel, and 0.5 mg magnesium stearate (Shimada 7:57-8:10; cf Spec. 17:27-29 (Appellants disclose that Avicel is a commercially available form of microcrystalline cellulose); see Final Act. 5). FF 6. Examiner finds that Shimada does "not teach tablet formulations comprising microcrystalline cellulose in an amount of 10-30 wt.% of the tablet" (Final Act. 5). FF 7. Oren relates to a sustained release pharmaceutical formulation in tablet unit dosage form which provides prolonged plasma levels of an active agent and comprises about 60.0% to about 80.0% by weight of the active agent, about 1.0% to about 15.0% by weight of a pharmaceutically acceptable excipient, about 3.0% 4 Appeal2018-003965 Application 10/515,204 to about 15.0% by weight of a disintegrant, about 2.0% to about 10. 0% by weight of a pharmaceutically acceptable binder and about 0.5% to about 3.0% by weight of a tablet lubricant. (Oren 1:20-30 (emphasis added); see generally id. 2:15-3:19 (Oren's formulation may also comprise a binder, lubricant, and surface active agent); Final Act. 5.) FF 8. Oren discloses that lactose is a preferred excipient, starch as a preferred or suitable disintegrant, magnesium stearate is a preferred lubricant, and acceptable binders include microcrystalline cellulose (see Oren 2:15-3:28; see generally Final Act. 5). FF 9. Oren discloses that its tablets may be coated, if desired, with one of many readily available coating systems. Coating the tablets serves to mask the taste of the drug, make the tablet easier to swallow and, in some cases, improve the appearance of the dosage form. The tablets can be sugar coated according to procedures well known in the art, or can be coated with any one of numerous polymeric film coating agents frequently employed by formulation chemists. Representative examples of such film coating agents include hydroxypropyl methyl cellulose, carboxymethylcellu- lose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, acrylic resins, povidone, polyvinyl diethylaminoacetate, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, acrylic latex emulsions, ethyl cellulose latex emulsions or other commercially available preparations such as Pharmacoat. (Oren 3:58--4:6; see Final Act. 5.) FF 10. Reier discloses "[t ]he development of microcrystalline cellulose has made available to the pharmaceutical industry an extremely valuable tableting agent. . . . Microcrystalline cellulose tablets will disintegrate very slowly in solvents of a relatively low polarity" (Reier, Abstract; see Final Act. 6 ("one would have been motivated to use microcrystalline cellulose in 5 Appeal2018-003965 Application 10/515,204 Shimada' s composition since Reier ... [discloses] the excipient is extremely valuable in that it does not separate components during compression and does not negatively affect the release of medicinal compounds from tablets"). ANALYSIS Based on the combination of Shimada, Oren, and Reier, Examiner concludes that, at the time Appellants' invention was made, a person of ordinary skill in this art would have understood that Oren's "micro crystalline cellulose and Shimada' s binder (hydroxypropyl cellulose) are both conventional binders utilized in tablets," therefore, it would have been prima facie obvious to "utilize the binders of Oren ... or Shimada" (Final Act. 6; see id. ("one would have been motivated to incorporate microcrystalline cellulose in the composition of Shimada ... with an expectation of similar results since Oren ... teach the instant binder's equivalency with hydroxypropyl cellulose")). In re Fout, 675 F.2d 297, 301, 213 USPQ 532,536 (CCPA 1982) ("Express suggestion to substitute one equivalent for another need not be present to render such substitution obvious"). As Examiner explains, those of ordinary skill in this art would have had "a reasonable expectation [ of success in using] microcrystalline cellulose in Shimada's composition because Reier ... [discloses] that the characteristics of tablets produced with microcrystalline cellulose are outstanding" (Final Act. 6-7). Claim 1: The evidence of record establishes that those of ordinary skill in this art recognized that microcrystalline cellulose is known in "the 6 Appeal2018-003965 Application 10/515,204 pharmaceutical industry [as] an extremely valuable tableting agent," specifically a binder (see FF 7-10). The evidence of record exemplifies a tablet comprising 10% 6 Appellants' compound IA; 71. 7% 7 lactose, an excipient; 15%8 potato starch, a disintegrating agent; 0.3%9 magnesium stearate, a lubricant; and 3% 10 hydroxypropyl cellulose, a binder (see FF 3- 4). This record also establishes that tablet formulations were known in this art comprising: about 60.0% to about 80.0% by weight of [an] active agent, about 1.0% to about 15.0% by weight of a pharmaceutically acceptable excipient,[ such as lactose;] about 3.0% to about 15.0% by weight of a disintegrant,[ such as starch;] about 2.0% to about 10. 0% by weight of a pharmaceutically acceptable binder[, such as microcrystalline cellulose;] and about 0.5% to about 3.0% by weight of a tablet lubricant[, such as magnesium stearate]. (FF 7-8.) Thus, the evidence of record establishes the general conditions of the tablet set forth in Appellants' claim 5. In this regard, we note that "where 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 (CCP A 1955). Furthermore, "[a] prima facie case of obviousness typically exists when the 6 20 mg Compound I + 200 mg total weight X 100% = 10% Compound I by weight of the tablet (see FF 4). 7 143.4 mg Lactose+ 200 mg total weight X 100% = 71.7% Lactose by weight of the tablet (see FF 4). 8 30 mg Potato Starch + 200 mg total weight X 100% = 15% Potato Starch by weight of the tablet (see FF 4). 9 0.6 mg Magnesium Stearate + 200 mg total weight X 100% = 0.3% Magnesium Stearate by weight of the tablet (see FF 4). 10 6 mg Hydroxypropyl Cellulose+ 200 mg total weight X 100% = 3% Hydroxypropyl Cellulose by weight of the tablet (see FF 4). 7 Appeal2018-003965 Application 10/515,204 ranges of a claimed composition overlap the ranges disclosed in the prior art." In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003). We note that a claimed range overlaps with a prior art range if the two ranges share a common endpoint. See, e.g., In re Geisler, 116 F.3d 1465,1469 (Fed. Cir. 1997) (noting that a claim range of 50-100 A overlapped with a prior art range of 100-600 A). Therefore, we find no error in Examiner's conclusion that the combination of Shimada, Oren, and Reier makes obvious a tablet comprising 2-30% by total weight of the tablet of (E)-1,3-diethyl-8-(3,4- dimethoxystyryl)-7-methylxanthine or a pharmaceutically acceptable salt thereof and 10-30% by total weight of the tablet of microcrystalline cellulose (see FF 1-8). We are not persuaded by Appellants' contention that "[t]here is no reason of record why those of ordinary skill would expect that microcrystalline cellulose prevents olefin bond [ cis-trans or E-Z] isomerization" (App. Br. 8; see also Reply Br. 11 7-8). Notwithstanding Appellants' contention to the contrary, the inquiry is not whether a person of ordinary skill in this art would have used microcrystalline cellulose to prevent olefin bond isomerization. To the contrary, the question is whether the combination of Shimada, Oren, and Reier makes obvious a tablet comprising: (a) 2-30% by total weight of the tablet of (E)-1,3-diethyl-8- (3,4-dimethoxystyryl)-7-methylxanthine or a pharmaceutically acceptable salt thereof and (b) 10-30% by total weight of the tablet of microcrystalline cellulose (see App. Br. 16). For the reasons discussed above, we find that the evidence of record supports Examiner's conclusion of obviousness. The 11 Appellants' March 2, 2018 Reply Brief. 8 Appeal2018-003965 Application 10/515,204 fact that Appellants use microcrystalline cellulose "for a different purpose does not alter the conclusion that its use in a prior art composition would be prima facie obvious [for] the purpose disclosed in the references." In re Lintner, 458 F.2d 1013, 1016 (CCPA 1972). We are also not persuaded by Appellants' evidence of unexpected results (see App. Br. 8-14; see also Reply Br. 8-12). Evidence of "unexpected results must be commensurate in scope with the claimed range." In re Greenfield, 571 F.2d 1185, 1189 (CCPA 1978) ("Establishing that one ( or a small number of) species gives unexpected results is inadequate proof, for 'it is the view of this court that objective evidence of non-obviousness must be commensurate in scope with the claims which the evidence is offered to support"') ( quoting In re Tiffin, 448 F .2d 791, 792 (CCPA 1971)). On this record, Appellants contend that the August 12, 2009 Declaration of Dr. Ishikawa (August 12, 2009 Ishikawa Dec.) provides evidence that "the claimed process yields tablets that exhibit 74% less decomposition than those of Shimada, the closest prior art" (App. Br. 10). In support of this contention, Appellants direct attention to comparisons between compositions, within the scope of Appellants' claimed invention, that comprise about 23% microcrystalline cellulose and various other compositions (see id. at 10-12 (citing the August 12, 2009 Ishikawa Dec.; 9 Appeal2018-003965 Application 10/515,204 May 16, 2012 Ishikawa Dec.; 12 June 27, 2012 Ishikawa Dec.; 13 October 20, 2014 Ishikawa Dec.; 14 and February 29, 2016 Ishikawa Dec. 15)). 16, 17 Although Appellants' contentions relate to a composition comprising as little as 23 wt% microcrystalline cellulose, Appellants recognize that their "claims recite [] 10-30 wt% microcrystalline cellulose" (App. Br. 13; see Reply Br. 6 (Appellants' "claims relate to tablets comprising compound (IA) and 10 to 30% total weight microcrystalline cellulose")). Thus, it is unclear on this record if a composition comprising 10 wt% to not quite 23 wt% microcrystalline cellulose would exhibit the unexpected properties asserted by Appellants. Given the foregoing, we find no evidentiary basis on this record that supports Ishikawa's "opinion that those of ordinary skill in this art understand the evidence of record [] establishes that unexpected results are obtained for tablets and processes throughout the scope from 10 to 30 total wt.% microcrystalline cellulose" (May 16, 2012 Ishikawa Dec. ,r 11; see also June 27, 2012 Ishikawa Dec. ,r 11). The evidence on this record only supports a conclusion that a tablet comprising as little as 23 wt% 12 Declaration of Dr. Ishikawa, signed May 16, 2012. 13 Declaration of Dr. Ishikawa, signed June 27, 2012. 14 Declaration of Dr. Ishikawa, signed October 20, 2014. 15 Declaration of Dr. Ishikawa, signed February 29, 2016. 16 Ishikawa states that the August 14, 2009 Ishikawa Dec. "evaluated an example with 23 wt.% microcrystalline cellulose" and "that Table 3 at specification page 21 evaluated Tablet obtained in Example 2 having 24.1 wt.% microcrystalline cellulose" (June 27, 2012 Ishikawa Dec. ,r 7). 17 Ishikawa takes "note of[] Examiner's contention that the evidence of record indicates superior results only for 29.9 and 32.9 wt.% microcrystalline cellulose, whereas the claims [] recite a range of 10 to 30 wt.% microcrystalline cellulose" (May 16, 2012 Ishikawa Dec. ,r 4; see also June 27, 2012 Ishikawa Dec. ,r 4). 10 Appeal2018-003965 Application 10/515,204 microcrystalline cellulose will exhibit the "unexpected results" asserted by Appellants and Declarant, with no evidence that such would be observed at less than 23 wt% microcrystalline cellulose. Stated differently, we find Appellants' evidence of unexpected results is not commensurate in scope with the microcrystalline cellulose range set forth in Appellants' claimed invention. See In re Greenfield, 571 F.2d at 1189. Appellants' contentions regarding disintegration rates, hardness and corresponding discussion of Oren, Reier and Fox 18 also relate to the amount of microcrystalline cellulose in Appellants' tablet and are, therefore, as discussed above, not commensurate in scope with Appellants' claimed invention (see App. Br. 13 ("those of ordinary skill understand that microcrystalline cellulose slows dissolution of the active ingredient so as to achieve sustained release. . . . In contrast, the claimed tablets disintegrate rapidly and so increase availability of the active ingredient" and "one of ordinary skill herein would not have expected simultaneous improvements in each of hardness, disintegration time and formulation stability"); see also Reply Br. 12 ("The record does not establish that those of ordinary skill herein would have expected either the improved photostability or the improved disintegration rate attained by the present invention, let alone the simultaneous improvements in both, even in view of Fox and Reier"); see generally Reply Br. 6-7 and 10-12). Appellants do not identify and we do not find evidence of a long felt need or commercial success on this record (cf App. Br. 14). Therefore, we are not persuaded by Appellants' contention that "the secondary 18 C. David Fox et al., Microcrystalline Cellulose in Tableting, 92 DRUG AND COSMETIC INDUSTRY 161 (1963). 11 Appeal2018-003965 Application 10/515,204 considerations of the claimed invention's satisfaction of a long felt need and commercial success would overcome ... [the] primafacie case" of obviousness on this record (App. Br. 14). Claim 7: Examiner reasons that because Oren discloses tablet formulations compnsmg amounts of microcrystalline cellulose and sugar that encompass[ es] the limitations of ... [Appellants'] claims. Thus, ... [E]xaminer's position [is] that it would have been obvious to an artisan of ordinary skill to manipulate and optimize the relative amount of the sugar component ( e.g. lactose) and the microcrystalline cellulose as taught by Oren. (Final Act. 7.) Examiner further reasons that "[ o ]ptimization of parameters is a routine practice that would be obvious to a person of ordinary skill in the art to employ and reasonably expect success," thus, "[ o ]ne would have been motivated to determine the optimal amount of each ingredient in order to best achieve the desired results" (id. ( citing In re Aller, 220 F .2d at 456). Appellants contend, however, that "there is no appreciation in the art that the ratio of sugar to microcrystalline cellulose is a result-effective variable" (App. Br. 14). Thus, Appellants contend that a tablet that comprises, inter alia, a sugar to microcrystalline cellulose ratio of 1: 1-9: 1 parts by weight is "not prima facie obvious over the prior art" relied on by Examiner (id. at 15). We are not persuaded. 12 Appeal2018-003965 Application 10/515,204 The evidence of record exemplifies tablets comprising a sugar to binder ratio of23.9:l 19 (FF 4) and between 0.1:1-7.5:1 20 (FF 7), wherein the evidence of record recognizes that microcrystalline cellulose is a suitable binder (FF 7-8). Thus, the evidence of record establishes that the sugar to microcrystalline cellulose ratio of tablets suggested by the prior art overlaps Appellants' claimed ratio. Overlapping ranges support a prima facie case of obviousness. See In re Geisler, 116 F.3d 1465, 1468 (Fed. Cir. 1997). In addition, the evidence of record establishes the general conditions of the tablet set forth in Appellants' claim 7 and "it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d at 456. Thus, we find that a person of ordinary skill in this art would have found it prima facie obvious to adjust the ratio of the sugar to microcrystalline cellulose, as well as other ingredients, within the finite ranges expressly disclosed for the tablet suggested by the combination of Shimada, Oren, and Reier in order to optimize the manufacture and properties of the tablet (see FF 3--4 and 7-8; see generally FF 1-10). Therefore, we are not persuaded by Appellants' contentions that if the ratio of microcrystalline cellulose: sugar is greater than 1: 1, problems in manufacturing are engendered, and the stability of tablets is adversely influenced. On the other hand, if the ratio of microcrystalline cellulose: sugar is less than 1: 10, 19 71.7% lactose to 3% binder equals a sugar to binder ratio of23.9:1 parts by weight (see FF 4) 20 1.0% lactose to 10% microcrystalline cellulose binder equals a sugar to microcrystalline cellulose binder ratio of 0.1: 1 parts by weight (see FF 7). 13 Appeal2018-003965 Application 10/515,204 the tablets will be insufficiently hard and disintegration time is adversely influences. (Reply Br. 13.) CONCLUSION The preponderance of evidence relied upon by Examiner support a conclusion of obviousness. The rejection of claims 5 and 7 under 35 U.S.C. Â§ 103(a) as unpatentable over the combination of Shimada, Oren, and Reier is affirmed. Claims 5, 6, 19, 21, 30, 32, 33, 36-41, and 43-53 are not separately argued and fall with claim 1. Claims 8, 9, 34, and 35 are not separately argued and fall with claim 7. TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 3 7 C.F .R. Â§ 1.13 6( a). AFFIRMED 14