PHARMATHEN S.A.Download PDFPatent Trials and Appeals BoardNov 23, 20212020005284 (P.T.A.B. Nov. 23, 2021) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE 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 APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 15/326,767 01/17/2017 EVANGELOS KARAVAS PHARMA-132 9218 27769 7590 11/23/2021 AKC PATENTS 215 GROVE ST. NEWTON, MA 02466 EXAMINER BROWE, DAVID ART UNIT PAPER NUMBER 1617 NOTIFICATION DATE DELIVERY MODE 11/23/2021 ELECTRONIC 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. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): acollins@akcpatents.com aliki@alum.mit.edu PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte EVANGELOS KARAVAS, EFTHYMIOS KOUTRIS, VASILIKI SAMARA, IOANNA KOUTRI, ANASTASIA KALASKANI, LIDA KALANTZI, ANDREAS KAKOURIS, AMALIA DIAKIDOU, GEORGE GOTZAMANIS, ZAHARIAS GEORGOUSIS, and LOUIZA KONSTANTI Appeal 2020-005284 Application 15/326,767 Technology Center 1600 Before ULRIKE W. JENKS, JOHN G. NEW, and RACHEL H. TOWNSEND, Administrative Patent Judges. Opinion for the Board filed by Administrative Patent Judge JENKS. Opinion Dissenting filed by Administrative Patent Judge TOWNSEND. JENKS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from Examiner’s decision to reject claims directed to a water dispersible minitablet as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 1 We use the word Appellant to refer to “applicant” as defined in 37 C.F.R. § 1.42(a). Appellant identifies the real party in interest as Pharmathen S.A. Appeal Br. 2. Appeal 2020-005284 Application 15/326,767 2 STATEMENT OF THE CASE Enalapril is an angiotensin-converting enzyme (ACE) prodrug inhibitor. “It is rapidly hydrolyzed in the liver to Enalaprilat following oral administration and is excreted primarily by renal excretion. In addition to treating hypertension, Enalapril has been used for treatment of symptomatic heart failure and assyptomatic [sic] left ventricular dysfunction.” Spec. 3:16– 19. The Specification explains that there is a need to manufacture a dosage form [of Enalapril] for the treatment of hypertension in a pediatric population from 0 to 18 years of age that is easy to swallow, it has no risk of choking and/or aspiration, it has a pleasant taste and therefore it has increased compliance compared to other dosage forms targeting adult populations and is has an easy and cost effective manufacturing process. Id. at 4:32–5:1. CLAIMED SUBJECT MATTER The claims 1–7 are directed to a water dispersible minitablet. Claim 1, reproduced below, is illustrative of the claimed subject matter: 1. A water-dispersible minitablet comprising: Enalapril or pharmaceutically acceptable salts thereof as an active ingredient, a disintegrant, a diluent, a lubricant and a glidant; wherein the active ingredient is distributed evenly in the minitablet; wherein the minitablet has a diameter of 3mm; wherein the disintegrant comprises Crospovidone; and wherein the minitablet disintegrates in less than 15 seconds in water. Appeal Br. 13 (Claims App.). Appeal 2020-005284 Application 15/326,767 3 REJECTION Appellant requests review of Examiner’s rejection of claims 1–7 as obvious over Patel2 in view of Thomson,3 Momma,4 and Uzunovic.5 OPINION The issue before us is whether the preponderance of evidence of record supports Examiner’s conclusion that an enalapril containing water dispersible minitablet using crospovidone as a disintegrant is obvious. Examiner finds that Patel teaches an oral, water-dispersible tablet comprising enalapril, mannitol, “2–6 wt% disintegrant, e.g., crospovidone,” talc, magnesium stearate, aspartame and camphor, where the tablet “can exhibit a dispersion time in water of less than 15 seconds.” Final Act. 5. Examiner acknowledges that Patel teaches enalapril formulations with 2–6% Kyron t314 as the disintegrant, as well as enalapril formulations with 2–6% sodium starch glycolate as the disintegrant. Ans. 5. Examiner also acknowledges that Patel discloses that batch “A2” containing Kyron t314 had the lowest disintegration time among the batches A1–A6 tested. Id. However, Examiner finds that “Table 6 simply does not properly establish that Kyron t314 is significantly superior to either crospovidone or to sodium starch glycolate in producing a faster MDT disintegration time” because (1) 2 Patel et al., Formulation and Evaluation of Mouth Dissolving Tablet for Anti-Hypertensive Drug, 1 PHARMAGENE 10–21 (2013) (“Patel”). 3 Thomson et al., Minitablets: New Modality to Deliver Medicines to Preschool-Aged Children, 123 PEDIATRICS e235-8 (2009) (“Thomson”). 4 Momma, ACE Inhibitors in Pediatric Patients with Heart Failure, 8 PAEDIATR. DRUGS (2006) (Abstract only). 5 Uzunovic & Vranic, Effects of Magnesium Stearate Concentration on Dissolution Properties of Ranitidine Hydrochloride Coated Tablets, 7 BOSNIAN J. BASIC MED. SCI. 279–283 (2007) (“Uzunovic”). Appeal 2020-005284 Application 15/326,767 4 Patel does not disclose the composition for each of the 6 batches A1–A6 in table 6, which is a table reporting disintegration time of screening formulations, (2) nine screening formulations were made (Kyron t314 (2, 4, 6 %), crospovidone (2, 4, 6%), and sodium starch glycolate (2, 4, 6%)), yet only 6 batches are shown in table 6, and (3) while “Figure 1 compares the several superdisintegrants, . . .the graph is so illegible as to be inconclusive as well.” Ans. 5–6. Examiner finds that “Patel teaches that camphor is a results-effective variable. Increasing the amount of camphor will significantly decrease the disintegration time for any given concentration of superdisintegrant employed.” Final Act. 8. Based on these teachings of Patel, Examiner concludes that “one of ordinary skill in the art would find it just as obvious to select crospovidone as Kyron t 314 as the superdisintegrant, and to optimize the formulation with the combined amounts of both the superdisintegrant and the camphor to achieve the desired disintegration time.” Id. Appellant contends, and we agree, that Patel does not provide a reason to select crospovidone as the starting disintegrant for further optimizing the disintegration time of the mouth dissolving tablets (MDTs). Appeal Br. 6. (“Patel teaches away from using Crospovidone as a disintegrant for Enalapril tablets that would require a disintegration time of less than 15 sec.”). “[E]xaminer bears the initial burden, on review of the prior art or on any other ground, of presenting a prima facie case of unpatentability.” In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). In satisfying this initial burden, “[i]t is impermissible to use the claimed invention as an instruction manual or ‘template’ to piece together the teachings of the prior art so that Appeal 2020-005284 Application 15/326,767 5 the claimed invention is rendered obvious.” In re Fritch, 972 F.2d 1260, 1266 (Fed. Cir. 1992). Stated differently, to establish obviousness, there must be “an apparent reason to combine the known elements in the fashion” recited in the claims. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). Patel teaches that mouth dissolving tablets (“MDTs”) are particularly useful in the pediatric and elderly patient population. Patel 10–11. Mouth dissolving tablets offer substantial advantages like rapid onset of action, beneficial for patients having difficulties in swallowing and in conditions where access to water is difficult. Patel Abstr. With MDTs the goal is to minimize the disintegration time and to provide fast drug release. Id. Patel teaches that “MDTs having of Kyron t 314, crosspovidone & sodium starch glycholate were prepared separately as batches Al to A6 in 2%, 4%, [and] 6% concentration.” Patel 11. According to Patel “batch A2 showed lowest disintegration time (13 [s]ec), so [K]yron t 314 was taken as main super-disintegrating agent in further factorial design.” Patel 14, see also id. at Table 6, Fig. 1. Both Examiner and Appellant, however, agree that Patel does not provide a list of the components in the screening formulations A1–A6 other than identifying that A2 contains Kyron t 314 as the disintegrant.6 See Appeal Br. 7; Final Act. 7–8. Based on Patel’s disclosure, 6 The Dissent agrees that Patel is not clear whether any of the screening formulations A1 and A3–A6 contain crospovidone. See Dissent 10–11 (“It is not clear which of, or if any of A1 or A3–A6 contained crospovidone, but, it is not inconceivable that A1 did include the super-disintegrant crospovidone, which formulation disintegrated in 30 seconds. . . . If 30 seconds was a screening result from crospovidone, a reduction of 17 seconds would bring the composition within the claimed disintegration time.”) Admittedly, the interpretation that A1 contains crospovidone is conceivable. Speculation, however, is not a sufficient basis for a prima facie case of obviousness. See Appeal 2020-005284 Application 15/326,767 6 there is also no reason to believe that the formulations contained mixtures of the listed disintegrates. See Patel Table 2. Thomson, Momma, and Uzunovic relied upon by Examiner are directed at tablet size, suitable enalapril concentration for pediatric application, and magnesium stearate as a lubricant. None of these references discuss crospovidone as a disintegrant, or provide a reason to include crospovidone in a MDT tablet. Based on the combined references, we find that Examiner has not provided a sufficiently articulated rationale based on evidence in this record that would suggest selecting crospovidone as a reasonable starting disintegrant for optimization based on the teachings of Patel. Examiner has also not advanced a reasonable alternative rationale explaining why an ordinary artisan would have added crospovidone to a Kyron t 314 containing MDT. Accordingly, we are not persuaded that the Examiner has made out a prima facie case of obviousness as to claim 1. CONCLUSION Examiner has not pointed to any teaching in Patel that would have led the ordinary artisan to select crospovidone as the disintegrant for optimization. We, therefore, reverse the rejection of claims 1–7 under 35 U.S.C. § 103 based on Patel, Thomson, Momma, and Uzunovic. In re Warner, 379 F.2d 1011, 1017 (CCPA 1967); In re Sporck, 301 F.2d 686, 690 (CCPA 1962) (“We are unwilling to substitute speculation and hindsight appraisal of the prior art for such factual data.”). Appeal 2020-005284 Application 15/326,767 7 DECISION SUMMARY In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1–7 103 Patel, Thomson, Momma, Uzunovic 1–7 REVERSED Appeal 2020-005284 Application 15/326,767 8 TOWNSEND, Administrative Patent Judge, dissenting. I respectfully dissent from the decision to overturn the Examiner’s rejection. Claim 1, reproduced below, is illustrative of the claimed subject matter: 1. A water-dispersible minitablet comprising: Enalapril or pharmaceutically acceptable salts thereof as an active ingredient, a disintegrant, a diluent, a lubricant and a glidant; wherein the active ingredient is distributed evenly in the minitablet; wherein the minitablet has a diameter of 3mm; wherein the disintegrant comprises Crospovidone; and wherein the minitablet disintegrates in less than 15 seconds in water. Appeal Br. 13 (Claims App.). Notably, the composition claimed does not recite any required or limiting amounts of any of the recited ingredients. Moreover, the claim includes the open-ended transition phrase “comprising,” “which means that the named elements are essential, but other elements may be added and still form a construct within the scope of the claim.” Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501 (Fed. Cir. 1997). Thus, for example, camphor is not excluded from being part of the composition. Patel reports on research work “to develop a mouth dissolving tablet [(MDT)] of Enalapril maleate prepared with kyronT-314, camphor and D(-) mannitol . . . selected on the basis of pre formulation studies.” (Patel Abstr.) Patel explains that a “screening study” using 3 different super disintegrants was carried out; the super disintegrants were Kyron t 314, crospovidone and Appeal 2020-005284 Application 15/326,767 9 sodium starch glycolate. (Patel 11, 14.) Patel states that “MDTs having Kyron t 314, cros[]povidone & sodium starch glyc[]olate were prepared separately as Batches A1 to A6 in 2%, 4%, & 6% concentration.” (Id. at 11.) As the Examiner noted in the rejection, Patel does not explain what the formulations of A1–A6 are. It is agreed by Appellant, that the only thing that is known from the reference regarding the screening compositions is that A2 included Kyron t 314 and had a disintegration time that was lowest (13 seconds) of the six screening formulations A1–A6. (Id. at 14, and Table 6.) Based on that disintegration time further formulations with Kyron t 314 were studied. (Id. at 14.) Patel states “factorial design was applied to develop an optimized formulation” where “the concentration of kyron t 314 (X1) and concentration of camphor (X2) were selected as independent variables.” (Id. at 11.) The formulations tested in the factorial design are set forth in Table 2. (Id. at 12.) I note that in the factorial design, not only was camphor and Kyron t 314 modified, but so was mannitol. (See id. Table 2.) As the amounts of these ingredients were modified, the disintegration time changed. (See id. at Table 2 and Table 9.) In F1-F3 Kyron t 314 was used in 2%, 4%, and 6% respectively, and mannitol was present at 82%, 80%, and 78%, respectively, but camphor was held constant at 5%. (Id.) The in vitro disintegration was highest in F1 (about 27 seconds) and decreased 3 seconds in F2 and 3 more seconds in F3. (Id.) When camphor was increased to 10% and mannitol was further decreased, the disintegration times were reduced even further. (Id.) F4 disintegration was about 7 seconds less than F1, both of which contained 2% Kyron t 314. F6 which had 6% Kyron t 314, 10% camphor and 73% mannitol disintegrated about 10 seconds faster than F1. (Id.) Appeal 2020-005284 Application 15/326,767 10 Similarly, when camphor was increased to 15% and mannitol was further decreased, the disintegration times were reduced even further. (Id.) F9 which had 6% Kyron t 314, 15% camphor, and 68% mannitol disintegrated about 17 seconds faster than F1, (10 seconds). (Id.) Furthermore, F7 which also had 15% camphor, but only 2% Kyron t 314 and 72% mannitol disintegrated in just about 15 seconds, and F8 which had 15% camphor, but 4% Kyron t 314, and 70% mannitol disintegrated in 12 seconds. There is nothing in Patel that suggests the results observed with Kyron t 314 would not be observed when combining a different super-disintegrant with camphor. All that Patel indicates with respect to the selection of Kyron t 314 as the super disintegrant was a decision to pursue MDT compositions with it based on studying screening formulations that included 2, 4, or 6% of Kyron t 314 or starch glycolate or crospovidone. The remaining contents of the screening formulation are unknown though presumably it included Enalapril. It is not clear which of, or if any of A1 or A3–A6 contained crospovidone, but, it is not inconceivable that A1 did include the super- disintegrant crospovidone, which formulation disintegrated in 30 seconds. But even if A1 did not include crospovidone, I find that what one of ordinary skill in the art would reasonably take away from Patel is that the percentage of super-disintegrant, the percentage of camphor, and the percentage of mannitol in the composition are known results effective variables and that increasing the super-disintegrant and camphor percentages in the composition while also decreasing the mannitol percentages would reasonably have been expected to decrease the disintegrating time. Patel teaches that it was able to reduce disintegration times up to 17 seconds by manipulating those variables. Applying that knowledge, one of ordinary skill in the art would have reasonably concluded that formulations of Appeal 2020-005284 Application 15/326,767 11 crospovidone with camphor and mannitol and enalapril could be arrived at and achieve similar reductions in disintegration time, if not more given the additional teachings discussed below regarding size of tablet and effects of magnesium stearate. “[D]iscovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272, 276 (CCPA 1980). As to the specific disintegration time of less than 15 seconds, one of ordinary skill in the art would have understood from Patel that less than 15 seconds was the desirable target range, and would have found it obvious to optimize the percentages of crospovidone with camphor and mannitol to arrive at this disintegration limit. If 30 seconds was a screening result from crospovidone, a reduction of 17 seconds would bring the composition within the claimed disintegration time. But, as noted, even assuming A1 was not a formulation including crospovidone, the teachings of Patel are sufficient regarding the fact that percentages of super-distintegrant and camphor and mannitol are results effective variables that can be manipulated to significantly reduce the disintegration time of the screening compositions. Moreover, selecting crospovidone as the super-disintegrant instead of Kyron t 314 for use in the combination would have been an obvious substitution of one known super- disintegrant for another. Appellant’s claim “recites a combination of elements that were all known in the prior art, and all that was required to obtain that combination was to substitute one well-known . . . agent for another.” Wm. Wrigley Jr. Co. v. Cadbury Adams USA LLC, 683 F.3d 1356, 1364 (Fed. Cir. 2012). While it might be true that Patel did not describe “the combination of Enalapril with Crospovidone . . . result[ing] in disintegration time of less than 15 sec” (Appeal Br. 6), that is not dispositive of whether a Appeal 2020-005284 Application 15/326,767 12 composition that would achieve that disintegration time would have been obvious from all of the teachings of Patel and particularly in view of the additional references the Examiner relied upon regarding dosage amounts of active in a minitablet for pediatric use. The Examiner provided evidence that for pediatric patients, a much lower amount of enalapril can be used than the amount in the Patel tablet (100 mg tablets (Patel 11) with 5% being enalapril (i.e., 5 mg) (Patel 12)). (Momma (once or twice a day doses ranging from 0.1 to 0.5 mg/kg).) Thus, one of ordinary skill in the art would reasonably have been motivated to develop a pediatric MDT formulation of Enalapril and would have consequently, found it obvious to reduce the active ingredient amount. Additionally, the Examiner provided further evidence that at the time the invention was made minitablet formulations for young children were being developed (3 mm). (See Thomson.) That tablet size is half the size of what was tested in Patel. (Patel 11 (6 mm tablets).) One of ordinary skill in the art would have had motivation to prepare smaller MDT tablets of Enalapril for pediatric patients, which had less active agent than taught in Patel, and which one would have reasonably expected to necessarily dissolve in less time than the tablets described in Patel. Furthermore, the Examiner also provided evidence that it was known at the time the invention was made that magnesium stearate which is used as a lubricant for tablet formulation, could form a film on tablet excipients and lead to prolonged liberation time of the active. (Uzonovic 280.) This is an ingredient in the Patel tablets. I agree with the Examiner that one of ordinary skill in the art would reasonably have been motivated from the prior art to develop a pediatric MDT formulation and would have sought to limit the amount of magnesium stearate in the formulation disclosed in Patel. Appeal 2020-005284 Application 15/326,767 13 And in doing so, one of ordinary skill in the art would have understood that ingredient to be another results effective variable that if lowered would reasonably be expected to assist in decreasing disintegration times. Thus, I would find that the combination of teachings of the prior art supports the Examiner’s conclusion that given all the results-effective variables known in the art that would be expected to be able to be manipulated to reduce the disintegration time of an MDT tablet of enalapril, i.e., the amounts of crospovidone, camphor, mannitol, talc and magnesium stearate, and size of the tablet, the invention recited by claim 1 would have been obvious. Based on the foregoing, I would have affirmed the Examiner’s obviousness rejection. Copy with citationCopy as parenthetical citation