Ex Parte Goldsmith et alDownload PDFPatent Trial and Appeal BoardJul 18, 201611696554 (P.T.A.B. Jul. 18, 2016) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 111696,554 0410412007 Mark A. Goldsmith 26111 7590 07119/2016 STERNE, KESSLER, GOLDSTEIN & FOX P.L.L.C. 1100 NEW YORK A VENUE, N.W. WASHINGTON, DC 20005 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. 2662.0040002/JAG/KRM 4665 EXAMINER WESTERBERG, NISSA M ART UNIT PAPER NUMBER 1618 MAILDATE DELIVERY MODE 07/19/2016 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 MARK A. GOLDSMITH and ELIZABETH VADAS 1 Appeal2013-009985 Application 11/696,554 Technology Center 1600 Before DONALD E. ADAMS, ERIC B. GRIMES, and JACQUELINE T. HARLOW, Administrative Patent Judges. GRIMES, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to a pharmaceutical dosage form, which have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b ). We reverse. STATEMENT OF THE CASE "Antiplatelet drugs, which decrease platelet aggregation and inhibit thrombus formation, have been shown to be beneficial in the treatment and prevention of thrombotic disorders." (Spec. i-f 3.) However, "antiplatelet 1 Appellants identify the Real Party in Interest as KG Acquisition, LLC. (Br. 3.) Appeal2013-009985 Application 11/696,554 agents, such as aspirin and clopidogrel, have been associated with gastrointestinal disorders such as ulcers and gastrointestinal bleeding." (Id. at i-f 4.) The Specification discloses oral dosage forms that contain both an antiplatelet drug, such as clopidogrel, and a proton pump inhibitor (PPI) such as omeprazole. (Id. at i-f 6.) Claims 195, 200, 202, and 203 are on appeal. Claims 195 and 200 are illustrative and read as follows: 195. A single unit oral dosage form comprising: a) an adenosine diphosphate (ADP) or P2Y12 antagonist or a pharmaceutically acceptable salt or enantiomer thereof, in a therapeutically effective amount to provide anti platelet activity; and b) a proton pump inhibitor (PPI) or a pharmaceutically acceptable salt or enantiomer thereof, in a therapeutically effective amount to prevent or reduce a gastrointestinal disorder associated with use of said ADP or P2 Y12 antagonist or said ADP or P2 Y12 antagonist and aspirin, wherein said PPI is enterically coated. 200. The single unit oral dosage form of claim 195, wherein said i\~DP or P2 Y i2 antagonist or pharmaceutically acceptable salt or enantiomer thereof is clopidogrel and said PPI or pharmaceutically acceptable salt or enantiomer thereof is omeprazole. DISCUSSION The Examiner has rejected claims 195 and 200 under 35 U.S.C. § 103(a) as obvious based on Ng2 and Chen3 (Ans. 3), and has rejected 2 Ng et al., High incidence of clopidogrel-associated gastrointestinal bleeding in patients with previous peptic ulcer disease, 18 Aliment Pharmacol. Ther. 443--449 (2003). 3 Chen et al., US 2004/0175427 Al, published Sept. 9, 2004. 2 Appeal2013-009985 Application 11/696,554 claims 202 and 203 under 35 U.S.C. § 103(a) as obvious based on Ng, Chen, and Herbert4 (Ans. 6). The same issue is dispositive for both rejections. The Examiner finds that Ng discloses treating patients with a combination of clopidogrel and a PPI (lansoprazole or omeprazole ). (Ans. 3.) The Examiner finds that Ng teaches that none of the patients administered clopidogrel and a PPI exhibited re-bleeding, but nine of the other patients (who were administered either clopidogrel alone or clopidogrel and an H2-receptor antagonist) did. (Id.) The Examiner finds that Chen discloses enteric coating of omeprazole. (Id. at 5.) The Examiner concludes that it would have been obvious to combine clopidogrel and omeprazole in a single oral dosage form to reduce the number of pills a patient must take and increase patient compliance (id. at 4), and to enterically coat the dosage form because Chen teaches that omeprazole is inactivated by acidic conditions (id. at 5). Appellants argue that the references would not have made it prima facie obvious to combine clopidogrel and omeprazole in a single oral dosage form. (Appeal Br. 7-13.) Appellants also argue that they have provided secondary evidence of nonobviousness; specifically, evidence of skepticism in the art (id. at 13-20) and unexpected results (id. at 21-25). We agree with Appellants that the rejections are not supported by a preponderance of the evidence of record. However, as the Examiner concluded, Ng supports a prima facie case of obviousness, although not a particularly strong one. Ng states that anti-platelet therapy using aspirin is 4 Herbert et al., US 5,576,328, issued Nov. 19, 1996. 3 Appeal2013-009985 Application 11/696,554 frequently associated with gastrointestinal adverse events, including bleeding. (Ng 443, left col.) Ng states that clopidogrel is an anti-platelet agent that is associated with significantly less GI hemorrhage than aspirin. (Id. at 444, left col.) Ng describes a "retrospective study ... to evaluate the incidence of upper gastrointestinal complications in high-risk patients receiving clopidogrel." (Id.) Ng found that "[o]fthe 70 high-risk patients recruited, clopidogrel- associated significant gastrointestinal bleeding occurred in nine (14%)." (Id. at 447, right col.) "Re-bleeding occurred in four of 24 patients (16%) receiving H2-receptor antagonist, but in none of the patients receiving proton pump inhibitor." (Id. at 448, left col.) Ng states that "[c]lopidogrel treatment alone may not be safe in high-risk patients and concomitant proton pump inhibitor prophylaxis should be considered." (Id.) Thus, Ng expressly suggests that treatment of patients with both clopidogrel and a PPI (including omeprazole, see id. at 444, left col.) should be considered, at least for high-risk patients. On the other hand, Ng notes the limits of its study. Ng states that " [ f]urther studies are needed to clarify the effectiveness of concomitant proton pump inhibitor in reducing the recurrence of peptic ulcer in high-risk patients taking clopidogrel." (Id. at 448, left col.) Ng also states that its study has limitations: it was retrospective; the sample size was too small to allow firm conclusions; there was no control group of patients not taking clopidogrel; and use of acid suppression was not standardized. (Id. at 448.) In summary, Ng provides a reason to treat patients with a combination of clopidogrel and omeprazole, and states that its data show that the 4 Appeal2013-009985 Application 11/696,554 combination reduces the incidence of re-bleeding but notes that its conclusions are based on data having significant limitations. Appellants have submitted evidence of secondary considerations. Specifically, Appellants rely on the Declaration under 37 C.F.R. § 1.132 of Thomas J. Simon, dated Sept. 24, 2010. Appellants argue that the Simon Declaration and references cited therein provide evidence that a person of ordinary skill in the art would been skeptical about practicing the claimed dosage form with a reasonable expectation of success. (Br. 13.) More specifically, Appellants argue that Dr. Simon opined that those skilled in the art would have been skeptical of success because of, among other things, concerns that the interactions of clopidogrel and omeprazole with cytochrome P450 would reduce the efficacy of the clopidogrel. (Id. at 14.) Dr. Simon testified that "clopidogrel is a prodrug, which depends on the function of several cytochrome P450 (CYP) enzymes, including CYP 3A4 and CYP 2C19, for metabolic activation." (Simon Deel. i-f 21.) Dr. Simon cites several prior art references as support for this statement. 5 Savi6 states that clopidogrel is inactive in vitro and requires metabolic activation in 5 Some of the references cited in the Simon Declaration were published after the filing date of the instant application. Appellants argue that these references should be considered nonetheless as evidence of skepticism at the time of the invention. (See Br. 17-19.) With respect to the COGENT trial presentation, discussed further below, we agree. We find it unnecessary to rely on any of the other post-filing references in order to decide the issue on appeal. 6 Savi et al., The Antiaggregating Activity of Clopidogrel Is due to a Metabolic Activation by the Hepatic Cytochrome P450-JA, 72 Thrombosis and Haemostasis 313-317 (1994). 5 Appeal2013-009985 Application 11/696,554 the liver to be effective in vivo. (Savi 313, left col.) Savi reports that "SKF- 525-A, a global cytochrome P450 inhibitor, dramatically decreased the antiaggregating effect of clopidogrel, therefore indicating that cytochrome P450 enzymes are involved in the hepatic activation." (Id., abstract.) Clarke7 states that, "[t]o identify the human P450s responsible for clopidogrel oxidation, genetically engineered microsomes containing a single human P450 isozyme were tested for their ability to oxidize clopidogrel." (Clarke, abstract.) Clarke reports that "CYP3A4 and 3A5 metabolized clopidogrel at a significantly higher rate than eight other P450 isozymes, suggesting that CYP3A4 and 3A5 are primarily responsible for in vivo clopidogrel metabolism." (Id.) Lau8 likewise reports that CYP3A4 is involved in clopidogrel's metabolic activation. (Lau 166, abstract.) Lau states that "[e]rythromycin and troleandomycin, CYP3A4 inhibitors, decreased clopidogrel efficacy, as did atorvastatin lactone, a competitive CYP3A4 substrate." (Id. at 168, right col.) The cited evidence amply supports Dr. Simon's testimony that CYP3A4, at least, was known as of the filing date of the present application to be involved in metabolic activation of clopidogrel. 7 Clarke and Waskell, The Metabolism of Clopidogrel is Catalyzed by Human Cytochrome P450 3A and is Inhibited by Atorvastatin, 31 Drug Metabolism and Disposition 53-59 (2003). 8 Lau et al., Contribution of Hepatic Cytochrome P450 3A4 Metabolic Activity to the Phenomenon of Clopidogrel Resistance, 109 Circulation 166- 171 (2004). 6 Appeal2013-009985 Application 11/696,554 Dr. Simon also testified that omeprazole inhibits CYP3A4. (Simon Deel. ,-r 24.) Dr. Simon cites Marechal9 and Li, 10 among other references, in support. Marechal presents "in silico predictions based on the crystal structures of CYP3A4" and concludes that "of 33 common[ly] comedicated drugs, 10 were predicted to be inhibitors of CYP3A4." (Marechal 534, abstract.) Marechal states that "omeprazole ... w[as] identified by our in silico and in vitro screens as [a] relatively potent inhibitor[] of CYP3A4." (Id.) Li "compare[s] the potency and specificity of [five] PPis ... as inhibitors of four cytochrome P450 enzymes (CYP2C9, 2C19, 2D6, and 3A4)." (Li 821, abstract.) Lee reports that omeprazole inhibits the activity of CYP3A4 activity with a Ki of 42 µM. (Id. at 824, right col.) Thus, the cited evidence supports Dr. Simon's position that, as of this application's filing date, omeprazole was known to inhibit the activity of CYP3A4. In sum, the Simon Declaration provides evidence that a person of ordinary skill in the art, as of this application's effective filing date, would have been skeptical that clopidogrel and omeprazole could be combined in a single dosage form without decreasing the efficacy of clopidogrel' s efficacy as an anti-platelet drug. 9 Marechal et al., In Silica and In Vitro Screening for Inhibition of Cytochrome P450 CYP3A4 by Comedications Commonly Used by Patients with Cancer, 34 Drug Metabolism and Disposition 534--538 (2006)). 10 Li et al., Comparison of Inhibitory Effects of the Proton Pump-Inhibiting Drugs Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, and Rabeprazole on Human Cytochrome P450 Activities, 32 Drug Metabolism and Disposition 821-827 (2004). 7 Appeal2013-009985 Application 11/696,554 The COGENT trial presentation that is of record confirms this skepticism. 11 The presentation states that one of the aims of the trial was "[t]o determine if there was any cardiovascular interaction between clopidogrel and PPL" (COGENT presentation, "Aims" slide.) The presentation describes the COGENT trial as a multi-center, international phase 3 efficacy and safety study of administration of aspirin in combination with a single-dosage form comprising clopidogrel and omeprazole, as compared to administration of aspirin and clopidogrel. (Id., first "Methods" slide.) The presentation states that the initial planned sample size was 3200 patients (id., second "Methods" slide), although a total of 3627 patients were actually enrolled (id., "Results" slide). Thus, the COGENT trial presentation is evidence that, even as late as 2008 to 2009, 12 those skilled in the relevant art considered a large-scale clinical trial to be necessary to determine whether there was a cardiovascular interaction between clopidogrel and omeprazole. In other words, despite the publication of Ng in 2003, its tentative recommendation to co-administer clopidogrel and omeprazole had not been accepted in the art. In our view, the COGENT trial presentation provides evidence that, even as of the instant application's filing date, a person of ordinary skill in the art would have been skeptical about combining clopidogrel and omeprazole in a single oral dosage form. 11 Dr. Simon cites the COGENT trial results as evidence of unexpected results but in our view it is also evidence of skepticism in the art. For the reasons discussed above, we do not reach the issue of unexpected results. 12 The COGENT trial presentation was presented at a meeting in September 2009, but the presentation does not state when the COGENT trial began. 8 Appeal2013-009985 Application 11/696,554 In summary, Ng provides a reason for combining clopidogrel and omeprazole in a single dosage form, but Appellants have provided evidence that a person of ordinary skill in the art would have had reason to doubt whether the combination would successfully provide the anti-platelet effect for which clopidogrel is administered. On balance, therefore, we cannot say that the rejection is supported by a preponderance of the evidence of record. "After evidence or argument is submitted by the applicant in response [to the prima face case], patentability is determined on the totality of the record, by a preponderance of evidence with due consideration to persuasiveness of argument." In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). Because the rejection based on Ng and Chen is not supported by a preponderance of the evidence, we reverse it. The Examiner has rejected claims 202 and 203 as obvious based on Ng, Chen, and Herbert (Ans. 6). However, Herbert is relied on only for its disclosure of clopidogrel in powder form. (Id.) Thus, we reverse this rejection for the same reasons discussed above. SUMMARY We reverse both of the rejections on appeal. REVERSED 9 Copy with citationCopy as parenthetical citation