Genzyme CorporationDownload PDFPatent Trials and Appeals BoardApr 30, 202015049946 - (D) (P.T.A.B. Apr. 30, 2020) 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. 15/049,946 02/22/2016 Hanlan Liu 15979-20148.01 7001 89300 7590 04/30/2020 Sanofi/Genzyme c/o Morrison & Foerster LLP 755 Page Mill Road Palo Alto, CA 94304 EXAMINER HAVLIN, ROBERT H ART UNIT PAPER NUMBER 1639 NOTIFICATION DATE DELIVERY MODE 04/30/2020 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): EOfficePA@mofo.com PatentDocket@mofo.com pair_mofo@firsttofile.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte HANLAN LIU, CHRIS WILLIS, RENU BHARDWAJ, DIANE P. COPELAND, ABIZER HARIANAWALA, JEFFREY SKELL, JOHN MARSHALL, JIANMEI KOCHLING, GERARD PALACE, JUDITH PETERSCHMITT, CRAIG SIEGEL, and SENG CHENG ____________ Appeal 2019-003550 Application 15/049,9461 Technology Center 1600 ____________ Before FRANCISCO C. PRATS, TAWEN CHANG, and DAVID D. COTTA, Administrative Patent Judges. COTTA, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to a method of treating a human patient with Gaucher disease. The Examiner rejected the claims on appeal as obvious under 35 U.S.C. § 103(a) and on the ground of nonstatutory obviousness-type double patenting. A hearing was held on March 2, 2020.2 We reverse. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. According to Appellant, the real party in interest is Genzyme Corporation. App. Br. 3. 2 A transcript from the hearing has been entered into the record (“Tr.”). Appeal 2019-003550 Application 15/049,946 2 STATEMENT OF THE CASE The Specification discloses that glycosphingolipids (“GSLs”) are a class of naturally occurring compounds, the accumulation of which has been linked to a number of disease, including Gaucher disease. Spec. 1. “GSLs are derived from glucosylceramide (GlcCer).” Id. According to the Specification, “[c]ompounds which inhibit GlcCer synthase can lower GSL concentrations and have been reported to be useful for treating a subject with [Gaucher] disease[].” Id. at 2. The Specification discloses that “[t]he compound of Formula (I), shown below, is a GlcCer synthase inhibitor currently in clinical trials for the treatment of Gaucher disease: .” Id. According to the Specification, “[i]t has now been found that the compound of Formula (I) and pharmaceutically acceptable salts thereof (including Formula (I) Hemitartrate) is metabolized by the liver, primarily by cytochrome P450 enzymes.” Id. at 20. The Specification discloses that “[t]he level of activity of P450 enzymes differs according to the individual,” and that an “embodiment of the invention is to determine whether the subject is a poor, intermediate and extensive/ultra rapid P450 metabolizer.” Id. at 20–21. The Specification teaches that “[i]f the subject is an intermediate or extensive/ultra rapid metabolizer, then the dose administered to that subject should be raised to an ‘adjusted effective dose’, i.e., the Appeal 2019-003550 Application 15/049,946 3 amount which results in trough plasma levels of the compound of at least 5 ng/ml.” Id. at 21. Claims 157–181 are on appeal. Claim 157 is representative and reads as follows: 157. A method of treating a human patient with Gaucher disease in need of treatment comprising: (i) assessing said patient with Gaucher disease, prior to initiation of treatment, through CYP2D6 genotyping, as being a poor, intermediate, or extensive CYP2D6 P450 metabolizer; and (ii) administering a therapeutically effective amount of a compound of formula (I). or a pharmaceutically acceptable salt thereof to the patient assessed as being a poor metabolizer, wherein the effective amount of the compound is 84 mg per day of the compound of formula (I), or an equivalent amount of a pharmaceutically acceptable salt thereof. App. Br. 20. Appeal 2019-003550 Application 15/049,946 4 The claims stand rejected as follows: Claims 157–181 were rejected under 35 U.S.C. §103 as obvious over the combination of Shayman,3 McEachern,4 Emoto,5 De Leon,6 FDA,7 and Colby.8 Claims 157–181 were rejected on the ground of nonstatutory obviousness-type double patenting over claims 1, 2, 6–9, 13, and 14 of U.S. Patent No. 6,916,802 in view of McEachern, Emoto, De Leon, FDA, and Colby. OBVIOUSNESS Shayman discloses “compounds which inhibit glucosyl ceramide (GlyCer) formation by inhibiting the enzyme GlyCer synthase, thereby lowering the level of glycosphingolipids.” Shayman Abstract. The Examiner finds, and Appellant does not dispute, that the genus of compounds disclosed in Shayman encompasses the claimed compound. Ans. 4; App. Br. 6. Shayman further discloses that its Glycer synthase 3 Shayman et al., US Patent No. 6,916,802 B2, issued July 12, 2005 (“Shayman”). 4 K. McEachern et al., A Specific and Potent Inhibitor of Glucosylceramide Synthase for Substrate Inhibition Therapy of Gaucher Disease, 91 Molecular Genetics and Metabolism 259–267 (2007) (“McEachern”). 5 C. Emoto et al., Approach to Predict the Contribution of Cytochrome P450 Enzymes to Drug Metabolism in the Early Drug-Discovery Stage: The Effect of the Expression of Cytochrome b5 with Recombinant P450 Enzymes, 37(9) Xenobiotica 986–999 (2007) (“Emoto”). 6 J. De Leon et al, The AmpliChip™ CYP450 Genotyping Test, 10(3) Mol. Diag. Ther. 135–151 (2006) (“De Leon”). 7 United States Food and Drug Administration, Guidance for Industry Pharmacogenomic Data Submissions, March 2005 (“FDA”). 8 Colby et al., US Patent Publication No. 2009/0307179 A1, published Dec. 10, 2009 (“Colby”). Appeal 2019-003550 Application 15/049,946 5 inhibitors compounds are useful for treating Gaucher disease. Shayman, 34:46–49. McEachern discloses the claimed compound and teaches that “therapy with [the claimed compound] represents a viable alternative approach to enzyme therapy to treat the visceral pathology in Gaucher disease.” McEachern Abstract. The Examiner acknowledges, however, that neither Shayman nor McEachern teach “assessing the cytochrome P450 (CYP2D6) metabolizer status of a patient prior to administration of the compound as in the instant claims.” Ans. 7. With respect to the claim requirement for assessing cytochrome P450 (CYP2D6) metabolizer status, the Examiner found that “it was known in the art at the time of invention that the cytochrome P450 metabolism of a drug affects the safe and effective dosage which should be determined.” Ans. 7–8 (citing Emoto, De Leon, Colby, and FDA as support). The Examiner further found Shayman taught that that cytochrome P450 inactivates compounds related to the claimed compound and that McEachern disclosed that ADME studies – which the Examiner asserts include probing cytochrome P450 (id. at 6) – were conducted on the claimed compound. Id. at 7. The Examiner thus concluded that the ordinary artisan “following the teachings of Shayman and McEachern would have an expectation that a patient’s metabolism of [the claimed compound] would affect the safe and effective dosage which is determined by the cytochrome P450 activity.” Id. at 8. Accordingly, the Examiner concluded that: In determining the safe and effective dosage, one of ordinary skill in the art would be motivated to determine a patient’s metabolizer status of the “valid biomarker” CYP2D6 as suggested by Emoto, Deleon, Colby, and FDA and readily utilize the commercially available AmpliChip to make the determination and arrive at the claimed invention, including the Appeal 2019-003550 Application 15/049,946 6 optimum safe and effective dosage for each metabolizer status - i.e. 100 mg/day (84 mg/day eliglustat hemitartrate) for a PM and twice that for the other metabolizers. Id. The Examiner reasoned that “selecting the appropriate dosage is within the ability of those of ordinary skill in the art . . . as specifically taught by Shayman” and that “dosage adjustment based on CYP2D6 metabolizer status has been successfully applied to other drugs (i.e. De Leon).” Id. at 10. The Examiner thus concluded that “implementing the therapy identified by Shayman and McEachern in a manner to account for the CYP2D6 metabolizer status as suggested by Emoto, De Leon, FDA and Colby would be obvious.” Id. Appellant argues that the cited art does not sufficiently connect the claimed compound to dosing in a way that takes into account the CYP2D6 genotype of patients. See generally, App. Br.; Reply Br. As stated in In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992): “[T]he examiner bears the initial burden . . . of presenting a prima facie case of unpatentability.” Appellant has persuaded us that the Examiner has not carried the burden of establishing that the claimed invention would have been obvious over the cited art. We recognize that it was known in the art to use the claimed compound to treat Gaucher disease. See, e.g., McEachern, Abstract. We further recognize that it was known to assess the contribution of cytochrome P450 for certain drugs (Emoto, Abstract) and, more specifically, to assess the contribution of CYP2D6 to metabolism of a particular drug. De Leon, Abstract. However, it is also true that testing of CYP2D6 during the relevant time period was poorly developed and focused on psychiatric drugs rather than drugs for treatment of Gaucher disease. Id. at 148 (noting that it Appeal 2019-003550 Application 15/049,946 7 is “difficult to predict which drug will become the first to include pharmacogenetic testing as standard practice” and that “almost no published knowledge supports CYP2D6 genotyping use” and thus “studies are needed”) (emphasis added); id. (noting that “pharmacogenetics may move faster in psychiatry than in other areas of medicine” because “many CYP2D6 dependent drugs are psychiatric drugs”). We also recognize that Shayman discusses cytochrome P450 metabolism in the context of compounds disclosed to inhibit GlyCer synthase. Specifically, Shayman discloses: D-threo-PDMP was as found to be rather active in delaying tumor cell growth or in producing complete cures in mice (Inokuchi, J. et al., “Antitumor Activity in Mice of an Inhibitor of Glycosphingolipid Biosynthesis,” Cancer Lett,. 38:23-30 (1987)) but high doses were needed. From the data in FIG. 1, the inhibitors of the present invention are approximately 30 times as active, so the dosage levels are typical of clinically useful drugs. The need to use high doses with PDMP was attributed to rapid inactivation by cytochrome P450 (Shukla, A. et al., “Metabolism of D-[3H]PDMP, an Inhibitor of Glucosylceramide Synthesis, and the Synergistic Action of an Inhibitor of Microsomal Monooxygenase,” J. Lipid Res., 32:713-722 (1991)). Cytochrome P450 can be readily blocked by various nontoxic drugs such as cimetidine, therefore high levels of the compounds of the present invention can be maintained. Shayman, 22:11–27. The Examiner relies on this passage as teaching that “a related compound was metabolized by cytochrome P450” and as suggesting to block cytochrome P450 metabolism of the inventive compounds by administering a P450 inhibitor such as cimetidine. Ans. 7; see also, id. at 5. However, we are not persuaded that this passage supports administering the claimed compound taking into account a patient’s CYP2D6 metabolism. Appeal 2019-003550 Application 15/049,946 8 First, the above passage focuses on cytochrome P450. The art teaches that cytochrome P450 is a “superfamily of haem-containing monooxygenases associated with the metabolism of many drugs.” Emoto, 987; see also, Spec. 20 (teaching that there are 11 CYPs expressed in a typical human liver); Colby ¶ 165 (identifying 30 variants of CYP genes). CYP2D6 is but one member of the cytochrome P450 superfamily. Spec. 20. The Examiner does not identify, and we do not find, anything in Shayman that directs the ordinary artisan to focus specifically on CYP2D6. Second, other than asserting – without explanation – that the claimed compound is “related” to PDMP, the Examiner does explain why the ordinary artisan would have expected the claimed compound to be metabolized in the same manner as PDMP. Ans. 5, 7, 10. As Appellant points out, the claimed compound and PDMP have significant structural differences. App. Br. 8. We acknowledge Shayman’s teaching that high levels of the inventive compounds can be maintained by co-administering them with cimetidine, a compound known to block PDMP. Shayman, 22:11–27. However, Shayman also teaches that the “inhibitors of the present invention are approximately 30 times as active” as PDMP, and that the need to use high doses of PDMP is attributable to “rapid inactivation by cytochrome P450.” Id. This suggests that the Shayman’s inventive compounds, in contrast to PDMP, may not be rapidly metabolized by cytochrome P450. Third, the above quoted passage in Shayman does not suggest taking a patient’s cytochrome P450 genotype into account when determining dosing. Id. At best, Shayman suggests the comparatively blunt instrument approach of blocking cytochrome P450 metabolism by administering cimetidine. Appeal 2019-003550 Application 15/049,946 9 The Examiner points to McEachern’s teaching that the claimed compound “was readily metabolized and cleared; both parent compound and metabolites effectively cleared within 24 h as shown in single and repeat oral dose ADME studies with 14C-radiolabelled compound in rats and dogs.” McEachern, 264. According to the Examiner, “[a]n ‘ADME’ study typically includes testing for metabolism pathways (i.e. Liu et al. (Curr. Drug. Metab. 2007 Dec, 8(8), p. 815-829), probing cytochrome P450 including CYP2D6; NDA 205-494: pages 86-125, including testing for CYP2D6 metabolism (p. 98-99)).” Ans. 6. However, that ADME studies for a given compound may include testing for CYP2D6 metabolism, does not necessarily support that the compound is metabolized by CYP2D6. Thus, the Examiner has not persuasively explained why the general statement in McEachern that the claimed compound was “readily metabolized and cleared” would have suggested to the ordinary artisan that the claimed compound was metabolized by CYP2D6, much less that dosing for the claimed compound should be adjusted based on CYP2D6 genotype. In sum, particularly given the relatively poorly developed state of the art with respect to CYP2D6 pharmacogenetic drug dosing, we do not find in the cited art a persuasive connection between, on the one hand, pharmacogenetic assessment of CYP2D6 metabolism, and, on the other hand, the claimed compound, compounds that inhibit GlyCer synthase, and/or compounds that treat Gaucher disease. Absent such a persuasive connection, we agree with Appellant that the Examiner has not carried the burden to establish that the claimed method would have been obvious over the cited art. Accordingly we reverse the Examiner’s rejection of claims 157–181 as obvious over the cited art. Appeal 2019-003550 Application 15/049,946 10 DOUBLE PATENTING The Examiner rejected claims 157–181 on the ground of non-statutory obviousness-type double patenting. The reference patent in this rejection – U.S. Patent No. 6,912,802 – is the Shayman reference discussed above in connection with the Examiner’s obviousness rejection. According to the Examiner, “the basis for this rejection is the same as in the 35 USC 103 rejection.” Ans. 13. Accordingly, we reverse the Examiner’s rejection of claims 157–181 on the basis of non-statutory obviousness type double patenting for the reasons discussed above in connection with the Examiner’s obviousness rejection. CONCLUSION In summary: Claims Rejected 35 U.S.C. § Basis Affirmed Reversed 157–181 103 Shayman, McEachern, Colby, Emoto, De Leon, FDA 157–181 157–181 Double patenting Shayman, McEachern, Colby, Emoto, De Leon, FDA 157–181 Overall Outcome 157–181 REVERSED Copy with citationCopy as parenthetical citation