Ex Parte Baranowska-Kortylewicz et alDownload PDFPatent Trial and Appeal BoardDec 13, 201613512966 (P.T.A.B. Dec. 13, 2016) 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. 13/512,966 07/09/2012 Janine Baranowska-Kortylewicz 48259 2883 23589 7590 12/15/2016 Hovey Williams LLP 10801 Mastin Blvd., Suite 1000 Overland Park, KS 66210 EXAMINER DONOHUE, SEAN R ART UNIT PAPER NUMBER 1618 NOTIFICATION DATE DELIVERY MODE 12/15/2016 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): patents @ hovey williams, com amalik @hovey williams .com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte JANINA BARANOWSKA-KORTYLEWICZ AND ZBIGNIEW P. KORTYLEWICZ Appeal 2015-006217 Application 13/512,966 Technology Center 1600 Before JEFFREY N. FREDMAN, ROBERT A. POLLOCK and JACQUELINE T. HARLOW, Administrative Patent Judges. POLLOCK, Administrative Patent Judge. DECISION ON APPEAL Appellants appeal under 35 U.S.C. § 134(a) from the final rejection of claims 29-31. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. STATEMENT OF THE CASE According to the Specification, the invention relates to therapeutic and diagnostic applications of radiolabeled synthetic compounds, which are effective to (1) kill cancer cells undergoing DNA replication or repair by incorporation into the growing DNA strand resulting in DNA double strand breaks, (2) specifically target two membrane proteins expressed in cancer cells and implicated in tumorogenesis, butyrylcholinesterase (BChE) and the androgen receptor Appeal 2015-006217 Application 13/512,966 (AR). The compounds of the invention are taken up selectively by malignant tumor cells and are incorporated into the nucleus of such cells, where they produce a cytotoxic effect and/or are detectable via nuclear medicine imaging techniques. Spec. 1. Appealed Claims Claims 29-31 are on appeal. Claim 29, the sole independent claim on appeal, recites: 29. A compound of the formula: 0 wherein X represents H, F, Cl, or a C1-C4 alkyl, or C1-C4 alkoxy group; Y represents H or a C1-C4 alkyl group; Z represents H or a C1-C4 alkyl group; R represents halogen, radiohalogen, or a C1-C4 alkyl, C6-C14 aryl, Ci-Cg alkylthio, Ci-Cg alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C3-C12 cycloalkyl, or Sn(Ci-C4 alkyl)3 group; any of said alkyl, alkenyl, alkynyl, alkylthio, alkoxy, and cycloalkyl group being optionally substituted by at least one halogen, OH, SH, NH2, C1-C4 monoalkylamino, Ci- C4 dialkylamino, COOH, CN, NO2, C1-C4 alkyl, C1-C4 alkoxy or phenyl group, any of said aryl and phenyl group being optionally substituted by at least one halogen, OH, SH, NH2, C1-C4 monoalkylamino, C1-C4 dialkylamino, COOH, CN, NO2, C1-C4 alkyl or C1-C4 alkoxy group; 2 Appeal 2015-006217 Application 13/512,966 L is a cleavable bifunctional linking moiety; and said radiohalogen represents 123I, 124I, 125I, 1311,211At, 18F, 76Br, 77Br, or 80mBr; and stereoisomeric forms and pharmaceutically acceptable salts of said compound. Claim 31 recites a kit comprising a compound of claim 29 and a pharmaceutically acceptable carrier medium. Also depending from claim 29, claim 30 is drawn to a compound of the formula: O Grounds of Rejection I. Claims 29-31 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Baranowska- Kortylewicz,1 Meier I2, Meier II,3 Dadachova4 and Kortylewicz.5 1 Baranowska-Kortylewicz et al., US 2005/0069495 Al, published March 31,2005. 2 Meir et al., Interaction of cvcloSal-Pronucleotides with Cholinesterases from Different Origins. A Structure-Activity Relationship, 47 J. Med. Chem. 2839-2852 (2004). 3 Meier and Balzarini, Application of the cvcloSal-prodrug approach for improving the biological potential of phosphorylated biomolecules, 71 Antiviral Res. 282—292 (2006). 4 Dadachova et al., US 2006/0018827 Al, published Jan. 26, 2006. 5 Kortylewicz et al., US 2009/0117041 Al, published May 7, 2009. 3 Appeal 2015-006217 Application 13/512,966 II. Claims 29—31 stand rejected as unpatentable for obviousness- type double patenting over claims 1—6 of the ’730 Patent,6,7 in view of Meier II, and Dadachova. I We have reviewed Appellants’ contentions that the Examiner erred in rejecting claims 29-31 as unpatentable over the cited art. App. Br. 4—8; Reply 1—2. Except as otherwise discussed in footnote 8, we disagree with Appellants contentions and adopt as our own the findings and analysis set forth in the Examiner’s Answer. For emphasis and clarity, we highlight and address the following: Findings of Fact FF1. Baranowska-Kortylewicz discloses “conjugates composed of a radiolabeled, cell cycle-dependent therapeutic agent chemically coupled to a ligand that targets androgen receptor (AR). The conjugates of the invention are taken up selectively by malignant tumor cells that have androgen receptor and are incorporated into the nucleus of such cells, where they produce a cytotoxic effect and/or are detectable via radioimaging techniques.” Baranowska-Kortylewicz 12; see also, 19 (“[T]he radiolabeled conjugates of the present invention [] are capable of targeting and being selectively taken up and degraded by a tumor cell, and thereby delivering to the tumor cell nucleus radioisotope capable of being incorporated into the nuclear material, so as to produce a cytotoxic 6 Baranowska-Kortylewicz et al., US 7,220,730 B2, issued May 22, 2007. 7 The ’730 Patent issued from US 2005/0069495 Al, the application that published as Baranowska-Kortylewicz. 4 Appeal 2015-006217 Application 13/512,966 effect and/or to render the cell detectable by radioimaging.”). The reference explains that “[u]pon administration, the conjugate first binds to the sex hormone binding globulin, which in turn carries it exclusively to cells that have AR [androgen receptor]. Subsequent to this interaction, the entire conjugate is transported into the cell. Intracellular enzymes cleave the linking moiety, thus releasing and trapping within the cell the portion of the conjugate that is responsible for killing tumor cells.” Id. | FF2. Baranowska-Kortylewicz discloses a general formula for the conjugates {id. at || 10-11) and then focuses on the synthesis, chemistry, and biological properties of a small number of specific examples designated conjugates 1, 2, 3, 4, 4a, and 5. See id. at || 25—76. Conjugates 1 and 2, respectively, have the formulas: FF3. With respect to conjugate 1, Baranowska-Kortylewicz states that, The release of 125IUdR from the succinate ester appears to be very effective, both in vitro in cell culture and in vivo in tumor bearing animals. The half-life in vivo is short and may be detrimental to the delivery of therapeutic doses to tumor. On the other hand, because the half-life is short, repeated injections should be possible without a large radioactive burden in normal tissue. 13. Id. 143. 5 Appeal 2015-006217 Application 13/512,966 FF4. Baranowska-Kortylewicz also states that, Conjugate 2 is the most hydrophilic of the conjugates described herein (two negative charges on the monophosphate group). It cannot cross the cell membrane by itself, i.e., it requires the active transport mechanism from the systemic circulation into the tumor cells with the aid of sex hormone binding globulin. Id. 1 50. FF5. Baranowska-Kortylewicz describes conjugate 5 as “the most hydrophobic of all the conjugates described herein. It may be best suited for local/regional administration (e.g., intra peritoneal in the case of ovarian cancer) with a slow diffusion from the site of injection.” Id. | 63. FF6. Meier I discloses that cycloSal-phosphate triesters represent a particular class of pronucleotides. These lipophilic derivatives of various antiviral and antitumor active nucleoside analogues have been developed as intracellular delivery forms of the corresponding nucleotide analogues. By releasing the nucleotide, the metabolic bottleneck of the conversion of the nucleoside into the nucleotide by cellular or viral enzymes can be bypassed (chemical trojan horse concept). The cycloSal approach relies on a chemically driven hydrolysis reaction. The initial chemical hydrolysis step intrinsically activates the remaining masking group which is then spontaneously cleaved to yield the nucleotide (tripartite prodrug). Meir I, 2839; see also Figure 2 (disclosing representative cycloSal-phosphate esters). FF7. Meier II teaches that the administration of therapeutic nucleotides such as d4TMP is hindered because “nucleotides are charged molecules under physiological conditions and do not efficiently penetrate cell membranes. This difficulty can be surmounted by attaching suitably 6 Appeal 2015-006217 Application 13/512,966 degradable lipophilic groups to the phosphate moiety that leads to neutral, membrane-permeable masked.” Id. at 283. In particular, Meier II teaches that salicyl alcohol moieties may be used as cyclic bifimctional masking units for phosphate triesters where the addition of the lipophilic cycloSal moiety enhances the membrane penetration of phosphate triesters. See id. at 290-291. Once inside the cell, the cycloSal moiety dissociates leaving the more polar nucleotide “locked- in,” i.e., trapped inside the cell. See id. at 290. FF8. Meier II figure 3 is reproduced below: Ss s; _ y'^v’v''oA ...............X"-vr" J O.o*wscm c«?;«cai afitp- 5 iissiiay: pfesspnaS* dsasssri * Hjv1 SgFtSvIjd ’iisp b « X- OH J, A " 0--B; rfAod4T sfsp d ? ptx&ptim dieses; Ffg, X UvPm. g-UP‘.Y;iof ths L'-Y /,YS:tE-:.i4 ! MF oiootOY 2 Meier II, figure 3 illustrates the hydrolysis pathway of cyc/oSal-dTMP triesters. Meier II teaches that the hydrolysis pathway is independent of the nucleoside analog attached to the phosphate moiety. Id. at 285. FF9. Meier II teaches that cycloSal derivatives may useful for the intracellular delivery of bioactive nucleotides including antiviral and antitumor nucleoside analogs, moreover, “the delivery of biologically active phosphorylated compounds from cycloSal—phosphate triesters 7 Appeal 2015-006217 Application 13/512,966 generally may lead to a strong improvement in [] bioactivity.” Id. at 291, see id. at Abstract, 286. FF10. Meier II further discloses a series of cycloSal nucleotide triesters and their ability to inhibit AChE (acetylcholinesterase), BChE (butyrylcholinesterase), and HIV replication in cell culture. See e.g., id. Abstract, Tables 1 and 2. FF11. Kortylewicz discloses cyc/oSalingenyl pyrimidine nucleoside monophosphates comprising positron emitters or gamma-emitting radiohalides having the general formula which bind to BChE in the brain and are useful for monitoring Alzheimer's disease progression. Kortylewicz || 3, 13, 20, 22. FF12. Dadachova teaches kits comprising positron emitters for the treatment of inflammation, infection, and disease. See Dadachova, Abstract H 39, Appellants argue that “a chemist of ordinary skill would not have selected conjugate 1 or conjugate 2 of Baranowska-Kortylewicz as a starting point for further chemical modification.” App. Br. 4—5 (citing Otsuka Pharmaceutical Co. Ltd., v. Sandoz, Inc., 678 F.3d 1280, 1291—1292 (Fed. Cir. 2012). In particular, Appellants suggest that Baranowska-Kortylewicz teaches away from the selection of those compounds because conjugate 1 is described “as having a short half-life, which may be detrimental to the 48. Analysis 8 Appeal 2015-006217 Application 13/512,966 delivery of therapeutic doses to tumors, possibly requiring repeated injections,” whereas Baranowska-Kortylewicz reports that conjugate 2 “cannot cross the membrane by itself, i.e., it requires the active transport mechanism from the systemic circulation into the tumor cells with the aid of sex hormone binding globulin.” Id. at 5—6. Rather, Appellants argue, one of ordinary skill in the art would have selected compound 5 for further development as Baranowska-Kortylewicz describes it as “best suited for local/regional administration . . . with a slow diffusion from the site of injection.’” Id. at 6 (quoting Baranowska-Kortylewicz 163). We do not find Appellants argument persuasive. The lead compound analysis begins with the identification of “a compound in the prior art that would be most promising to modify in order to improve upon its . . . activity and obtain a compound with better activity.” Otsuka, 678 F.3d at 1291 (citing Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd., 492 F.3d 1350, 1357 (Fed. Cir. 2007)). As such, a lead compound is “a natural choice for further development efforts.” Altana Pharma AG v. Teva Pharm. USA, Inc., 566 F.3d 999, 1008 (Fed. Cir. 2009). Otsuka, however, expressly acknowledges the possibility that there can be “one or more lead compounds.” 678 F.3d at 1291; see also Altana, 566 F.3d at 1008 (“to the extent Altana suggests that the prior art must point to only a single lead compound for further development efforts, that restrictive view of the lead compound test would present a rigid test similar to the teaching- suggestion-motivation test that the Supreme Court explicitly rejected in KSR Inti Co. v. Teleflex Inc., 550 U.S. 398, 419 (2007)”). In the present case, we agree with the Examiner that one of ordinary skill in the art would have reasonably looked to any of the small number of 9 Appeal 2015-006217 Application 13/512,966 compounds highlighted in the Baranowska-Kortylewicz reference.8 See Ans. 12. With respect to Appellants argument one of ordinary skill in the art would not have selected conjugate 1 as a lead compound because its short half-life “may be detrimental to the delivery of therapeutic doses to tumors” (App. Br. 5), we note that Baranowska-Kortylewicz teaches that the conjugates are useful for their “cytotoxic effect and/or . . . radioimaging techniques.” See FF 1 (emphasis added). With respect to the latter, the reference clearly teaches the benefit of conjugate 1, stating that “because the half-life is short, repeated injections should be possible without a large radioactive burden in normal tissue.” See FF 3. As noted by the Examiner, Baranowska-Kortylewicz teaches the use of androgen receptor/globulin complexes in transporting the disclosed conjugates across cell membranes, whereupon the transported compounds are released and beneficially retained within the cell. See Ans. 12—13; FF 1. Accordingly, we do not understand the hydrophilicity of conjugate 2 and its specificity for active transport as a reason not to select conjugate 2 for further development. Moreover, to the extent we accept Appellant’s argument regarding the active transport requirement of conjugate 2, Meier II teaches the addition of 8 Appellants argue that the Examiner errs in referencing compounds claimed in Baranowska-Kortylewicz “while effectively disregarding other relevant disclosure which would plainly influence the selectin of a lead compound.” Reply 1—2. To the extent the Examiner may have improperly looked to the claims as evidence of the scope and teachings of the prior art, such error is harmless because, as recognized by the Examiner, the reference clearly focuses on the chemistry and biology of a small number of representative compounds. See FF 2—5. We also recognize that the Examiner does not distinguish between compounds 4 and 4a but do not find this point determinative. 10 Appeal 2015-006217 Application 13/512,966 lipophilic cycloSal moieties to charged nucleotides that do not efficiently penetrate cell membranes. See FF 7; see also Ans. 13 (“[A] chemist of ordinary skill would have understood that the substitution of polar phosphate radical in compound 2 discussed above with nonpolar cyc/oSal radical advantageously enables intracellular delivery and chemical hydrolysis to corresponding nucleotide.”). Finally with respect to Appellants’ position that one of ordinary skill in the art would have looked exclusively to conjugate 5 for further development, we note that Baranowska-Kortylewicz’s teaching that conjugate 5 “may be best suited for local/regional administration” in no way suggests that it is best suited for ah applications including systemic administration. See FF 4, 5. Appellants also argue that “the cited references provide no reason to modify any compound described therein to arrive at the compounds of claims 29-31 with a reasonable expectation of success.” App. Br. 5. We do not find Appellants’ argument persuasive. As explained by the Examiner, it would have been obvious to modify Baranowska-Kortylewicz compounds 1 and 2 by incorporating a cyc/oSal moiety having substituents at the 3, 5, and/or 6 positions as taught by Meier I, Meier II, and Kortylewicz, as well as Dadachova,9 to “advantageously enable improved intracellular delivery of radiotherapeutic nucleoside conjugate.” Ans. 8. The Examiner further finds that “[tjhere would have been a reasonable expectation of success because [Meier I and Meier II] teach that [the] cyc/oSal moiety acts as lipophilic 9 Dadachova is cited with respect to claim 31 as teaching positron emitters in kit form. See Ans. 7. 11 Appeal 2015-006217 Application 13/512,966 prodrug which undergoes hydrolysis within cells and bypasses the metabolic bottleneck of converting nucleoside into nucleotide and [Meier II] teach[es] that the hydrolysis pathway is independent on the nucleoside analog.” Id.', see id. at 14. For the above reasons, we affirm. II Appellants rely on the same arguments with respect to the rejection for obviousness-type double patenting over claims 1—6 of the ’730 Patent, in view of Meier II, and Dadachova. App. Br. 8—9. As indicated above, the ’730 Patent issued from the application that published as Baranowska- Kortylewicz. Claims 1—6 of the ’730 patent disclose compounds bearing the cycloSal radical including conjugates 1 and 2, discussed above with respect to Baranowska-Kortylewicz. Finding no error in the Examiner’s rejection based on obviousness, we likewise affirm the rejection for obviousness-type double patenting. SUMMARY I. We affirm the rejection of claims 29-31 under § 35 U.S.C. 103(a) as obvious over the combination of Baranowska-Kortylewicz, Meier I, Meier II, Dadachova and Kortylewicz. II. We affirm the rejection of claims 29-31 as unpatentable for obviousness-type double patenting over claims 1—6 of the ’730 Patent, in view of Meier II, and Dadachova. 12 Appeal 2015-006217 Application 13/512,966 TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED 13 Copy with citationCopy as parenthetical citation