Lipomedix Pharmaceuticals LTD. et al.Download PDFPatent Trials and Appeals BoardMar 18, 20212020003764 (P.T.A.B. Mar. 18, 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. 15/559,395 09/18/2017 Alberto Gabizon 094893-0026/8003.US00 1096 108547 7590 03/18/2021 McDermott Will & Emery LLP 500 North Capitol Street NW Washington, DC 20001 EXAMINER SHOMER, ISAAC ART UNIT PAPER NUMBER 1612 NOTIFICATION DATE DELIVERY MODE 03/18/2021 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): mweipdocket@mwe.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte ALBERTO GABIZON and PATRICIA OHANA1 Appeal 2020-003764 Application 15/559,395 Technology Center 1600 Before ERIC B. GRIMES, JEFFREY N. FREDMAN, and ULRIKE W. JENKS, Administrative Patent Judges. GRIMES, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134(a) involving claims to a method of treating bladder cancer, which have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. STATEMENT OF THE CASE “The present disclosure is based in part on the finding that folate- targeted liposomes with a prodrug of mitomycin C are stable in urine for a 1 Appellant identifies the real party in interest as Lipomedix Pharmaceuticals Ltd. Appeal Br. 1. We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appeal 2020-003764 Application 15/559,395 2 time sufficient for therapy in the bladder.” Spec. ¶ 27. “The prodrug conjugate is not toxic, and after administration and upon exposure to endogenous reducing agents or exposure to an exogenous reducing agent, the conjugate decomposes to yield mitomycin C in its native state and with biological activity.” Id. ¶ 30. Claims 1 and 5–11 are on appeal. Claim 1, reproduced below, is illustrative: 1. A method for treating bladder cancer, comprising: administering to an individual with bladder cancer liposomes comprising a folate targeting moiety and a prodrug of mitomycin C, the liposomes administered in an amount that yields a therapeutically-effective amount of mitomycin C for the treatment of bladder cancer, wherein administering comprises administering via intravesical instillation, wherein the prodrug of mitomycin C is a conjugate of mitomycin C releasably attached to a lipophilic moiety, and is of the form: , wherein L is a hydrophobic moiety, R1 represents a mitomycin C residue, orientation of the –CH2R1 group is selected from the ortho position and the para position. Appeal 2020-003764 Application 15/559,395 3 The claims stand rejected as follows: Claims 1 and 5–11 under 35 U.S.C. § 103 as obvious based on Zalipsky,2 Gabizon,3 and Dalton4 (Final Action5 3); and Claims 1 and 5–11 under 35 U.S.C. § 103 as obvious based on Zalipsky, Li,6 and Dalton (Final Action 7). OPINION Obviousness: Zalipsky, Gabizon, and Dalton All of the claims stand rejected as obvious based on Zalipsky, Gabizon, and Dalton. The Examiner finds that Zalipsky teaches a method of treating tumors, including bladder cancer, by administering a prodrug conjugate of mitomycin C in the form of a liposome composition. Final Action 3. The Examiner finds that the prodrug conjugate taught by Zalipsky corresponds to the structure in claim 1. Id. at 5–6. The Examiner finds that Zalipsky does not teach a folate targeting moiety, but Gabizon teaches liposome-entrapped drugs targeted to tumor cells via folate attached to the phospholipids of the liposome. Id. at 3–4. The Examiner concludes that it would have been obvious “to have attached folic acid (i.e. folate), as of Gabizon to the liposome lipids in the liposome of 2 Zalipsky et al., US 2004/0161455 A1, published Aug. 19, 2004. 3 Gabizon et al., Tumor cell targeting of liposome-entrapped drugs with phospholipid-anchored folic acid-PEG conjugates, Advanced Drug Delivery Reviews, 56:1177–1192 (2004). 4 Dalton et al., Pharmacokinetics of Intravesical Mitomycin C in Superficial Bladder Cancer Patients, Cancer Research, 51:5144–5152 (1991). 5 Office Action dated June 19, 2019. 6 Li et al., Therapeutic Effect of Folate-Targeted and PEGylated Phytosomes Loaded with a Mitomycin C-Soybean Phosphatidylcholine Complex, Molecular Pharmaceutics, 11:3017–3026 (2014). Appeal 2020-003764 Application 15/559,395 4 Zalipsky” because Zalipsky teaches treating cancer and “Gabizon teaches that folate is useful for targeting tumors because folate receptor is expressed on tumor cells.” Id. at 4. The Examiner acknowledges that Zalipsky and Gabizon do not teach intravesical instillation, but finds that Dalton teaches intravesical administration of mitomycin C to treat superficial bladder cancer. Id. at 4–5. The Examiner concludes that it would have been obvious “to have administered the liposome comprising mitomycin C prodrug of Zalipsky, as modified with folate by Gabizon, in an intravesical manner in order to treat bladder cancer” because “Dalton indicates that mitomycin C may be administered intravesically to treat bladder cancer.” Id. at 5. We agree with the Examiner that the cited references support a prima facie case of obviousness. Zalipsky states that “[m]itomycin is an established chemotherapeutic agent given for several different types of cancer, including breast, stomach, gullet and bladder cancer. The agent acts by cross-linking DNA so the cancer cells are unable to proliferate.” Zalipsky ¶ 3 (emphasis added). Zalipsky discloses “a method for reducing the cytotoxicity of mitomycin C,” by providing the mitomycin C in the form of a “prodrug conjugate [that] is comprised of a lipid linked to the drug via a cleavable linkage, the lipid being incorporated into a liposomal formulation.” Id. ¶ 2. Zalipsky describes providing mitomycin C in the form of a liposome composition comprised of a vesicle-forming lipid and . . . a conjugate having the general form: Appeal 2020-003764 Application 15/559,395 5 wherein L is a hydrophobic moiety suitable for incorporation into a liposomal lipid bilayer, R1 is mitomycin C covalently attached to the dithiobenzyl moiety, and where orientation of the CH2R1 group is selected from the ortho position and the para position. Id. ¶¶ 13–14. Thus, Zalipsky teaches or suggests a method of treating bladder cancer comprising administering liposomes comprising the mitomycin C prodrug recited in Appellant’s claim 1. Zalipsky does not teach including a folate targeting moiety in its liposomes, but Gabizon teaches that “[t]argeting of liposomes with phospholipid-anchored folate conjugates is an attractive approach to deliver chemotherapeutic agents to folate receptor (FR) expressing tumors.” Gabizon 1177, Abstract. Gabizon’s Figure 17 is reproduced below: 7 The figure reproduced here is from page 7 of the Answer due to the poor quality of the figure in the record copy of Gabizon. Appeal 2020-003764 Application 15/559,395 6 Gabizon’s Figure 1 shows “[a] schematic illustration of the folate liposome targeting concept.” Id. at 1178, left col. More specifically, the figure shows “[t]he various steps involved in the targeting process . . . numerically designated from 1 to 6.” Id. at 1179, legend to Fig. 1. In step (1), “[l]iposomes with long-circulating properties increase the number of passages through the tumor microvasculature.” Id. In step (2), “[i]ncreased vascular permeability in tumor tissue enables . . . liposomes to extravasate and reach the tumor interstitial fluid.” Id. In step (3), “[d]rug is gradually released from liposomes . . . and enters tumor cells as free drug to exert a cytotoxic effect.” Id. Gabizon states that “[s]teps 1–3 are common to nontargeted and targeted liposomes. Steps 4–6 are specific to FTL [folate-targeted liposomes].” Id. In step (4), “liposomes bind to the FR [folate receptor] expressed on the tumor cell membrane via the folate ligand.” Id. In step (5), “[l]iposomes are internalized by tumor cells.” Id. In step (6), “[i]nternalized liposomes release their drug content in the cytosol enabling the drug to exert its cytotoxic effect.” Id. That is, with folate-targeted liposomes (FTL), “once liposomes have penetrated the tumor interstitial fluid, binding of targeted liposomes to FR may occur thus shifting the intra-tumor distribution from the extracellular compartment to the tumor cell compartment.” Id. at 1178, right col. Gabizon states that “the theoretical advantages of FTL over NTL [non-targeted liposomes] are related to a shift of liposome distribution to the tumor cell compartment, delivery of liposomal contents to an intra-cellular compartment in liposome-associated form, and, possibly, prolonged liposome retention in the tumor.” Id. Appeal 2020-003764 Application 15/559,395 7 Gabizon concludes that the current body of data does not support the claim that folate targeting increases to a sizable extent the overall liposome concentration in subcutaneously-growing tumor implants. However, folate targeting may still lead to significant pharmacodynamic changes with improvement of the therapeutic index by shifting drug distribution from the extracellular to the intracellular tumor compartment while systemic toxicity is left unchanged or even reduced. Id. at 1190, right col. Based on Gabizon’s disclosure, it would have been obvious to a person of ordinary skill in the art to modify the mitomycin C prodrug- containing liposomes taught by Zalipsky to include phospholipid-anchored folate conjugates, as taught by Gabizon. Motivation to do so is provided by Gabizon, which teaches that folate-targeted liposomes (FTL) target folate receptor-expressing tumors by binding to the folate receptor, being internalized by the tumor cells, and releasing their drug contents in the cytosol of the tumor cells. Thus, FTLs “shift[] the intra-tumor distribution from the extracellular compartment to the tumor cell compartment,” id. at 1178, right col., leading to an “improvement of the therapeutic index.” Id. at 1190, right col. Neither Zalipsky nor Gabizon specifically teach intravesical instillation in the treatment of bladder cancer, but Dalton teaches that “[i]ntravesical mitomycin C (MMC) therapy is used to treat superficial bladder cancer.” Dalton 5144, Abstract. Dalton teaches, in fact, that “[t]ransurethral tumor resection and intravesical chemotherapy are the most commonly used treatment modality for superficial bladder cancer.” Id. at 5144, left col. Appeal 2020-003764 Application 15/559,395 8 Therefore, it would have been obvious to treat bladder cancer by administering the mitomycin C prodrug-containing liposomes taught by Zalipsky, modified to include a folate targeting moiety as suggested by Gabizon, by intravesical instillation, because Dalton teaches that that method of administration is the most commonly used treatment modality for treating superficial bladder cancer. Appellant argues that “Zalipsky teaches . . . that the liposomal mitomycin C prodrug exerts its therapeutic effect via extracellular cleavage of the mitomycin C prodrug to release mitomycin C which is then taken up by the tumor cells.” Appeal Br. 4. Appellant argues that the Gabizon Declaration8 states that “neither liposomal mitomycin C prodrug as taught in Zalipsky nor mitomycin C prodrug itself can be internalized into the cell for intracellular cleavage of the mitomycin C prodrug to exert cytotoxicity, whereas “ mitomycin C in free form can be taken up by cancer cell very quickly.” Id., citing Gabizon Decl. ¶¶ 9, 10. This argument is unpersuasive. Zalipsky states that its results show that the disclosed mitomycin C prodrug is less toxic when administered in vivo than free mitomycin C, and that “multi-drug resistant cells are able to take up the mitomycin C when administered in the form of the [prodrug] conjugate.” Zalipsky ¶ 117. The Gabizon Declaration clarifies that Zalipsky is referring to “uptake of mitomycin C in its free form after the free-form mitomycin C is extracellularly released from the liposomal mitomycin C prodrug.” Gabizon Decl. ¶ 8. 8 Declaration under 37 C.F.R. § 1.132 of Alberto A. Gabizon, filed May 20, 2019. Appeal 2020-003764 Application 15/559,395 9 Zalipsky’s disclosure thus is consistent with the disclosure of the Gabizon reference, which states that non-targeted liposomes extravasate from the vasculature in the vicinity of tumor tissues, after which “[d]rug is gradually released from liposomes remaining in the interstitial fluid and enters tumor cells as free drug to exert a cytotoxic effect.” Gabizon 1179, legend to Fig. 1. Gabizon also discloses that folate-targeted liposomes have the added property of being taken up by tumor cells after they bind to folate receptors and being internalized; the folate-targeted liposomes then release their drug contents in the cytosol of the tumor cells. Id. A skilled artisan therefore would have expected that modification of Zalipsky’s liposomes to include a folate targeting moiety would result in “a shift of liposome distribution to the tumor cell compartment, delivery of liposomal contents to an intra-cellular compartment in liposome-associated form, and, possibly, prolonged liposome retention in the tumor.” Id. at 1178, right col. Appellant notes that “Gabizon teaches including a folate receptor targeting moiety on the liposomal exterior surface . . . so that the liposome is internalized by the cell.” Appeal Br. 4. Appellant argues, however, that [a]dding folate targeting ligands as taught by Gabizon to Zalipsky’s liposomes has the potential outcome that the folate ligand achieves the desired intracellular uptake of the liposomes sans a mitomycin C prodrug conjugate due to its release prior to intracellular uptake. Accordingly, there is no benefit to adding a folate targeting moiety as an empty, drug-free liposome delivered intracellularly has no benefit. Id. This argument is also unpersuasive. Appellant has pointed to no evidence showing that modifying Zalipsky’s liposomes to include a folate targeting moiety, as suggested by Gabizon, would result in the liposomes Appeal 2020-003764 Application 15/559,395 10 releasing all of their mitomycin C prodrug contents extracellularly, so that any liposomes taken up by the tumor cells would be empty. Gabizon’s disclosure is to the contrary. Gabizon states that both non-targeted and folate-targeted liposomes release some of their contents extracellularly. See Gabizon 1179, legend to Fig. 1 (“Steps 1–3 are common to nontargeted and targeted liposomes. . . . (3) Drug is gradually released from liposomes remaining in the interstitial fluid and enters tumor cells as free drug to exert a cytotoxic effect.”). Folate-targeted liposomes, however, also have the property of being taken up by tumor cells and releasing their drug contents in the tumor cells’ cytosol. See id. (“(5) Liposomes are internalized by tumor cells. . . . (6) Internalized liposomes release their drug content in the cytosol.”). Appellant argues that “Gabizon . . . discloses that in three tumor models, FTL-Dox and NTL-Dox were equally active. Gabizon cautions that ‘the concept of ligand-mediated active liposome targeting still needs further experimental proof of validity in animal models and surely in clinical trials.’” Appeal Br. 5 (citation omitted). Appellant argues that, therefore, a skilled artisan would not be motivated to add folate to Zalipsky’s liposomes “because Gabizon indeed teaches that liposomes with or without folate have similar bio-distribution in tumors and similar anti-tumor activity.” Id. This argument is also unpersuasive. While Gabizon indicates that further testing of folate-targeted liposomes was still needed, it also states that folate-targeted liposomes should provide advantages compared to non- targeted liposomes. See Gabizon 1178, right col. (“[T]he theoretical advantages of FTL over NTL are related to a shift of liposome distribution to the tumor cell compartment, delivery of liposomal contents to an intra- Appeal 2020-003764 Application 15/559,395 11 cellular compartment in liposome-associated form, and, possibly, prolonged liposome retention in the tumor.”); id. at 1190, right col. (“[F]olate targeting may still lead to significant pharmacodynamic changes with improvement of the therapeutic index by shifting drug distribution from the extracellular to the intracellular tumor compartment while systemic toxicity is left unchanged or even reduced.”). Thus, Gabizon would have provided a skilled artisan with a reasonable expectation that adding a folate targeting moiety to Zalipsky’s liposomes would result in an improved therapeutic agent, at least because it would shift drug distribution from the extracellular to the intracellular tumor compartment. “Only a reasonable expectation of success, not absolute predictability, is necessary for a conclusion of obviousness.” In re Longi, 759 F.2d 887, 897 (Fed. Cir. 1985). Appellant also argues that [t]he liposomal drugs disclosed in Gabizon are free drugs, NOT prodrugs. . . . [N]o discussion of administration of folate targeted liposome encapsulated drugs by intravesical instillation, hence no discussion of effectiveness of this route of administration of folate targeted liposome encapsulated drugs, is provided. Accordingly, there is no reasonable expectation of success with respect to the claimed method. Appeal Br. 6. Appellant argues that “[t]here is further lack of expectation of success in view of the fact that mitomycin C is not stable in urine. Dalton repeatedly makes the point that mitomycin C degrades in urine.” Id. Appellant argues that “[r]elease of mitomycin C in the bladder, for treating bladder cancer, potentially exposes the mitomycin C to urine, where it is subject to degradation. Accordingly, it is unclear whether the prodrug- Appeal 2020-003764 Application 15/559,395 12 conjugate liposomes of Zalipsky would be effective to treat bladder cancer.” Id. This argument is also unpersuasive. Although Gabizon does not teach liposome-encapsulated prodrugs, Zalipsky teaches that free mitomycin C is released from its prodrug under reducing conditions, such as those found in the vicinity of tumor cells. See Zalipsky ¶ 2 (“The prodrug conjugate is cleavable under mild thiolytic conditions in vivo for release of mitomycin C.”); id. ¶ 117 (“The increased level of thioredoxin in tumor cells offers a unique synergy with the mitomycin C conjugate described here, since a natural source of a reducing enzyme is concentrated in the target tissue.”). With regard to the potential degradation of mitomycin C in urine, Dalton refers to “drug removal by degradation and absorption” during therapy or during bladder exposure to mitomycin C (MMC). See Dalton 5144, Abstract. However, Dalton also discloses how to minimize such degradation. See id. at 5150, right col. (“[T]he rate of nonenzymatic degradation of MMC was 12-fold slower at pH 7 relative to pH 5. It would be logical to buffer the bladder instillate to pH 7 during therapy in order to decrease the rate of nonenzymatic degradation.”); id. at 5151, left col. (“Further enhancement of target site exposure requires . . . more complete bladder emptying, control of the urine pH for optimal drug activity and stability, decreased fluid intake prior to and during therapy, increased instillation periods, and more complete distribution and mixing of the dosing solution within the bladder during therapy.”). We therefore conclude that the cited references would have provided a reasonable expectation of success in combining Gabizon’s folate targeting moiety with Zalipsky’s liposomes, and administering them via intravesical instillation as suggested by Dalton. Appeal 2020-003764 Application 15/559,395 13 We affirm the rejection of claim 1 under 35 U.S.C. § 103 based on Zalipsky, Gabizon, and Dalton. Claims 5–11 fall with claim 1 because they were not argued separately. 37 C.F.R. § 41.37(c)(1)(iv). Obviousness: Zalipsky, Li, and Dalton All of the claims stand rejected as obvious based on Zalipsky, Li, and Dalton. The Examiner relies on Zalipsky and Dalton for the same disclosures discussed above. Final Action 7–9. The Examiner finds that Li teaches “a folate targeted ‘phytosome’ comprising mitomycin C,” where “[t]he term ‘phytosome’ refers to a liposome with a lower phospholipid dosage as compared with liposomes.” Id. at 8. The Examiner finds that “Li teaches folate as a targeting element to target cancer.” Id. The Examiner concludes that it would have been obvious “to have attached folic acid (i.e. folate), as of Li, to the liposome lipids in the liposome of Zalipsky . . . in order to have predictably targeted said liposome to tumors with a reasonable expectation of success.” Id. at 8–9. The Examiner also concludes that it would have been obvious “to have administered the liposome comprising mitomycin C prodrug of Zalipsky, as modified with folate by Li, in an intravesical manner in order to treat bladder cancer” because “Dalton indicates that mitomycin C may be administered intravesically to treat bladder cancer.” Id. at 9. We agree with, and adopt, the Examiner’s fact-finding and conclusions. Zalipsky and Dalton are discussed above. Li states that “[a] mitomycin C (MMC)-soybean phosphatidylcholine complex loaded in phytosomes was previously reported . . . , but this approach was limited by rapid elimination from the body and lack of target specificity.” Li 3017, Appeal 2020-003764 Application 15/559,395 14 Abstract.9 Li reports that, to overcome these issues, the MMC-loaded phytosomes “were surface-functionalized with folate-PEG (FA-PEG) to achieve reduced toxicity and a superior MMC-mediated therapeutic effect.” Id. Li states that “[t]he remarkable features of FA-PEG-MMC-loaded phytosomes included increased cellular uptake in HeLa cells and higher accumulation in H22 tumor-bearing mice over that of the PEG-MMC-loaded phytosomes.” Id. Further, Li reports that “FA-PEG-MMC-loaded phytosomes were associated with enhanced cytotoxic activity in vitro and an improved antitumor effect in vivo compared to that resulting from free MMC injection.” Id. Based on these teachings, it would have been obvious to modify Zalipsky’s liposomes, containing mitomycin C prodrug, by surface- functionalizing them with folate-PEG, as taught by Li, because Li teaches that FA-PEG-modified phytosomes have enhanced cytotoxic activity in vitro and improved antitumor effect in vivo compared to free mitomycin C. It would also have been obvious to administer the modified liposomes by intravesical administration to treat bladder cancer, because Zalipsky teaches that its liposomes can be used to treat bladder cancer and Dalton teaches that intravesical chemotherapy is a commonly used treatment for bladder cancer. Thus, the combined disclosures of Zalipsky, Li, and Dalton would have made obvious the method of claim 1 to a person of ordinary skill in the art. 9 “A phytosome is a type of drug-phospholipid complex-based soft NP [nanoparticle] that is advantageous for drug delivery because of its lower phospholipid dosage compared to that of liposomes.” Li 3017, left col. Appeal 2020-003764 Application 15/559,395 15 Appellant argues that, “[a]ssuming folate ligand attached phytosomes target tumor cells more than phytosomes without folate ligand attached, a [s]killed artisan would not be motivated to attach a folate ligand to liposomes of Zalipsky because liposomes were found to be inferior to phytosomes according to Li.” Appeal Br. 7. This argument is unpersuasive. Li teaches that phytosomes are “advantageous for drug delivery because of [their] lower phospholipid dosage compared to that of liposomes.” Li 3017, left col. However, Li also notes that “Zalipsky et al. reported a MMC drug delivery system in which the liposome acted as a drug carrier.” Id. at 3017, right col. Li does not indicate that Zalipsky’s liposome-based formulation was ineffective for delivering mitomycin C, and thus would not have discouraged a skilled artisan from modifying Zalipsky’s liposomes in the same manner that Li teaches for its MMC-containing phytosomes. Appellant also argues that “Li discloses administration route by IV injection, which is completely different from the claimed intravesical administration,” and “[a]ny advantages or success associated with IV injection as disclosed by Li cannot be reasonably expected from intravesical instillation.” Appeal Br. 7. These arguments are also unpersuasive. Dalton discloses that intravesical administration of chemotherapeutic agents is a commonly used treatment modality for bladder cancer, and therefore an obvious route of administering the mitomycin C prodrug-containing liposomes made obvious by the combination of Zalipsky and Li. Appellant has cited no evidence to show that the advantages disclosed by Li would not also apply to liposomes administered by intravesical administration, and “[a]ttorneys’ argument is no Appeal 2020-003764 Application 15/559,395 16 substitute for evidence.” Johnston v. IVAC Corp., 885 F.2d 1574, 1581 (Fed. Cir. 1989). We affirm the rejection of claim 1 under 35 U.S.C. § 103 based on Zalipsky, Li, and Dalton. Claims 5–11 fall with claim 1 because they were not argued separately. 37 C.F.R. § 41.37(c)(1)(iv). DECISION SUMMARY In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 5–11 103 Zalipsky, Gabizon, Dalton 1, 5–11 1, 5–11 103 Zalipsky, Li, Dalton 1, 5–11 Overall Outcome 1, 5–11 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). See 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED Copy with citationCopy as parenthetical citation