Biocompatibles UK LimitedDownload PDFPatent Trials and Appeals BoardAug 19, 20212020005983 (P.T.A.B. Aug. 19, 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. 13/981,706 10/10/2013 Koorosh Ashrafi 8150.0688 5973 121974 7590 08/19/2021 Kacvinsky Daisak Bluni PLLC (8150) 2601 Weston Parkway, Suite 103 Cary, NC 27513 EXAMINER MATTISON, LORI K ART UNIT PAPER NUMBER 1619 NOTIFICATION DATE DELIVERY MODE 08/19/2021 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): docketing@kdbfirm.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte KOOROSH ASHRAFI, ANDREW LENNARD LEWIS, CLARE HEAYSMAN, ANDREW LLOYD, and GARY PHILIPS __________ Appeal 2020-005983 Application 13/981,706 Technology Center 1600 __________ Before RICHARD M. LEBOVITZ, JEFFREY N. FREDMAN, and ULRIKE W. JENKS, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35 U.S.C. § 134(a) involving claims to microspheres suitable for use in embolisation of a tumor. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the Real Party in Interest as Biocompatibles UK Limited (see Appeal Br. 3). We refer to the Specification of July 25, 2013 (“Spec.”); Final Action of Sept. 19, 2019 (“Final Act.”); Appeal Brief of May 21, 2020 (“Appeal Br.”); Examiner’s Answer of June 18, 2020 (“Ans.”); and Reply Brief of Aug. 18, 2020 (“Reply Br.”). Appeal 2020-005983 Application 13/981,706 2 Statement of the Case Background “[P]olymer microspheres can be useful in the treatment of embolisation. Embolisation involves the introduction of embolic agents into the arteries feeding a tumour to starve it of its nutrients and oxygen” (Spec. 4:29–31). “There is evidence from preclinical tumour models, that embolisation alone may induce hypoxia in the tumour” (id. at 5:2–3). “[H]ypoxic tumours are known to possess a reductive environment” (id. at 3:4). “Polymers that contain disulfide functionality can be considered both redox and thiol responsive” (id. at 2:29–30). Prior art describes microcapsules “cross-linked with disulfides by layer-by-layer deposition of thiolated PMA” that were used “for loading doxorubicin and delivering the drug to colon cancer cells in vitro” (id. at 4:1–3; 4:24–25). The Claims Claims 1, 5, 9–15, and 21–31 are pending.2 Independent claim 1 is representative and reads as follows: 1. Microspheres suitable for use in embolisation of a tumor, comprising a gel body, wherein the gel body comprises a synthetic polymer and a drug, wherein the microparticles have an average diameter in the range 40 to 1500 μm, wherein the polymer comprises polyvinyl alcohol wherein the polymer is cross-linked by a cross linking agent of the formula: A-(CH2)n-S-S-(CH2)n'-A' wherein A and A' are independently selected from groups which can form a covalent bond with the polymer; n and n' are integers ranging from 1 to 10; and wherein at least one of the - 2 We note that claims 16–19 and 32 were identified as withdrawn from consideration by the Examiner in the Final Action. Appeal 2020-005983 Application 13/981,706 3 (CH2)n and -(CH2)n'- groups are substituted with groups which are capable of electrostatically associating with the drug; and wherein the polymer is in the form of a hydrogel, and wherein the groups capable of electrostatically associating with the drug are carboxyl groups. The Issue The Examiner rejected claims 1, 5, 9–15, and 21–32 under 35 U.S.C. § 103(a) as obvious over Lewis,3 Stein,4 Ilangovan,5 and Meng6 (Final Act. 5–11). The issue with respect to this rejection is: Does a preponderance of the evidence of record support the Examiner’s conclusion that the prior art renders the claims obvious? Findings of Fact 1. Lewis teaches microspheres suitable for embolisation, comprises particles having a matrix of water-swellable water-insoluble polymer and, absorbed in the matrix, a water-soluble therapeutic agent, and is characterised in that the polymer has an overall anionic charge at a pH in the range 6 to 8, in that the particles, when swollen to equilibrium in water have particle sizes in the range 40-1500 μm and in that the therapeutic agent is an anthracycline compound having at least one amine group. (Lewis ¶¶ 11, 40). Lewis teaches “composition is of use for embolising tumours and delivering cytotoxic agents thereto” (Lewis ¶ 1). 3 Lewis et al., US 2004/0161466 A1, published Aug. 19, 2004. 4 Stein et al., US 2002/0076443 A1, published June 20, 2002. 5 Ilangovan et al., In vivo measurement of tumor redox environment using EPR spectroscopy, 234/235 Mol. Cellular Biochemistry 393–98 (2002). 6 Meng et al., Reduction-sensitive polymers and bioconjugates for biomedical applications, 30 Biomaterials 2180–98 (2009). Appeal 2020-005983 Application 13/981,706 4 2. Lewis teaches a “type of polymer which may be used to form the water-swellable water-insoluble matrix is polyvinyl alcohol crosslinked using aldehyde type crosslinking agents” (Lewis ¶ 13). 3. Lewis teaches the “the polymer will form a hydrogel. Generally the polymer is covalently crosslinked” (Lewis ¶ 12). 4. The Examiner acknowledges that Lewis does “not teach disulfide crosslinking of the polyvinyl alcohol” (Final Act. 6). 5. Stein teaches “cross-linked polymer matrices” (Stein ¶ 8) including polyvinyl alcohol polymers (Stein ¶ 17) “such that an entrapped therapeutic agent or agents is released from the matrix under zero order, pseudo zero order or first order kinetics. The release characteristics are adjustable by selection of the appropriate phases, polymer(s), cross-linking agent(s), and excipients, among other factors” (Stein ¶ 11). 6. Stein teaches “[p]referably, the polymer comprises at least two thiol groups, and may be a homopolymer or a copolymer” (Stein ¶ 18). 7. Stein teaches: A matrix of the present invention may be prepared by cross- linking the polymer on which at least two thiol groups are present in the presence of the therapeutic agent. The cross- linking of the polymer on which at least two thiol groups are present may include disulfide bonds, thioether bonds, and combinations thereof. (Stein ¶ 64). 8. Stein teaches: controlled release of the therapeutic agent from the matrix is believed to occur as a consequence of the diffusion from and/or biodegradation of the matrix by one or more in-vivo degradation pathways. . . . degradation of the matrix is achieved by local factors at the site of administration such as reducing agents . . . The varied presence of these various degradation Appeal 2020-005983 Application 13/981,706 5 agents in particular compartments in the body provides further guidance on selecting the appropriate site for administration, and also in the preparation of a matrix to provide the desired release kinetics in the presence of the particular degradative machinery at the site. (Stein ¶ 87). 9. Ilangovan teaches “[s]olid tumors are characterized by a number of physiological properties such as occurrence of significant hypoxia, large amounts of cellular reducing equivalents” (Ilangovan, abstract). 10. Ilangovan teaches the “enhanced reduction of the nitroxide in tumor compared to normal tissue, thus, may be due to lower oxygen concentration as well as to the significantly enhanced GSH levels in the tumor” (Ilangovan 396, col. 2). 11. Meng teaches “reduction-sensitive biodegradable polymers and conjugates have emerged as a fascinating class of biomedical materials that can be elegantly applied for the development of sophisticated delivery systems for both biotherapeutics” (Meng 2180, col. 1). 12. Meng teaches: These materials usually contain characteristic disulfide linkage(s) in the main chain, at the side chain, or in the cross- linker. The disulfide bonds, though sufficiently stable in the circulation and in the extracellular milieu, may be prone to rapid cleavage, at a time scale from minutes to hours, under a reductive environment through thiol-disulfide exchange reactions. (Meng 2180, col. 1). 13. Meng teaches “of particular interest is that tumor tissues are highly reducing and hypoxic compared with normal tissues, with at least 4- fold higher concentrations of GSH in the tumor tissues over normal tissues, Appeal 2020-005983 Application 13/981,706 6 rendering the reducible bioconjugates valuable for tumor-specific drug and gene delivery” (Meng 2180, col. 2 to 2181, col. 1). 14. Scheme I of Meng is reproduced below “Scheme 1. Chemical structures of disulfide-containing cross-linking agents” (Meng 2182; cf. Spec. 7). Appeal 2020-005983 Application 13/981,706 7 Principles of Law A prima facie case for obviousness “requires a suggestion of all limitations in a claim,” CFMT, Inc. v. Yieldup Int’l Corp., 349 F.3d 1333, 1342 (Fed. Cir. 2003) and “a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). Analysis We adopt the Examiner’s findings of fact and reasoning regarding the scope and content of the prior art (Final Act. 5–11; FF 1–14) and agree that claims 1, 22, and 23 are rendered obvious by Lewis, Stein, Ilangovan, and Meng. We address Appellant’s arguments below. Claim 1 Appellant contends “that polyvinyl alcohol is only one polymer among a ‘large number’ of polymers in Stein that have at least two functional or reactive groups, which include amino, carboxyl, thiol and hydroxy groups, among others” (Appeal Br. 9). Appellant also contends “that the controlled release of therapeutic agent occurring as a consequence of biodegradation of the matrix by an in-vivo degradation pathway via reducing agents, as described by Stein, is a completely different release mechanism than that taught by Lewis” (id.). We find these arguments unpersuasive because they fail to address the references in combination. Lewis teaches particles composed of polyvinyl alcohol polymers for embolization of tumors (FF 1–3) and Stein demonstrates that polymers including polyvinyl alcohol may be cross-linked using disulfide groups (FF 5–8). And as to the release mechanisms, Meng Appeal 2020-005983 Application 13/981,706 8 provides persuasive reasoning to utilize disulfide groups as taught by Stein in the particles of Lewis because disulfide linking groups may be “elegantly applied for the development of sophisticated delivery systems” (FF 11) such as delivery to a hypoxic tumor making the “reducible bioconjugates valuable for tumor-specific” delivery (FF 13). “Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references. . . . [The reference] must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). Appellant contends “the dithiobis(succinimydylpropionate) crosslinker . . . of Meng, is distinct from the claimed crosslinker, A-(CH2)n- S-S-(CH2)n'-A', in which at least one of the -(CH2)n- and -(CH2)n'- groups are substituted with carboxyl groups which are capable of electrostatically associating with a drug” (Appeal Br. 11). We find that this argument is factually incorrect because it does not address all of the crosslinkers taught by Meng. Meng teaches a set of crosslinkers (FF 14) identical to those recited in the Specification (see Spec. 7). Indeed, Meng teaches an L-cystine bisacrylamide crosslinker having carboxy groups that is structurally identical to the crosslinker recited in claims 25 and 26 (FF 14, compound BACy). Thus, Meng teaches a crosslinker substituted with carboxyl groups that, to the extent Appellant is Appeal 2020-005983 Application 13/981,706 9 correct, will inherently be capable of electrostatically associating with a drug (cf. Appeal Br. 11). Appellant contends Turning to the L-cystine bisacrylamide (BACy) crosslinker of Meng, it would not be obvious to select such a crosslinker in order to produce a polyvinyl alcohol release system containing disulfide linkages in its structure. First, the L-cystine bisacrylamide (BACy) is described in conjunction with bioreducible polyethylenimine (PEI) polymers and networks in Meng, rather than polyvinyl alcohol. Moreover, one of ordinary skill in the art would not have simply “recognized from the structure of the L-cystine bisacrylamide (BACy)” that it is suitable for crosslinking the Nelfilcon B of Lewis et al. as the Nelfilcon B contains pendant ethylenically unsaturated groups, as urged in the Office Action, because there is no teaching or suggestion in the references to do so. (Appeal Br. 11). We are not persuaded because the prior art “is presumptively enabling barring any showing to the contrary by a patent applicant.” In re Antor Media Corp., 689 F.3d 1282, 1288 (Fed. Cir. 2012). Appellant has provided no evidence that the crosslinkers of Meng would not function to crosslink polyvinyl alcohol. Indeed, Appellant lacks any evidence showing any doubt regarding the functionality of Meng’s crosslinkers. And “attorney argument [is] not the kind of factual evidence that is required to rebut a prima facie case of obviousness.” In re Geisler, 116 F.3d 1465, 1470 (Fed. Cir. 1997). As to whether the Meng’s crosslinkers would have been suitable for Nelfilcon B, Meng teaches these are crosslinking agents and Appellant Appeal 2020-005983 Application 13/981,706 10 provides no evidence that the crosslinking agents would be ineffective against any particular compound. Appellant contends one would not have been motivated to select one of the crosslinkers taught by Meng and use it to crosslink the Nelfilcon B of Lewis et al. because the crosslinked product would not be expected to provide rapid degradation under a reductive environment present in intracellular compartments and one would not have been motivated to provide disulfide linkage(s) in order to control the release of the drug, as argued in the Office Action. This is true at least because the pendant ethylenically unsaturated groups of the Nelfilcon B would be expected to crosslink the polymer (as they had in Lewis), and the resulting crosslinks would not contain a disulfide linkage and thus would not be expected to be reduction-sensitive. (Appeal Br. 11). We find this argument unpersuasive for several reasons. First, claim 1 lacks any recitation regarding the rate of degradation and, therefore, “appellant’s arguments fail from the outset because . . . they are not based on limitations appearing in the claims.” In re Self, 671 F.2d 1344, 1348 (CCPA 1982). Second, Meng specifically teaches that “tumor tissues are highly reducing and hypoxic” (FF 13) and “disulfide bonds, though sufficiently stable in the circulation and in the extracellular milieu, may be prone to rapid cleavage, at a time scale from minutes to hours, under a reductive environment” (FF 12). Thus, Meng expressly suggests that rapid cleavage would be expected to occur using the disulfide bonds in the hypoxic environment of a tumor consistent with Lewis’ tumor embolization treatment (FF 1). Third, Appellant’s discussion of the “expected” operation of the prior art lacks any evidentiary support and fails to properly apply the Appeal 2020-005983 Application 13/981,706 11 crosslinkers of Meng (identical to that of claim 26). Geisler, 116 F.3d at 1470. Claims 22 and 23 Appellant again contends that the “dithiobis(succinimydylpropionate) crosslinker . . . of Meng comprises leaving groups that are susceptible to nucleophilic attack. However, this crosslinker is distinct from the claimed crosslinker” (Appeal Br. 12). We again find this argument unpersuasive because Meng is not limited to a single crosslinker, but teaches a variety of different functional crosslinkers including an L-cystine bisacrylamide crosslinker that is structurally identical to the crosslinkers recited in claims 25 and 26 (FF 14, compound BACy). Moreover, Meng teaches a set of crosslinkers (FF 14) identical to those shown in the Specification (see Spec. 7), where the Specification acknowledges that the “chemical structures of some of the more common disulfide-containing crosslinkers that may be used in the invention are shown below” (Spec. 6:20–21). Consequently, Appellant’s argument not only lacks evidentiary support but is actually inconsistent with the direct teachings of Appellant’s own Specification, which suggests that Meng’s crosslinkers may be used in the invention. Conclusions of Law A preponderance of the evidence of record support the Examiner’s conclusion that the prior art renders the claims obvious. Appeal 2020-005983 Application 13/981,706 12 DECISION SUMMARY In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 5, 9–15, 21–31 103(a) Lewis, Stein, Ilangovan, Meng 1, 5, 9–15, 21–31 No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED Copy with citationCopy as parenthetical citation