Ex Parte Chang et alDownload PDFPatent Trial and Appeal BoardMar 17, 201713483761 (P.T.A.B. Mar. 17, 2017) 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. IBC118US10 2268 EXAMINER HUYNH, PHUONG N ART UNIT PAPER NUMBER 1644 MAIL DATE DELIVERY MODE 13/483,761 05/30/2012 63322 7590 03/17/2017 IMMUNOMEDICS, INC. 300 AMERICAN ROAD MORRIS PLAINS, NJ 07950 Chien-Hsing Chang 03/17/2017 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 CHIEN-HSING CHANG, DAVID M. GOLDENBERG, and EDMUND A. ROSSI Appeal 2014-002802 Application 13/483,761 Technology Center 1600 Before DEBORAH KATZ, ULRIKE W. JENKS, and JOHN G. NEW, Administrative Patent Judges. KATZ, Administrative Patent Judge. DECISION ON APPEAL Appeal 2014-002802 Application 13/528,077 Appellants1 seeks our review, under 35 U.S.C. § 134(a), of the Examiner’s decision to reject claims 1 and 3-6. (App. Br. 1.) We have jurisdiction under 35 U.S.C. § 6(b). We affirm. Appellants indicate that the appeal in application 13/528,077 (Appeal 2014-002239) is related to the current appeal. (See App. Br. 2.) Appellants also indicate that the appeal in application 13/295,647 is related (id.), although it appears a subsequent request for continued examination was made in that application. Introduction Claims 1 and 3-6 are currently pending in this application, in light of the cancellation of claims 2, 7-8, and 17 and the withdrawal of claims 9-16 and 18-23. (App. Br. 2.) We consider the rejections of claims 1 and 3-6. Appellants claim fusion proteins comprising an antibody or a fragment of an antibody and a dimerization and docking domain (“DDD”). (App. Br. 2.) Figure 3 of Appellants’ Specification is reproduced below. 1 The real party in interest are said to be IBC Pharmaceuticals, Inc. (App. Br. 1.) 2 Appeal 2014-002802 Application 13/528,077 N-DM)2-Fab-hMN44 iDD»2f m L.B hMN-14-YH s'- hMN-14-VK RStfitWi .iCKi 1 Figure 3 Figure 3 depicts a schematic diagram of a DDD domain fused to an antigen binding antibody fragment (N-DDD2-Fab-hMN-14) in panel A, and the putative structure formed by DDD2-mediated dimerization of two of these N-DDD2-Fab fusion proteins in panel B. (Spec., 141.) Claim 1 recites:2 A fusion protein comprising: (i) an antibody or an antigen-binding antibody fragment; and (ii) a dimerization and docking domain (DDD) moiety of human protein kinase A regulatory subunit, wherein the amino acid sequence of the DDD moiety is selected from the group consisting of residues 1 to 44 of human PKA Rlla and residues 1 to 44 of human PKA RIip. (App. Br. 10, Appendix A.) Although Appellants’ Specification explains that hexameric complexes may be formed using the claimed fusion proteins along with others comprising an antibody fragment and an anchor domain (“AD”), to 2 Indentations added for clarity. 3 Appeal 2014-002802 Application 13/528,077 which the DDD domain binds (see, e.g. Spec., 122), Appellants’ claim 1 recites only the antibody or antigen-binding antibody fragment and a DDD moiety. The Examiner rejected claims 1 and 4-6 under 35 U.S.C. § 103 as being obvious over Makowski,3 Braun4, and either Banky5 or Newlon.6 (Ans. 2-5.) Appellants do not argue for the separate patentability of these claims. Accordingly, we designate claim 1 as the representative claim. See 37C.F.R. §41.37(c)(l)(iv). The Examiner also rejected claims 3 and 4 under 35 U.S.C. § 103 as being obvious over Makowski, Braun, and either Banky or Newlon, as well as Hansen.7 (Ans. 5-6.) Appellants state that the rejection of claims 3 and 4 is not argued separately from the rejection of claim 1. (App. Br. 4.) Accordingly, we focus on the rejection of claim 1 in our analysis. Findings of Fact 1. Makowski teaches fusion proteins comprising antibodies and antigen-binding antibody fragments fused to the dimerization sequence of the protein GCN4, which is a leucine zipper. (Makowski, || 222 and 239.) 3 U.S. Patent Application Publication No. 2003/0198956 Al, published October 23, 2003. 4 U.S. Patent Application Publication No. 2003/0232420 Al, published December 18, 2003. 5 Banky et al., 273 J. Biol. Chem. 35048-55 (1998). 6 Newlon et al., 6 Nature Structural Biology 222-27 (1999). 7 U.S. Patent Application Publication US 2002/0018750 Al, published February 14, 2002. 4 Appeal 2014-002802 Application 13/528,077 2. Figure 11 of Makowski is reproduced below. r,\. !/\s. re if®vyV d-G;; ■V Id)/ dtGtrtv Motifs c; M 7 --c \M"\ //V: /(^ Figure 11 depicts dimerization motifs such as leucine zipper motifs (depicted as elongated ovals in panels A and B) or four-helix bundle motifs (depicted as rectangles in panels C and D) that are fused to antigen-binding multimers. (Makowski, | 83.) 3. Makowski teaches that the dimerized antigen-binding multimers depicted in Figure 11 may be utilized as the structural and joining elements in assembly unit fabrication. (Makowski, | 83.) 4. Braun teaches that particular isoforms of Protein Kinase A (“PKA”), e.g., PKA-RIa or PKA-RIIa, bind to its target protein AKAP. (Braun 113.) 5. Braun teaches fusion proteins comprising the “dimerization/docking (D/D) domain” of the regulatory subunit of PKA, for example mouse Rlla, fused to green fluorescence protein (GFP). (Braun, 1269; see also 1254.) 5 Appeal 2014-002802 Application 13/528,077 6. Braun does not teach human DDDs. 7. Newlon teaches that amino acids 1-44 of the PKA Rlla protein are responsible for AKPA binding and for dimerization. (Newlon at 222, Fig. 1A, and abstract.) 8. Banky et al teach dimerization docking domains from various protein kinase A regulatory subunits such as human PKA Rlla (residues 1- 44) and human PKA RIip (residues 1-44). (Banky at 35054, Fig. 8.) Analysis “[W]hen a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). The Examiner concludes that it would have been obvious for one of ordinary skill in the art at the time to have modified the antibody fusion protein of Makowski (FFs 1-3) by substituting the GCN4 leucine zipper dimerization domain taught with a PKA-RIa or PKA-RIIa DDD taught in Braun (FFs 4 and 5) and also to use the human Rlla and RIip DDDs taught in Newlon (FF 7) and Banky (FF 8). (Ans. 4.) Alternatively, the Examiner determines that it would have been obvious to modify the DDD-GFP fusion proteins of Braun by fusing an antibody or antigen-binding antibody fragment as taught in Makowski to a DDD of Braun, using a human Rlla or RIip domain of Banky or Newlon. (Ans. 4.) The Examiner finds that one of ordinary skill in the art would have had reason to make these modifications because the DDD moiety is a known dimerization domain having the same function as the GCN4 leucine zipper dimerization domains of Makowski. (Ans. 5 and 9.) The Examiner also 6 Appeal 2014-002802 Application 13/528,077 finds that the human proteins of Banky and Newlon were known to be less immunogenic than the murine DDDs of Braun and, thus, those of ordinary skill in the art would have had reason to use them. (Ans. 5.) In addition, the Examiner finds that there would have been reason to dimerize antibody or antibody fragments in order to increase antigen binding as taught in Makowski. (Ans. 5.) The Examiner finds, further, that there would have been a reasonable expectation that combing the teachings of the cited references would be successful because the GCN4 leucine zipper domains taught by Makowski have similar secondary structure helices as the DDD moieties of Banky. (Ans. 8.) Appellants present several arguments that each of the prior art references cited by the Examiner do not alone render the claimed fusion proteins obvious. For example, Appellants argue that Makowski does not teach or suggest a fusion protein comprising a DDD moiety from PKA-RIIa or -RIip. (App. Br. 4.) Appellants also argue that Braun focuses on screening for AKAP polymorphisms, but does not teach or suggest using AD or DDD moieties to construct synthetic complexes for delivery of antibodies, antibody fragments, or other therapeutic proteins. (App. Br. 4- 5.) Appellants argue further that neither Newlon nor Banky teach using PKA DDD moieties to assemble synthetic complexes comprising antibody or antibody fragment moieties and that Hansen does not teach or suggest fusion proteins comprising DDD moieties. (App. Br. 5.) We are not persuaded by these arguments because “[n]on-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references.” In re 7 Appeal 2014-002802 Application 13/528,077 Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986). These arguments do not provide a reason why the combination of references cited by the Examiner do not teach the elements of the fusion proteins claimed by Appellants. Appellants also assert that Makowski teaches away from the invention of claim 1 because an ordinarily skilled artisan would have believed that Makowski teaches self-assembled structures to be unsuitable for the complexes it teaches. (App. Br. 5.) Appellants cite to paragraph 21 of Makowski, which states that “[t]he drawback of the method disclosed in WO 00/68248 is that fusion protein units are assembled into nanostructures by self-assembly and cannot spontaneously recognize where they belong within a larger framework.” Appellants also cite to paragraph 23 of Makowski, which states that “[t]he major drawback the method disclosed in WO 01/121646 [cited as background art]... is that fusion proteins are assembled into nanostructures by self-assembly, the formation of which is not readily controllable.” Appellants note that the abstract of Makowski explains: The present invention provides methods and assembly units for the construction of nanostructures. Assembly of nanostructures proceeds by sequential, non-covalent, vectorial addition of an assembly unit to an initiator or nanostructure intermediate during an assembly cycle, a process termed “staged assembly.” Attachment of each assembly unit is mediated by specific, non- covalent binding of a single pre-determined joining element of one assembly unit to a complementary joining element on a target initiator or nanostructure intermediate. Each interaction of a joining element is designed such that the joining element does not interact with any other joining element of the assembly unit. Self-association of the assembly unit is therefore obviated: only one assembly unit can be added at a time to a target initiator or nanostructure intermediate. 8 Appeal 2014-002802 Application 13/528,077 According to Appellants, these statements demonstrate that Makowski teaches the skilled artisan to avoid use of components that will self- assemble. (App. Br. 6.) Appellants contrast this asserted intended function for Makowski with the description in paragraph 958 of Appellants’ specification, which states: In some embodiments, A, consisting of two identical subunits (a2), is combined with B, consisting of one subunit (b), to form an assembly in the configuration of a2b. The association of A and B is site-specific and spontaneous, due to the strong binding interaction between the DDD and AD sequences that are built into A and B, respectively. Both A and B can be any entity and the precursor of A to which the DDD is linked may be different from or the same as the precursor of B to which the AD is linked. In the latter case, the resulting a2b complex, referred to as a3, is composed of three subunits, each containing the same precursor but linked to both DDD and AD. Appellants also cite to paragraph 96, which states that “[w]here A and B are produced in the same host cell, they may spontaneously assemble into an a2b complex.” (App. Br. 6.) We are not persuaded by Appellants’ argument because, as explained in their Specification, self-assembly occurs between components “A” and “B” of Appellants’ specification, wherein component “A” is linked to a DDD moiety and component B is linked to an AD moiety. (See Spec., 95 8 Appellants cite to paragraph 91, but that paragraph of the specification as filed does not include the quoted text recited by Appellants. Instead, paragraph 95 does. 9 Appeal 2014-002802 Application 13/528,077 and 96.) In contrast, Appellants’ claimed fusion proteins include antibodies or fragments fused to DDD moieties only. Appellants argue that antibody-DDD fusion proteins as claimed, exhibit self-assembly, citing to Figure 3 (reproduced above) and Figure 5 of their Specification as evidence. (App. Br. 7-8.) The fusion proteins depicted in Figures 3 and 5 are similar, having the same DDD and Fab components, except that the two figures depict the components in different orders. That is, whereas Figure 5 depicts the DDD moiety in the carboxy terminus of the fusion proteins, Figure 3 depicts a fusion protein with the DDD domain in the amino-terminus. Both Figures 3 and 5 show the two fusion proteins dimerized through the DDD moieties. We are not persuaded that Figures 3 and 5 depict self-assembly as discouraged by Makowski. We note that Figure 11 of Makowski also depicts dimerized fusion proteins. (See FF 2.) Appellants have not explained why the depicted dimerized fusion proteins in Figures 3 and 5 of its Specification are self-assembled when the depicted dimerized fusion proteins in Figure 11 of Makowski are not. Thus, we are not persuaded that Appellants’ claimed fusion protein self-assembles as discouraged by Makowski. Appellants also argue that paragraphs 96 and 100 of their Specification discuss other structures, such as tetrameric structures that can be formed by DDD fusion proteins. (See App. Br. 7.) For the same reasons as discussed above, we are not persuaded that these structures self-assemble as discouraged by Makowski. 10 Appeal 2014-002802 Application 13/528,077 Appellants argue further that the only use of their claimed antibody- DDD fusion proteins is as a component in the formation of a “dock-and- lock” complex, which is described to self-assemble in paragraphs 95 and 96 of their Specification. (App. Br. 7-8.) We are not persuaded by this argument because Appellants’ claimed fusion proteins require only an antibody or antibody fragment and a DDD. A DNL complex is not required in Appellants’ claims. Appellants do not direct us to evidence that their claimed fusion proteins would have no utility without the other components of a “dock-and-lock” complex. Accordingly, Appellants’ argument about the uses of the currently claimed fusion protein do not persuade us that they necessarily self- assemble as discouraged by Makowski. We note that the evidence of unexpected results presented by Appellants, discussed in more detail below, include a reference reporting results obtained with antibody- DDD fusion proteins in the absence of an AD moiety. (See App. Br. 8-9, citing Rossi (2008)9.) Contrary to Appellants’ argument, this reference tends to demonstrates that there are uses of Appellants’ claimed fusion proteins without an AD moiety. Appellants also argue that the fusion proteins taught in Makowski differ from the claimed fusion proteins in a fundamental way because the claimed fusion proteins are designed to form a three-part complex that inherently includes an AD moiety, while the fusion proteins of Makowski form only a two-part complex. (Reply Br. 2-4.) We are not persuaded by this argument because regardless of how Appellants’ claimed antibody-DDD component could be used, the required elements do not include any 68 Cancer Res 8384-92 (2008). 11 Appeal 2014-002802 Application 13/528,077 components other than an antibody or antigen-binding antibody fragment and a DDD. A “third” part allowing for self-assembly, such as an AD moiety, is not required in Appellants’ current claims. Thus, we are not persuaded that the fusion proteins Appellants claim differ fundamentally from those taught in Makowski. We consider the evidence presented by Appellants of unexpected results in our determination of whether the Examiner erred in rejecting Appellants’ current claims as being obvious. (See App. Br. 8-9; Reply Br. 5- 6.) Appellants cite to the following references: Rossi (2012),10 which provides results of anti-CD 19 Fab2-DDD fusion proteins attached to an anti-CD3-AD scFv fusion protein; Chang,* 11 which provides results of anti-IGF-IRhRl IgG-AD fusion protein attached to hRl Fab-DDD fusion protein (Hex-hRl); Gupta,12 which provides results of anti-CD20 or anti-CD74 IgG-AD fusion proteins with anti-CD74 or anti-CD20 FabDDD fusion proteins; and Rossi (2008), which provides results of anti-CD20 IgG-AD or anti- CD20 Fab-AD fusion proteins attached to anti-CD20 Fab-DDD fusion proteins. We are not persuaded by this evidence that Appellants’ claimed fusion proteins would not have been obvious because the results noted by Appellants are of antibody-DDD fusion proteins complexed with antibody- AD fusion proteins. Because the claimed fusion protein does not include a 10 Abstract No. 2762, 54th ASH Annual Meeting (2012). 11 PFoS One 7:e44235 (2012). 12 119 Blood 3767-78 (2012). 12 Appeal 2014-002802 Application 13/528,077 component fused to an AD moiety, this evidence is not commensurate in scope with Appellants’ claimed subject matter. See In re Grasselli, 713 F.2d 731, 743 (Fed. Cir. 1983) (“It is well settled ‘that objective evidence or non obviousness must be commensurate in scope with the claims which the evidence is offered to support.’” (quoting In re Tiffin, 448 F.2d 791 (CCPA 1971)). The results noted by Appellants relate only to the claimed fusion proteins in complex with an additional protein, but non-complexed fusion proteins are encompassed by Appellants’ claims because they are the only proteins expressly recited. Appellants also argue that Rossi (2008) also reports potent antiproliferative activity against cancer cells with a tetrameric Fab that includes four copies of antibody Ifagment-DDD fusion protein without an antibody-AD or antibody fragment-AD fusion protein. (App. Br. 8-9, citing Rossi (2008) at abstract, pg. 8386, col. 1, 3rd paragraph; pg. 8387, col. 1, 1st paragraph; and Figures 1, 4b and 5a.) We are not persuaded by the reported results of this antibody-DDD fusion protein because even if it demonstrates potent antiproliferative activity, Appellants do not direct us to evidence that such activity was unexpected. Appellants do not direct us to a comparison of this activity with the closest prior art or to evidence showing what those of ordinary skill in the art would have considered about the level of reported activity. Accordingly, we are not persuaded that the results obtained with the antibody-DDD fusion protein of Rossi 2008 would have been considered to be unexpected by an ordinarily skilled artisan. After reviewing Appellants’ arguments and evidence, we are not persuaded that the Examiner erred in rejecting Appellants’ current claims. Conclusion 13 Appeal 2014-002802 Application 13/528,077 Upon consideration of the record and for the reasons given by the Examiner, the rejection of claims 1 and 4-6 under 35 U.S.C. § 103(a) over Makowski, Braun, and either Banky or Newlon is sustained and the rejection of claim 3 under 35 U.S.C. § 103(a) over Makowski, Braun, and either Banky or Newlon, as well as Hansen, is sustained. Therefore, we affirm the decision of the Examiner. No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136. AFFIRMED 14 Copy with citationCopy as parenthetical citation