Ex Parte Gillies et al

Patent Trial and Appeal BoardJul 24, 2014

12238840 (P.T.A.B. Jul. 24, 2014)

UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte STEPHEN D. GILLIES and SCOTT LAUDER1 __________ Appeal 2012-006620 Application 12/238,840 Technology Center 1600 __________ Before TONI R. SCHEINER, MELANIE L. McCOLLUM, and SUSAN L. C. MITCHELL, Administrative Patent Judges. McCOLLUM, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to an Fc- EPO fusion protein. The Examiner has rejected the claims as anticipated or obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm-in-part. STATEMENT OF THE CASE Claims 1-13, 18-20, 22-28, 33, 45, 50, 51, and 53 are pending and rejected (App. Br. 2).2 Claims 1 and 50 are illustrative and read as follows: 1 Appellants identify the real party in interest as Merck Patent GmbH (App. Br. 2). 2 Claims 29-32 are also pending but have been withdrawn from consideration (App. Br. 2). Claim 21 is additionally pending but has been indicated to be allowed (id.). Appeal 2012-006620 Application 12/238,840 2 1. A population of purified Fc-EPO fusion proteins suitable for administration to a mammal, the Fc-EPO fusion proteins comprising an Fc portion towards the N-terminus of the Fc-EPO fusion proteins and an erythropoietin portion towards the C-terminus of the Fc-EPO fusion proteins, said population having an average of 11-28 sialic acid residues per purified Fc-EPO fusion protein. 50. An Fc-EPO fusion protein comprising an Fc portion towards the N-terminus of the Fc-EPO fusion protein and an erythropoietin portion towards the C-terminus of the Fc-EPO fusion protein, said Fc-EPO fusion protein produced by (a) maintaining a BHK cell under conditions suitable for expression of the Fc-EPO fusion protein, wherein the BHK cell comprises a nucleic acid sequence encoding the Fc-EPO fusion protein and is adapted for growth in a protein-free medium; and (b) recovering the expressed Fc-EPO fusion protein. Claims 1-5, 9-13, 18-20, 24, 25, 28, 33, 50, 51, and 53 stand rejected under 35 U.S.C. § 102(b) as anticipated by Egrie3 (Ans. 5). Claims 6-8 and 45 stand rejected under 35 U.S.C. § 103(a) as obvious over Egrie in view of Nimtz4 (Ans. 8). Claims 22 and 23 stand rejected under 35 U.S.C. § 103(a) as obvious over Egrie in view of Idusogie5 (Ans. 9). Claims 26 and 27 stand rejected under 35 U.S.C. § 103(a) as obvious over Egrie in view of Van Den Brink6 (Ans. 11). 3 Egrie et al., WO 01/81405 A2, Nov. 1, 2001. 4 Manfred Nimtz et al., Structures of sialylated oligosaccharides of human erythropoietin expressed in recombinant BHK-21 cells, 213 EUR. J. BIOCHEM. 39-56 (1993). 5 Esohe E. Idusogie et al., Mapping of the C1q Binding Site on Rituxan, a Chimeric Antibody with a Human IgG1 Fc, 164 J. IMMUNOLOGY 4178-4184 (2000). 6 Van Den Brink et al., WO 03/106484 A1, Dec. 24, 2003. Appeal 2012-006620 Application 12/238,840 3 Appellants do not appeal the rejections of claims 45, 51, and 53 (App. Br. 2). We therefore summarily affirm the rejections of these claims. Moreover, the Examiner is authorized to cancel these claims. See Ex parte Ghuman, 88 USPQ2d 1478, 1480 (BPAI 2008) (precedential) (citing MPEP § 1215.03). ANTICIPATION The Examiner finds: Egrie et al. teach hyperglycosylated analogs of human EPO used to treat anemia (page 1, lines 5-15). Egrie et al. teach that an increase in sialic acid content per EPO molecule gives a corresponding stepwise increase in in vivo biological activity and an increase in the serum half-life (page 3, lines 8-34). Egrie et al. teach a hyperglycosylated EPO analog designated N47 which has a longer serum half-life than recombinant human erythropoietin (rHuEPO) and a greater in vivo activity (page 5, lines 25-30). . . . Egrie et al. teach that this hyperglycosylated EPO analog has an average of 17-22 sialic acids (page 10, lines 7-35) . . . . Egrie et al. teach suitable host cells to recombinantly make these EPO hyperglycosylated analogs include Chinese hamster ovary cells (CHO) and baby hamster kidney cells (BHK)(page 15, lines 7-16) . . . . Egrie et al. teach that host cells harboring DNA sequences encoding these EPO hyperglycosylated analogs are cultured under conditions that permit expression of the analogs. The analogs are recovered from the cell media and purified. Egrie et al. teach that purification allows for the isolation of higher sialic acid containing EPO isoforms (page 15, lines 17-33). Egrie et al. teach that the invention provides for fusion proteins comprising these EPO hyperglycosylated analogs and a carboxy terminus of an immunoglobulin heavy chain constant region fused to the amino terminus of an EPO analog . . . . The immunoglobulin heavy chain constant region is an Fc region (page 19, lines 11-35). Egrie et al. teach that the term Fc refers to a molecule or sequence comprising the sequence of a non- Appeal 2012-006620 Application 12/238,840 4 antigen-binding portion of an antibody, whether in monomeric or multimeric form (page 20, lines 4-7). (Ans. 6-7.) Analysis With regard to claim 1, Appellants argue that Egrie does not teach a “population of purified Fc-EPO fusion proteins includ[ing] an average of 11- 28 sialic acid residues per purified Fc-EPO fusion protein” (App. Br. 5). We conclude that the evidence supports Appellants’ position. As noted by the Examiner (Ans. 6), Egrie discloses a hyperglycosylated EPO analog N47 having “isoforms of 17 to 22 sialic acids” (Egrie 10: 8-19). Egrie also discloses “fusion proteins of Epo hyperglycosylated analogs and an immunoglobulin heavy chain constant region” (id. at 19: 15-17). In particular, Egrie discloses that “[f]usions may be made at the amino terminus of an Epo hyperglycosylated analog” and that “the immunoglobulin heavy chain constant region [may be] an Fc region” (id. at 19: 17-26). However, according to Appellants, “a skilled artisan would understand that Fc-EPO fusion proteins are dimeric and would include two EPO moieties, such that if each EPO moiety contained 17-22 sialic acid residues, an Fc-EPO fusion protein would contain twice as many: 34-44 per Fc-EPO fusion protein” (App. Br. 6). In support of this position, Appellants point to Lauder,7 Gillies,8 and Jones9 (id.). Lauder teaches that it “is 7 Lauder et al., US 2005/0164352 A1, July 28, 2005. 8 Gillies et al., US 2006/0228332 A1, Oct. 12, 2006. 9 Tim D. Jones et al., The Development of a Modified Human IFN-α2b Linked to the Fc Portion of Human IgG1 as a Novel Potential Therapeutic Appeal 2012-006620 Application 12/238,840 5 understood that proteins with an Fc portion normally form a disulfide- bonded complex which normally include two polypeptide chains (unless the two Fc portions are present within the same polypeptide) and may be thought of as a ‘unit-dimer’” (Lauder ¶ 88). Gillies teaches that it “should be understood that the immunoglobulin Fc region including at least a portion of the hinge region, a CH2 domain and a CH3 domain, typically forms a dimer” (Gillies ¶ 66). Jones teaches that “the linkage to Fc and consequent dimeric nature of the fusion protein greatly increase its size, and this has been shown to give dramatic improvements in the serum half-life of Fc- linked cytokines in laboratory animals” (Jones 561). Thus, Appellants have provided evidence tending to show that Egrie’s fusion protein would have been dimeric and therefore would have contained 34-44 sialic acids per protein. In response, the Examiner argues that the “features upon which Appellant relies upon, i.e., dimeric structures, are not recited in the claims” (Ans. 14). However, the question is not whether claim 1 encompasses a population of monomeric fusion proteins. Instead, the question is whether Egrie discloses a population of monomeric fusion proteins, such that the population has an average of 11-28 sialic acid residues per purified Fc-EPO fusion protein. The evidence supports Appellants’ position that many, if not all, of Egrie’s fusion proteins would be dimeric, such that Egrie fails to teach a population having an average of 11-28 sialic acid residues per purified Fc- EPO fusion protein. for the Treatment of Hepatitis C Virus Infection, 24 J. INTERFERON & CYTOKINE RESEARCH 560-572 (2004). Appeal 2012-006620 Application 12/238,840 6 The Examiner also argues that Egrie teaches “that the term ‘Fc’ refers to a molecule or sequence comprising the sequence of a non- antigen-binding portion of antibody, whether in monomeric or multimeric form (page 20, lines 4-7)” (Ans. 14). According to Appellants: it is clear that Egrie was referring to the monomeric or multimeric structures of properly assembled IgG, IgA, IgM, IgE or IgD, rather than referring to some undescribed structure in which only half of an Fc structure was present by providing only one of the two chains of a complete Fc domain. (Reply Br. 7.)10 We conclude that Appellants’ explanation appears consistent with the language in Egrie. Thus, we cannot agree with the Examiner that Egrie clearly discloses a monomeric fusion protein. With regard to claim 50, which does not specify the average number of sialic acid residues per molecule of fusion protein, Appellants argue “that the Fc-EPO fusion protein produced in BHK cells wherein the BHK cells are adapted to grow[] in a protein-free medium exhibits unique structural properties” and that “Egrie does not teach an Fc-EPO fusion protein produced in BHK cells adapted to grow[] in a protein-free medium” (App. Br. 7- 8). We are not persuaded. 10 We note that Appellants cite to US 5,116,964 issued to Capon et al. on May 26, 1992, in support of this position (Reply Br. 6). Capon discloses: “IgM generally exists as a pentamer of, basic four-chain units held together by disulfide bonds. IgA globulin, and occasionally IgG globulin, may also exist in a multimeric form in serum.” (Capon, col. 10, ll. 34-39.) We recognize that it is generally improper to introduce evidence in a Reply Brief. However, as noted in the Reply Brief, “the final Office action did not raise this argument” (Reply Br. 6). Therefore, we have considered this teaching in Capon. Appeal 2012-006620 Application 12/238,840 7 As noted by the Examiner, Egrie teaches that suitable host cells include BHK cells (Ans. 6). While we recognize that the Examiner has not shown that Egrie teaches that the BHK cell is adapted for growth in a protein-free medium, the Examiner correctly notes that the “determination of patentability [of a product-by-process claim] is based on the product itself” (id. at 19). “Additionally, where the Patent Office has reason to believe that a . . . limitation asserted to be critical for establishing novelty in the claimed subject matter may, in fact, be an inherent characteristic of the prior art, it possesses the authority to require the applicant to prove that the subject matter shown to be in the prior art does not possess the characteristic relied on.” In re Best, 562 F.2d 1252, 1254-55 (CCPA 1977) (quoting In re Swinehart, 439 F.2d 210, 212-13 (CCPA 1971)). As noted by Appellants (App. Br. 7), the Specification discloses: In “[s]amples of the Fc-EPO fusion proteins synthesized in supplemented DMEM/F-12 protein-free media . . . [i]t was found that the protein product was sialylated to a greater extent and exhibited more homogeneous sialylation than the corresponding product obtained from cells grown in serum-free media such as VP-SFM” (Spec. ¶ 162). The Specification also discloses that “growth of BHK cells in supplemented protein-free DMEM/F- 12 medium had a positive effect on frequency of O-glycosylation” (id. at ¶ 155). Thus, the Specification supports Appellants’ position that proteins synthesized by BHK cells grown in a protein-free medium differ at least on average from proteins synthesized by BHK cells grown in a protein- Appeal 2012-006620 Application 12/238,840 8 containing medium. However, the evidence is insufficient to demonstrate that a protein-containing medium would not produce a single fusion protein that could also be produced in a protein-free medium. Therefore, we conclude that Appellants have not adequately shown that a recitation that the protein is produced by a BHK cell grown in a protein-free medium is sufficient to distinguish the product from Egrie. Moreover, it is not even clear that claim 50 requires growth in a protein-free medium. Instead, claim 50 merely recites that the BHK cell is adapted for growth in a protein-free medium. Conclusion The Examiner has not set forth a prima facie case that Egrie anticipates claim 1. We therefore reverse the anticipation rejection of claim 1 and of claims 2-5, 9-13, 18-20, 24, 25, 28, and 33, which depend either directly or indirectly from claim 1. However, the evidence supports the Examiner’s conclusion that Egrie anticipates claim 50. We therefore affirm the anticipation rejection of claim 50. OBVIOUSNESS Claims 6-8, 22, 23, 26, and 27 are each rejected as obvious over Egrie in view of an additional reference (Ans. 8-12). However, claim 6-8, 22, 23, 26, and 27 depend directly or indirectly from claim 1. In addition, the Examiner does not explain how the additional references relied upon in the obviousness rejections overcome the deficiency in Egrie discussed above (id.). Thus, we agree with Appellants that the Examiner has not set forth a Appeal 2012-006620 Application 12/238,840 9 prima facie case that claims 6-8, 22, 23, 26, and 27 would have been obvious. SUMMARY We affirm the anticipation rejection of claim 50. We also summarily affirm the anticipation rejection of claims 51 and 53 and the obviousness rejection of claim 45. However, we reverse the anticipation rejection of claims 1-5, 9-13, 18-20, 24, 25, 28, and 33 and the obviousness rejections of claims 6-8, 22, 23, 26, and 27. 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-IN-PART cdc