Ex Parte TakahashiDownload PDFPatent Trial and Appeal BoardJan 31, 201813879037 (P.T.A.B. Jan. 31, 2018) 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. 13/879,037 05/14/2013 Kenichi Takahashi HAYAK-0047 5820 23599 7590 02/02/2018 MILLEN, WHITE, ZELANO & BRANIGAN, P.C. 2200 CLARENDON BLVD. SUITE 1400 ARLINGTON, VA 22201 EXAMINER LEITH, NANCY J ART UNIT PAPER NUMBER 1636 NOTIFICATION DATE DELIVERY MODE 02/02/2018 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@mwzb.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte KENICHI TAKAHASHI1 Appeal 2016-000350 Application 13/879,037 Technology Center 1600 Before ERICA A. FRANKLIN, TAWEN CHANG, and RYAN H. FLAX, Administrative Patent Judges. CHANG, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134(a) involving claims to a transformant mammalian cell and method for production of a glycoprotein having N-glycosidic bond-linked sugar chains, which have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. STATEMENT OF THE CASE The Specification states that, [i]n mammalian cells, N-glycosidic bond-linked sugar chains of glycoproteins are those attached to asparagine residues of the proteins, 1 Appellant identifies the Real Party in Interest as JCR Pharmaceuticals Co., Ltd. (Appeal Br. 1.) Appeal 2016-000350 Application 13/879,037 through a complex pathway involving various enzymes, while the proteins, after translated from RNA, are transferred through the lumen of an endoplasmic reticulum to Golgi bodies. The major types of N-glycosidic bond-linked sugar chains are complex-type sugar chains and high mannose-type sugar chains. (Spec. 1:8—13.) “Complex-type sugar chains ... are characterized in that their non-reducing ends consist of sialic acid residues,” and they are “formed in Golgi bodies by additional modifications on the high mannose-type sugar chain.” (Id. at 1:14-16, 3:1-2.) Thus, the Specification explains that, [i]f mammalian cells, such as Chinese hamster ovary cells (CHO cells), are used in producing a recombinant glycoprotein, many of the sugar chains of the protein . . . obtained will be a complex-type in their structure, and sialic acid residues thus will occur at the non reducing ends of the sugar chains of such a recombinant glycoprotein. (Id. at 3:19-22.) Such glycoproteins have increased stability in the blood and are advantageous in situations in which elongation of glycoproteins’ half-lives in the blood is desirable. (Id. 3:22-4:5.) However, according to the Specification, for some recombinant glycoproteins “having sugar chains of a complex-type would be . . . disadvantageous.” (Id. at 4:9-10.) These would include, for instance, certain glycoprotein enzymes used to treat lysosomal storage diseases, which to be effective must be taken up into target cells via those cells’ membrane mannose receptors and thus must have mannose residues on their non-reducing ends. (Id. at 5:10-19.) Therefore, according to the Specification, “the objective of the present invention is to provide a novel method for production of recombinant glycoproteins having mannose residues at the non-reducing end of their N-glycosidic bond-linked sugar chains . . . using mammalian cells.” (Id. at 7:22—25.) 2 Appeal 2016-000350 Application 13/879,037 Claims 1—6, 8—12, and 14—17 are on appeal. Claim 1 is illustrative and reproduced below: 1. A transformant mammalian cell having an exogenous B- N-acetylglucosaminidase gene introduced and allowed to express itself therein and having an exogenous gene encoding a predetermined glycoprotein further introduced and allowed to express itself so as to produce the predetermined glycoprotein. (Appeal Br. 7 (Claims App.).) The Examiner rejects claims 1—6, 8—12, and 14—17 under 35 U.S.C. § 103(a) as being unpatentable over Rasmussen2 and Jarvis.3 (Ans. 3.) DISCUSSION Issue The Examiner finds that Rasmussen discloses introducing nucleic acid encoding human glucocerebrosidase, a glycoprotein, into Chinese Hamster Ovary (CHO) cells, which are mammalian cells, and expressing itself therein. (Ans. 3.) The Examiner finds that Rasmussen teaches using glucocerebrosidase to treat Gaucher’s disease and further teaches that, to be useful for such treatment, glucocerebrosidase should be correctly glycosylated, have one and preferably more exposed mannose, bind to and be taken up by macrophages, and target human mannose receptors. (Id. at 3—4.) The Examiner finds that Rasmussen does not suggest introducing and expressing an exogenous B-N-acetylglucosaminidase gene in a mammalian cell along with the glycoprotein. (Id. at 4.) However, the Examiner finds 2 Rasmussen et al., U.S. Patent No. 5,236,838, issued Aug. 17, 1993. 3 Jarvis et al., WO 2009/079376 A2, published June 25, 2009. 3 Appeal 2016-000350 Application 13/879,037 that Jarvis discloses several insect B-N-acetylglucosaminidase genes and further teaches that the action of such insect B-N-acetylglucosaminidases provides for glycosylated proteins having exposed mannose groups. {Id. at 4—5, 6—7.) The Examiner concludes that it would be obvious to one of ordinary skill in the art to use Jarvis’ insect enzyme genes [(i.e., insect B-N-acetylglucosaminidase genes)] in Rasmussen’s transformed CHO cells in order to obtain the desired and correct glycosylation pattern in order to optimally treat a Gaucher’s disease patient. Using the combination disclosed and suggested by Rasmussen and Jarvis, one of ordinary skill in the art would have a reasonable expectation of success in preparing and using Rasmussen’s transformed mammalian cells to produce correctly glycosylated glucocerebrosidase in a cell also transformed with Jarvis’ insect B-N-acetylglucosaminidase genes. {Id. at 5.) Appellant contends that the Examiner has not articulated a reason why a skilled artisan would combine the teachings of Rasmussen and Jarvis to arrive at the claimed invention and further contend that Jarvis teaches away from the claimed combination. (Appeal Br. 3—6; Reply Br. 1—5.) Appellant also contends that the Examiner relied upon improper hindsight in making the rejection. (Reply Br. 4.) The issue with respect to this rejection is whether a preponderance of evidence of record supports the Examiner’s conclusion that a skilled artisan would have a reason to combine the teachings of Rasmussen and Jarvis to arrive at the claimed invention. Findings of Fact 1. Rasmussen teaches “[rjecombinant enzymatically active glucocerebrosidase . . . produced by a eukaryotic cell” and “a method for producing enzymatically active glycocerebrosidase [that] includes steps of 4 Appeal 2016-000350 Application 13/879,037 introducing glucocerebrosidase-encoding nucleic acid into a eukaryotic cell, causing the cell to express glucocerebrosidase, and purifying the glucocerebrosidase from the cell.” (Rasmusen Abstract.) 2. The term “recombinant glucocerebrosidase,” or “recombinant GCR,” in Rasmussen refers to “any GCR produced from genetically manipulated GCR encoding nucleic acid inserted into a cell, such as, e.g., an insect cell, a yeast cell, or a mammalian cell such as, e.g., a CHO cell.” {Id. at 1:53-57.) 3. Rasmussen teaches that, “[i]n preferred embodiments, the nucleic acid is a vector including DNA encoding an amino acid sequence having at least 95% homology to an amino acid sequence of a naturally occurring GCR; most preferably ... a naturally occurring primate GCR such as, e.g., a human GCR.” {Id. at 2:49—54.) 4. Rasmussen teaches “examples of insertion of human GCR- encoding DNA into mammalian vectors and expression of the DNA by mammalian cells,” such as CHO cells. {Id. at 4:19-22, 9:57—12:30, 15:11— 20 (claim 1).) 5. In particular, Rasmussen teaches “recombinant enzymatically active GCR having at least one exposed mannose residue, wherein the GCR is capable of specifically binding with a human mannose receptor protein.” {Id. at 2:7—11; see also id. at 3:23—25, 12:33—54, 14:28—34.) Rasmussen teaches that “[t]he rGCR of [its] invention is suitable for administration to a human suffering from Gaucher’s disease using a standard enzyme replacement protocol.” {Id. at 3:24—27, see also id. at 12:33—38, 13:4—8 (stating that “GCR with high sialic acid content is unlikely to [be] useful in 5 Appeal 2016-000350 Application 13/879,037 this invention, but GCR with a low sialic acid content, i.e., uncharged GCR, is more likely to have exposed mannose moieties”), 14:23—30.) 6. Rasmussen teaches producing “rGCR having an appropriate carbohydrate structure ... by introducing GCR-encoding DNA into any vertebrate or invertebrate eukaryotic cell and treating that cell during its growth with inhibitors of carbohydrate processing” that “act to inhibit specific steps in the conversion of Glc3Man9GlcNac2 to smaller species shown in the figure, thus, providing a greater number of exposed mannose residues.” {Id. at 14:67—15:10.) 7. Jarvis teaches “novel nucleic acid sequences encoding B-A- acetylglucosaminidase enzymes and recombinant insect cell lines comprising the same for the production of therapeutic and commercially valuable glycoproteins,” i.e., “glycoproteins of interest that exhibit partial or complete patterns of mammalian glycosylation.” (Jarvis 1:21—24, 17:19-22; see also id. at 4:6—7, 12—14, 22—28 (describing the invention as providing “an isolated nucleic acid encoding an A-acetylglucosaminidase,” “expression vectors comprising [said] nucleic acid molecules,” “recombinant insect cells transformed with such expression vectors,” and “a method for enhancing production of mammalian-like A-glycans in insect cells” that entails providing recombinant insect cell lines comprising double stranded RNA molecules encoding an A-acetylglucosaminidase).) 8. Jarvis teaches that “[ijnsects . . . produce A-glycoproteins, but they typically process their A-linked glycans less extensively than mammals.” {Id. at 1:30-32.) 9. Jarvis teaches that 6 Appeal 2016-000350 Application 13/879,037 [ijnsect and mammalian protein A-glycosylation pathways each begin with the co-translational transfer of A-glycan precursors to nascent proteins. These precursors are subsequently trimmed and elongated by enzymes localized in the endoplasmic reticulum and Golgi apparatus of insect and mammalian cells to produce a common intermediate with the structure Mana6(GlcNAcB2Mana3)ManB4 GlcNAcB4GlcNAc-R. In mammalian cells, this intermediate is elongated by various glycosyltransferases to produce complex A- glycans, which often have terminal sialic acid residues. In contrast, insect cells usually fail to elongate this same intermediate and convert it, instead, to paucimannose A-glyeans with the core structure Mana6(Mana3)ManB4GlcNAcB4GlcNAc-R. An unusual B-A- acetylglucosaminidase is responsible for the production of these structures. This enzyme specifically removes the terminal A- acetylglucosamine residue from the a3 branch of Mana6(GlcNAcB2Mana3)ManB4GlcNAcB4GlcNAc-R, simultaneously eliminating the intermediate required for A-glycan elongation and producing the core paucimannose glycan typically found on insect cell-derived A-glycoproteins. (Id. at 1:36—2:14.) Jarvis teaches that, “[bjecause the A-glycan processing pathways leading to the production of [the] intermediate [Mana6(GlcNAcB2Mana3)ManB4 GlcNAcB4GlcNAc-R] are probably identical in insects and higher eukaryotes, the presence or absence of this specific, processing B-A-acetylglucosaminidase is a key factor distinguishing the processing pathways in these two different types of organisms.” (Id. at 8:2—6; see also id. at 2:16—17, 42:8—10.) 10. Jarvis teaches that “[the] difference between lower and higher eukaryotic protein A-glycosylation pathways is biotechnologically significant because insects and plants are used to produce recombinant mammalian glycoproteins for many different biomedical research applications.” (Id. at 1:33—35.) 7 Appeal 2016-000350 Application 13/879,037 Analysis Rasmussen teaches introducing a nucleic acid encoding enzymatically active glucocerebrosidase (a glycoprotein) into mammalian cells so as to cause the cells to express glucocerebrosidase and to administer glucocerebrosidase to treat humans suffering from Gaucher’s disease. (FF1— FF4.) Rasmussen does not teach also transforming the mammalian cells with a B-N-acetylglucosaminidase gene. However, Rasmussen teaches that, to be useful in treating Gaucher’s disease, the glucocerebrosidase should have at least one exposed mannose residue and that glucocerebrosidase with high sialic acid content is unlikely to be useful in this regard. (FF5, FF6.) Jarvis, on the other hand, teaches that, in contrast to mammalian cells where N-glycosylation pathways lead to complex N-glycans that often have terminal sialic acid residues, N-glycosylation in insect cells leads to paucimannose N-glycans with the core structure Mana6(Mana3)ManB4GlcNAcB4GlcNAc-R, i.e., glycoproteins having mannose residues. (FF9.) Jarvis further teaches that the presence of B-N- acetylglucosaminidase is a key factor in distinguishing the pathways in mammalian and insect cells. (FF9.) Given the above, we find that a skilled artisan would have a reason to combine the teachings of Rasmussen and Jarvis to arrive at the claimed invention, namely to produce glycoproteins having mannose residues in order to treat certain mammalian diseases such as Gaucher’s disease. Furthermore, given Jarvis’ teaching that the N-glycan processing pathways leading to the production of the intermediate acted upon by B-N- acetylglucosaminidase are probably identical between insects and higher eukaryotes such as mammals (FF9), we find that a skilled artisan would have 8 Appeal 2016-000350 Application 13/879,037 a reasonable expectation of success in combining the teachings of Rasmussen and Jarvis to arrive at the claimed invention. Accordingly, we agree with the Examiner that the combination of Rasmussen and Jarvis renders claim 1 obvious and adopt the Examiner’s findings of fact and reasoning regarding the scope and content of the prior art. (Final Act. 2—7; Ans. 2—9; FF1—10.) Appellant’s arguments do not persuade us otherwise, for the following reasons. Appellant first contends that Jarvis teaches away from the claimed invention because “Jarvis teaches that the expression of R-N- acetylglucosaminidase enzyme in insect cells is undesirable and seeks to inhibit its production.” (Appeal Br. 3; see also Reply Br. 5.) We are not persuaded. “[I]n general, a reference will teach away if it suggests that the line of development flowing from the reference’s disclosure is unlikely to be productive of the result sought by the applicant.” In re Gurley, 27 F.3d 551, 553 (Fed. Cir. 1994). While Jarvis focuses on producing mammalian-like glycoproteins (i.e., complex N-glycans having terminal sialic acid residues) in insect cells, nothing in Jarvis suggests more insect-like glycoproteins (i.e., N-glycans having mannose residues) cannot or should not be produced in mammalian cells. Appellant similarly argues that a skilled artisan would have no reason to combine Rasmussen and Jarvis to arrive at the claimed invention because Rasmussen does not teach B-N-acetylglucosaminidase expression and a skilled artisan “would have no reason to introduce the enzyme into the mammalian cells of Rasmussen as Jarvis clearly teaches that such B-N- acetylglucosaminidase expression is unwanted and is directed to expression in distinct cell lines (insect).” (Appeal Br. 3^4; see also Reply Br. 2—3.) In 9 Appeal 2016-000350 Application 13/879,037 particular, Appellant contends that in Jarvis not only is the B-N- acetylglucosaminidase gene ‘“not introduced and allowed to express itself,’ but also . . . modifications are made to downgrade the expression of the B-N- acetylglucosaminidase gene” so as to produce glycoproteins with mammalian-like N-glycans in insect cells. (Appeal Br. 4—6.) Appellant also argues that “[o]ne skilled in the art would clearly not look to insect cell lines of Jarvis when contemplating modification of the mammal cells of Rasmussen.” (Reply Br. 3.) We are not persuaded. “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). Here, while Jarvis does not teach the desirability of glycoproteins having increased mannose residues or transforming mammalian cells, Rasmussen teaches that such proteins are desirable for treating certain mammalian diseases and also teaches producing glycoproteins by transforming mammalian cells. Likewise, while Rasmussen does not teach expressing B- N-acetylglucosaminidase, Jarvis teaches that it is this enzyme that is key in producing glycoproteins that are more likely to contain mannose rather than sialic acid residues (i.e., the type of glycoproteins that Rasmussen suggests is desirable for use in its invention). Thus, Rasmussen and Jarvis together suggest and provide a skilled artisan with a reason for combining the references to arrive at the claimed invention. We also note, but are not persuaded by, Appellant’s argument that the Examiner relied on improper hindsight in making the rejection at issue. 10 Appeal 2016-000350 Application 13/879,037 (Reply Br. 4.) As Appellant alleges, the Examiner states that, “[bjecause . . . exposed mannose residues are exactly those required by the claims,” Jarvis’ disclosure of the role of B-N-acetylglucosaminidase in the glycosylation pathway is “clearly relevant and would lead one of ordinary skill in the art directly to the claimed invention.” (Ans. 7.) We agree that the teaching or suggestion for modifying the prior art to arrive at the claimed invention must be derived from prior art rather than Appellant’s own Specification. However, here the Examiner appears to be pointing to the claim limitations merely to show that Jarvis discloses some of the limitations of the claims and/or is analogous art, and properly relies on Rasmussen and Jarvis for the reason to combine. (Id. (finding that “Rasmussen clearly provides motivation to one of ordinary skill in the art to provide a protein . . . having [the] patterns [of exposed mannose residues taught by Jarvis].”) “Any judgment on obviousness is in a sense necessarily based upon hindsight reasoning . . . .” In re McLaughlin, 443 F.2d 1392, 1395. Such reconstruction is proper, however, if it relies on ordinary skill at the time of the invention, as here, and not on knowledge gained solely from Applicant’s disclosure. Neither are we persuaded that Rasmussen and Jarvis are not analogous art and that a skilled artisan would thus not look to Jarvis when contemplating modification of the mammal cells of Rasmussen. (See Reply Br. 1—4.) “Two criteria have evolved for determining whether prior art is analogous: (1) whether the art is from the same field of endeavor, regardless of the problem addressed, and (2) if the reference is not within the field of the inventor’s endeavor, whether the reference still is reasonably pertinent to the particular problem with which the inventor is involved.” In re Clay, 966 11 Appeal 2016-000350 Application 13/879,037 F.2d 656, 658-59, 23 USPQ2d 1058, 1060 (Fed. Cir. 1992). In this case, the instant application, Rasmussen, and Jarvis all relate to producing recombinant glycoproteins; thus, at the very least the second prong of the test for analogous is satisfied. Indeed, Jarvis teaches producing more mammalian-like N-glycans in insect cells and further explains that insects and plants are used to produce recombinant mammalian glycoproteins for many different biomedical research applications. (FF7, FF10.) Likewise, while Rasmussen teaches that for purposes of its disclosures the term “recombinant glucocerebrosidase” or “recombinant GCR” may refer to “any GCR produced from genetically manipulated GCR encoding nucleic acid inserted into a cell,” including an insect cell as well as mammalian cell. (FF2.) Thus, the evidence contradicts Appellant’s assertion that a skilled artisan would not look to Jarvis in modifying Rasmussen merely because Jarvis discusses insect rather than mammalian cell lines.4 In the Reply Brief, Appellant argues for the first time that a skilled artisan would not have a reasonable expectation of success in combining Rasmussen and Jarvis. (Reply Br. 4—5.) As an initial matter, Appellants have not persuasively explained why this argument could not have been raised in the Appeal Brief. Thus, we find that the argument has been waived. See Ex parte Nakashima, 93 USPQ2d 1834 (BPA1 2010) (informative) (arguments and evidence not timely presented in the Principal Brief will not be considered when filed in a Reply Brief, absent a 4 Appellant’s citation to In re Klein, 647 F.3d 1343 (Fed. Cir. 2011), is inapposite. As discussed above, in the instant case the cited references themselves show that a skilled artisan would look to prior art relating to both insect cells and mammalian cells when considering problems relating to the problem of producing recombinant glycoproteins. 12 Appeal 2016-000350 Application 13/879,037 showing of good cause explaining why the argument could not have been presented in the Principal Brief); Ex parte Borden, 93 USPQ2d 1473, 1477 (BPA1 2010) (informative) (explaining that “the Rules do not require the Board to take up a belated argument that has not been addressed by the Examiner, absent a showing of good cause”). Accordingly, we affirm the Examiner’s rejection of claim 1. Claims 2—6, 8—12, and 14—17, which have not been argued separately, fall with claim 1. 37 C.F.R. § 41.37(c)(l)(iv). SUMMARY For the reasons above, we affirm the Examiner’s rejection of claims 1-6, 8-12, and 1^U17. 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