Ex Parte Bout et alDownload PDFPatent Trial and Appeal BoardMay 22, 201713002797 (P.T.A.B. May. 22, 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. 13/002,797 04/08/2011 Abraham Bout H-HS-00021 WO/US 4369 (527786) 24289 7590 Mallinckrodt LLC 675 McDonnell Boulevard HAZELWOOD, MO 63042 05/24/2017 EXAMINER TSAY, MARSHA M ART UNIT PAPER NUMBER 1656 NOTIFICATION DATE DELIVERY MODE 05/24/2017 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): patents @ mallinckrodt.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte ABRAHAM BOUT, JOSEPH MARIA GRIMBERGEN, and JACOB LAURENS KOOPMAN Appeal 2017-0005181 Application 13/002,797 Technology Center 1600 Before RICHARD M. LEBOVITZ, RICHARD J. SMITH, and DEVON ZASTROW NEWMAN, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL This appeal involves claims directed to a pharmaceutical fibrinogen preparation that is homogeneous, comprising recombinant human fibrinogen. The Examiner rejected the claims as anticipated under 35 U.S.C. §102 and obvious under 35 U.S.C. § 103. We have jurisdiction under 35 U.S.C. § 6(b). The rejections are affirmed. 1 The Appeal Brief (“Appeal Br.”) 2 lists Profibrix B.V. as the real-party-in interest. Appeal 2017-000518 Application 13/002,797 STATEMENT OF THE CASE Appellants appeal from the Examiner’s rejection of claims 15, 18, 27, 29, and 38—41. Final Action (“Final Act.”). The claims stand rejected as follows: 1. Claims 15, 18, 38, 39, and 41 under 35 U.S.C. § 102(b) or, in the alternative, under § 103(a) over Matsuyama et al. (EP 1 661 989 Al, publ. May 31, 2006) (“Matsuyama”). Final Act. 3. 2. Claims 15, 27, 29, and 40 under 35 U.S.C. § 103(a) over Matsuyama as evidenced by Rixon et al. (Characterization of a Complementary Deoxyribonucleic Acid Coding for the a Chain of Human Fibrinogen, 22 Biochemistry 3237—44 (1983)) (“Rixon”), Chung et al. {Characterization of Complementary Deoxyribonucleic Acid and Genomic Deoxyribonucleic Acid for the ft Chain of Human Fibrinogen, 22 Biochemistry 3244—50 (1983)) (“Chung I”), and Chung et al. {Characterization of a Complementary Deoxyribonucleic Acid Coding for the y Chain of Human Fibrinogen, 22 Biochemistry 3250—56 (1983)) (“Chung II”). Final Act. 5. 3. Claims 15, 18, 38, 39, and 41 under 35 U.S.C. § 102(b) or, in the alternative, under § 103(a) over Huang et al. (US Pat. Publ. 2003/0221223 Al, publ. Nov. 27, 2003) (“Huang”). Final Act. 10. 4. Claims 15, 27, 29, and 40 under 35 U.S.C. § 103(a) over Huang in view of Matsuyama, and evidenced by Rixon, Chung I, and Chung II. Final Act. 11. 5. Claims 15, 18, 38, 39, and 41 under 35 U.S.C. § 103(a) over Roy et al. {Assembly and Secretion of Recombinant Human Fibrinogen, 266 J. Bio. 2 Appeal 2017-000518 Application 13/002,797 Chem. 4758—63 (1991)) ((“Roy (1991)”) also referred to as “Roy I”) in view of Matsuyama. Final Act. 15. 6. Claims 15, 27, 29, and 40 under 35 U.S.C. § 103(a) over Roy (1991) in view of Matsuyama, and evidenced by Rixon, Chung I, and Chung II. Final Act. 17. 7. Claims 15, 18, 38, 39, and 41 under 35 U.S.C. § 103(a) over Roy et al. (Over expression of Any Fibrinogen Chain by Hep G2 Cells Specifically Elevates the Expression of the Other Two Chains, 269 J. Bio. Chem. 691—95 (1994)) ((“Roy (1994)”) also referred to as “Roy II”2) in view of Matsuyama. Final Act. 20. The nonstatutory obviousness-type double patenting rejection over copending Application No. 13/520,615 is mooted because the copending application is abandoned. Appeal Br. 12. Appellants raise identical arguments for all seven rejections. Appellants also have not provided separate arguments for the dependent claims. Consequently, we have considered all the rejections together with claim 15 as representative as it is the only independent claim involved in the appeal. Claims 18, 27, 29, and 38-41 stand or fall with claim 15. 37 C.F.R. § 41.37(c)(l)(iv). CLAIM Claim 15 reads as follows: 15. A pharmaceutical fibrinogen preparation that is homogeneous comprising recombinant human fibrinogen that is free of protease inhibitors, is in a homogeneous form, and is biologically active, 2 This publication appears to be cumulative to Roy (1991). 3 Appeal 2017-000518 Application 13/002,797 wherein the recombinant human fibrinogen has an alpha chain, a beta chain and a gamma chain, wherein more than 85% of the recombinant human fibrinogen is in an intact form, as measured by an SDS-PAGE or Western blotting analysis, wherein the alpha chain is: 1) a 644 amino acid chain according to SEQ ID No. 8; 2) a 625 amino acid chain according to amino acids 20 to 644 of SEQ ID No. 8; 3) a 610 amino acid chain according to amino acids 20 to 629 of SEQ ID No. 8; 4) an 866 amino acid chain according to SEQ ID No. 11; or 5) a chain according amino acids 20 to 866 of SEQ ID No. 11, wherein the beta chain is: 1) a 491 amino acid chain according to SEQ ID No. 9; or 2) a 461 amino acid chain according to amino acids 31 to 491 of SEQ ID No. 9, wherein the gamma chain is: 1) a 437 amino acid chain according to SEQ ID No. 10; 2) a 411 amino acid chain according to amino acids 27 to 437 of SEQ ID No. 10; 3) a 453 amino acid chain according to SEQ ID No. 13; or 4) a 427 amino acid chain according to amino acids 27 to 453 of SEQ ID No. 13, and wherein the recombinant human fibrinogen is prepared by a method comprising the steps of: culturing a cell comprising: 1) three nucleotide sequences each encoding the alpha chain, the beta chain and the gamma chain of the recombinant human fibrinogen, wherein the three nucleotide sequences are optimized for expression in a mammalian cell culture system under conditions wherein the recombinant human fibrinogen is produced; or 2) a nucleotide construct comprising three nucleotide sequences each encoding the alpha chain, the beta chain and the gamma chain of the recombinant human fibrinogen, wherein the three nucleotide sequences are optimized for expression in the mammalian cell culture system under conditions wherein the recombinant human fibrinogen is produced, wherein the three nucleotide sequences each have a GC content of at least 60%, and wherein codons for the cis-acting sites are removed; and 4 Appeal 2017-000518 Application 13/002,797 recovering the recombinant human fibrinogen. CLAIM INTERPRETATION Independent claim 15 is directed to a “pharmaceutical fibrinogen preparation that is homogeneous comprising recombinant human fibrinogen that is free of protease inhibitors, is in a homogeneous form, and is biologically active.” The phrase “pharmaceutical. . . preparation” is not defined in the Specification. Appellants also do not provide a definition or guide us to the Specification where such a preparation is disclosed. Nonetheless, the Specification describes administration of recombinant fibrinogen to a human, e.g., intravenously, and describes medical uses of it. Spec. 2:15—29; 8:22—36. Based on these disclosures, we interpret a pharmaceutical fibrinogen preparation to be a preparation that is suitable for administration to a subject for medical applications. The term “homogenous” is also not expressly defined in the Specification. The Specification, however, teaches that fibrinogen present in the blood has a “high degree of heterogeneity” due to “[variations [that] arise through genetic polymorphisms, differences in glycosylation and phosphorylations, (partial) proteolysis of the carboxy-terminal part of the Aa chain and alternative splicing.” Spec. 1:19-22. The Specification describes expression of specific a, P, y fibrinogen chains in a cell culture system. Id. at 3:18—7:31. The Specification teaches “[i]n contrast to plasma derived fibrinogen, the fibrinogen preparation produced by this [expression in cell culture system] method will be rather homogeneous because specific fibrinogen chains are produced.” Id. at 8:16—18. In view of this disclosure, 5 Appeal 2017-000518 Application 13/002,797 we interpret “homogenous” to mean a fibrinogen comprised of the same specific a, P, y chains, rather than a mixture of different chain variants as found naturally in blood. The claim requires the fibrinogen to be “biologically active.” The Specification defines the term: “In the context of the present invention, ‘biologically active’ fibrinogen refers to fibrinogen which polymerizes into fibrin in the presence of thrombin.” Id. at 7:18—19. The claim also recites that “more than 85% of the recombinant human fibrinogen is in an intact form, as measured by an SDS-PAGE or Western blotting analysis.” The Specification teaches: In the context of the present invention, fibrinogen or a fibrinogen chain is “in intact form” when the amino acid sequence contains all the amino acids which were encoded for by the nucleotide sequence, optionally without the amino acids which are removed during normal cell (secretion) processing. Id. at 4:14-17. The fibrinogen of claim 15 is product-by-process claim because the fibrinogen is claimed as a product of a cell culture method. A product-by process limitation defines a product in terms of how it is made. SmithKline Beecham Corp. v. Apotex Corp., 439 F.3d 1312, 1315 (Fed. Cir. 2006). “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself.” In re Thorpe, 111 F.2d 695, 697 (Fed. Cir. 1985). Consequently, when comparing the claimed fibrinogen to the prior art, we must determine whether the recited process steps impart a structure or characteristic to the recombinant product that distinguishes it from products made by other processes. With respect to this comparison, the cells recite “culturing a cell” but do not define the type of cell; thus, the claimed fibrinogen is not restricted as to the 6 Appeal 2017-000518 Application 13/002,797 cell type it is produced in. FINDINGS OF FACT Matsuyama Ml. Matsuyama describes a process for producing recombinant human fibrinogen in an animal cell, such as a CHO cell. Matsuyama 1, 19, 45. M2. The cell is transformed with 1) an expression vector encoding alpha-chain and gamma-chain, and 2) expression vector encoding beta-chain and gamma-chain. Id. 119. M3. The gamma-chain gene is in “an equal amount to a 1000-fold amount” relative to the alpha- and beta-chain genes. Id. M4. “According to the method of mixing-expressing genes encoding three kinds of proteins constituting human fibrinogen, a recombinant producing cell which highly expresses fibrinogen, and a process for producing the same are provided.” Id. 124. M5. Figure 2, reproduced below, shows a Western blot of culture supernatant from a transformed CHO cell. Id. 149. M6. 1 2 3 4 . i, 1 -' CL 7 Appeal 2017-000518 Application 13/002,797 M7. A CHO cell was cultured overnight in YMM medium comprising fetal calf serum (FCS) and “on a next day, a medium was exchanged with a YMM medium containing no FCS, this was cultured at 37°C for 4 days . . ., and fibrinogen present in the culturing supernatant was used for analysis.” Id. M8. Results thereof are shown in Fig. 2. It was confirmed that, under reduction, fibrinogen produced in the CH001-1-2 culturing supernatant contains a protein having the same size as that of borhyl containing fibrinogen derived from plasma. In addition, these three bands were coincident with molecular weigh[t]s of the known respective fibrinogen chains: a chain; 66kDa, P chain; 52kDa, y chain; 46.5kDa. Id. at 51. Fig. 2 shows “lane 3: CH001-1-2 culture supernatant (8pl/lane), lane 4: CH001-1-2 culture supernatant (24pl/lane).” Id. 126. M9. Matsuyama investigated the “producing ability of a recombinant fibrinogen producing cell... at self-free culturing.” Id. 1 52. “[T]he cell established by the method of the present invention attained up to about 270jig/ml of a production amount on a serum-free medium regarding fibrinogen production, and it was shown that the cell is a highly productive cell which has not previously been obtained.” Id. 1 53. M10. Matsuyama teaches the recombinant human fibrinogen can be used as an antigen to produce antibodies, and as a tissue adhesive utilizing agglutination property of fibrin, for hemostasis, closure of a wound site, adhesive or suturing reinforcement of a nerve, a tendon, a vessel and a tissue, and therapy over a wide range such as closure of air leakage in lung, or as a suitable drug for a base of regeneration medicine for the purpose of tissue regeneration. 8 Appeal 2017-000518 Application 13/002,797 Id. H64, 65. Huang HI. Huang teaches expression of three plasmids coding for human fibrinogen alpha chain, beta chain and gamma chain, respectively, each under the control of the rice glutelin promoter Gtl. Huang 134. “These plasmids, including a plasmid (not shown) containing the hygromycin selectable marker, were bombarded into embryogenic rice callus to create transgenic rice plants expressing these three genes in mature rice seeds.” Id. H2. FIG. 3 shows the simultaneous expression of the three fibrinogen polypeptide chains (a, P and y) in transgenic rice seeds and analyzed via Western blot analysis. Fibrinogen polypeptides and protein aggregates were detected using antibody recognizing all three chains. Id. 136. H3. Fig. 3B is reproduced below: H4. FIG. 3B indicates total protein extracted from rice seeds in 2% SDS, 1 M urea, 1% pMe and PBS pH 7.4, and run on SDS- PAGE. Lane 1, positive control, native human fibrinogen 9 Appeal 2017-000518 Application 13/002,797 (obtained from the Red Cross) showing all three polypeptide chains; Lane 2, molecular weight standards; Lanes 3-5, three independent transgenic rice lines expressing all three fibrinigen [sic, fibrinogen] polypeptides. Id. H5. A purified blood protein recombinantly produced in a plant cell, preferably substantially free of contaminants of the host plant cell, and preferably comprising at least one plant glycosyl group is also provided by the invention. The plant glycosyl groups, while identifying that the blood protein was produced in a plant, does not significantly impair the biological activity of the blood protein in any of the applied therapeutic contexts (preferably less than 25% loss of activity, more preferably less than 10% loss of activity, as compared to a corresponding non recombinant human blood protein). Id. 192. H6. Huang teaches that the recombinant rice express and extracted human fibrinogen can be used as fibrin sealant/bandage. Id. 1133. Huang teaches that fibrin sealants are “effective hemostatic agents,” “a means for achieving tissue adhesion, preventing fluid accumulation and promotion of wound healing.” Id. “Fibrin sealants can also be used as a means of slowly releasing medications, including antibiotics, growth factors and other agents.” Id. Roy (1991) Rl. Roy (1991) describe stable transfection of COS-1 cells with three vectors, coding for Aa, Bp, and y chains, respectively, of human fibrinogen. Roy (1991) 4758. 10 Appeal 2017-000518 Application 13/002,797 R2. Fig. 4B, lane 1, shows fibrinogen-related proteins in cell lysates from COS-a,P,y cells (recombinant COS cells which transfected with express the a, P, and y chains of fibrinogen). R3. Fig. 5, reproduced below, shows secretion of expressed fibrinogen chains. R4. Fig. 5A shows “the immunoprecipitable proteins in the incubation medium were separated under reducing conditions.” Lane 8 shows expressed protein secreted into the medium from COS-a,P,y cells. COS a,P,y cells secreted the expressed proteins into the medium (Fig. 5A). When analyzed under nonreducing conditions the secreted fibrinogen chains were components of a high molecular weight disulfide-linked complex, with an apparent M, of 340,000 which is similar to that of plasma fibrinogen. This M, 340,000 complex accounts for 99.4% of the immunoprecipitable protein radioactivity secreted. No free fibrinogen chains, nor intermediate products of assembly were detected in the medium (Fig. 5B). A small amount of protein radioactivity (less than 1 %) was sometimes noted at about 130 kDa and this may be due to leakage from the cell or may be a degradative product of fibrinogen. 11 Appeal 2017-000518 Application 13/002,797 Id. at 4761. R5. Clotting of Recombinant Fibrinogen—To determine whether secreted recombinant fibrinogen is capable of clotting, the incubation medium of control (nontransfected) and COS-a,P,y cells, incubated for 24 h with L-[35S]methionine, was mixed with human plasma fibrinogen and induced to clot by the addition of thrombin . . . clots formed in the presence of radiolabeled media from COS-a,P,y cells . . . had 30 to 45 times background levels of radioactivity associated with the clot. Id. at 4762. R6. COS cells containing all three fibrinogen chain cDNAs express, assemble, and secrete the chains in a form which is capable of forming a thrombin-induced clot. Id. REJECTIONS The rejections are based on one of three different publications — Matsuyama, Huang, and Roy (1991) — cited for the same teaching of a tissue culture cell expressing DNA coding for the a, P, and y chains of fibrinogen and the expression by the cell of recombinant fibrinogen comprising the three specific chains. The Examiner found the fibrinogen in each publication was homogenous because each fibrinogen molecule was made from the same three specific chains, as required by the term “homogenous” (see Claim Interpretation supra at p.5—6). The Examiner also found more than 85% of the fibrinogent was intact based on gels showing three discrete bands (M6, M8, H2—H4, R3, R4). Based on statements that the fibrinogen was active (M10, H6) and working examples in which activity was 12 Appeal 2017-000518 Application 13/002,797 demonstrated (R5, R6), the Examiner found that the recombinant fibrinogen was biologically active as recited by claim 15. Appellants, without providing objective evidence, contend that the Examiner’s findings about homogeneity, intactness, and biological activity are erroneous. Specifically, Appellants contend that the Examiner made “conclusory” statements, remarks (Reply Br. 9, 10, 14), and assumptions (id. at 9), and complained about the lack of proof (id. at 10, 14, 16 (only prophetic statements)) and the absence of data in the cited publications (id. at 12, 14). Appellants have misconstrued the standard necessary for the Examiner to establish the claims prima facie anticipated or obvious based on Matsuyama, Huang, and Roy (1991). [Even] though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. MPEP § 2113 (8th ed., Rev. 2, May 2004) (quoting In re Thorpe, 111 F.2d at 698). SmithKline Beecham Corp., 439 F.3d at 1317. The PTO has the initial burden of providing a rationale to show that the product described by the prior art is the same product which is claimed. In re Marosi, 710 F.2d 799, 802 (Fed. Cir. 1983). As held in In re Best, 562 F.2d 1252, 1255 (CCPA 1977): Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an 13 Appeal 2017-000518 Application 13/002,797 applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. Whether the rejection is based on “inherency” under 35 U.S.C. § 102, on “prima facie obviousness” under 35 U.S.C. § 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO’s inability to manufacture products or to obtain and compare prior art products. Once “the PTO shows sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not.” In re Spada, 911 F.2d 705, 708 (Fed. Cir. 1990). Thus, upon establishing a prima facie case, the burden shifts to Appellants “to prove that the prior art products do not necessarily or inherently possess the characteristics of [their] claimed product.” In re Fitzgerald, 619 F.2d 67, 70 (CCPA 1980); Best, 562 F.2d at 1255. The Examiner cited specific disclosure in each of Matsuyama (Final Act. 3—4, 5), Huang (id. at 10-11, 13), and Roy (1991) (id. at 16, 19) as factual evidence the disclosed recombinant fibrinogen anticipated or rendered obvious the recombinant fibrinogen of claim 15. The findings are summarized above in the “Findings of Fact.” Appellants’ contentions that the Examiner has made conclusory statements misapprehends the Examiner’s findings and burden necessary to have made the prima facie rejection. First, the Examiner cited facts in each publication (M6, H3, R3) that showed the same three chains present in all fibrinogen molecules produced by the cell culture system constituting homogenous fibrinogen because each molecule was made of the same a, P, and y chains. 14 Appeal 2017-000518 Application 13/002,797 Secondly, based on this evidence as well as prophetic statements and actual working examples, the Examiner reasonably inferred that the molecules were biologically active, namely, fibrinogen that polymerizes into fibrin in the presence of thrombin (see Claim Interpretation supra at p. 6). The Examiner’s inference is reasonable because in each publication such activity is asserted (M10, H5, H6, R5 (activity is demonstrated in working example)) and a fully reconstituted fibrinogen is made. Thus, the Examiner had adequate factual basis to shift the burden to Appellants to prove that the fibrinogen was either not homogenous or not biologically active. Appellants did not provide adequate rebuttal arguments or objective evidence to prove that the Examiner erred. Homogenous Appellants contend that neither Matsuyama nor Roy (1991) describes a “homogenous” fibrinogen preparation. Reply Br. 7. Appellants state that “Matsuyama does not teach or suggest a homogeneous fibrinogen preparation because Matsuyama employs mixed and combined genes.” Reply Br. 8. Appellants state that Matsuyama “combines an expression vector having a gene encoding an alpha chain and a gamma chain and an expression vector having a gene encoding a beta chain and a gamma chain at an equal amount.” Id. Appellants also state that “Matsuyama teaches that the number of a gamma chain gene is an equal amount or more relative to a total number of an alpha chain gene and a beta chain gene,” making it “reasonable to expect that Matsuyama's method produces excess gamma chain products in the final fibrinogen preparation.” Id. 15 Appeal 2017-000518 Application 13/002,797 Matsuyama used only one a, one P, and one y chain. M2. Accordingly, any fibrinogen made from the three chains would be “homogenous” as that word is properly interpreted (see Claim Interpretation supra at p. 5—6). Matsuyama shows that the fibrinogen secreted into the culture medium is made of the same three fibrinogen chains. M4—M8. There is no discussion in Matsuyama that excess y chain is present in the reconstituted fibrinogen. Appellants have not guided us to factual grounds upon which this speculation is based. Furthermore, Matsuyama does not require an excess of y chain. M3. Thus, even were excess y chain a concern, not all embodiments described by Matsuyama require an excess. Id. Appellants also contend that Roy (1991) does not describe a homogenous fibrinogen preparation. Reply Br. 9. As evidence, Appellants point to Fig. 4 of Roy (1991). This argument is not persuasive. Fig. 4 shows fibrinogen-related proteins in cell lysates from transfected COS-a,P,y cells. R2. However, Roy (1991) also collected fibrinogen secreted into incubation medium. R3, R4. Roy (1991) teaches that the secreted fibrinogen molecular weight “340,000 complex [that] accounts for 99.4% of the immunoprecipitable protein radioactivity secreted. No free fibrinogen chains, nor intermediate products of assembly were detected in the medium.” R4. Thus, the secreted fibrinogen is homogenous because it is only comprised of three specific chains. Intact Appellants contend that fibrinogen described in Matsuyama is not intact. Reply Br. 9. Appellants contend that Fig. 2 shows “faint bands in 16 Appeal 2017-000518 Application 13/002,797 addition to each of the main alpha, beta and gamma bands in Fig. 2, suggesting a number of chain lengths for each of chain.” Id. at 13. Matsuyama shows a Western blot with three discrete bands and characterizes them as having discrete weights. M6—M8. While Appellants contend there are “faint bands” in Fig. 2, there is no mention of the bands or partial protein segments in Matsuyama, nor have Appellants pointed to “faint bands” in Fig. 2. To the contrary, Matsuyama states there were “three bands [shown in Fig. 2] . . . coincident with molecular weigh[t]s of the known respective fibrinogen chains: a chain; 66kDa, P chain; 52kDa, y chain; 46.5kDa.” M8. Moreover, even were there faint bands present in Fig. 2, Appellants have not met their burden to show that such bands constitute more than 15% of the total amount of protein and less than the “85% of the recombinant human fibrinogen is in an intact form” as required by claim 15. In sum, based on the express disclosure in Matsuyama, the Examiner had reasonable factual basis to insert that “more than 85% of the recombinant human fibrinogen is in an intact form, as measured by an SDS- PAGE or Western blotting analysis.” Appellants have not provided adequate rebuttal arguments or evidence that would dispel this reasonable fact-based conclusion. Appellants made the same contention about Huang (Reply Br. 10, 16), but have similarly failed to address the evidence in Huang of three discrete polypeptide chains shown on a Western blot is less than 85% intact human fibrinogen. H2—H4. Biologically active 17 Appeal 2017-000518 Application 13/002,797 The claims require the recombinant fibrinogen to be “biologically active.” Biological activity is defined in the Specification: “fibrinogen which polymerizes into fibrin in the presence of thrombin.” Spec. 7:18—19 (see Claim Interpretation supra.). Matsuyama and Huang each teach such activity. M10, H5,H6. Roy (1991) has a working example demonstrating this activity. R5, R6. Because the fibrinogen of Matsuyama and Huang is made up of all three chains present in native fibrinogen, the Examiner had a reasonable basis to conclude that it possessed the stated activity. Appellants improperly put the burden on the Examiner to prove that the fibrinogen of each of Matsuyama and Huang possesses the recited activity. Reply Br. 10, 14, 16, and 17. The Examiner does not have the burden to prove it; the Examiner must have a reasonable factual basis to make the assertion. Marosi, 710 F.2d at 802; Spada, 911 F.2d at 708; Fitzgerald, 619 F.2d at 70. The Examiner met this burden at least based on the statements in Matsuyama and Huang that the recombinant fibrinogens were biologically active and contained all three chains present in the native form, thus shifting the burden to Appellants to prove that the fibrinogens lacked biological activity. This burden was not met. Do process steps impart distinct structural characteristics? Appellants contend that the claimed process steps impart distinct structural characteristics, such as the absence of cis-acting sites. Reply Br. 6, 14. Appellants contend such characteristics include the recited “homogenous,” “intact form,” and “biological activity” (id. at 14), but a preponderance of the evidence as discussed above, supports the Examiner’s 18 Appeal 2017-000518 Application 13/002,797 conclusion that such features are characteristics of the cited Matsuyama, Huang, and Roy (1991) publications. Appellants further contend that the plant glycosyl groups present in Huang structurally distinguish their fibrinogen from the fibrinogen of the claims. Reply Br. 10. Appellants have not properly interpreted the breadth of the claim. The claim recites “culturing a cell” without specifying the type of cell (see Claim Interpretation supra at p. 6—7). Huang introduced its plasmids into rice callus (HI) which comprises rice cells. The claim does not exclude rice cells from its scope. Consequently, the claimed fibrinogen could be produced as in the Huang publication and therefore would be indistinguishable from it. SUMMARY For the forgoing reasons, we affirm the rejection of claim 15 as anticipated and obvious as set forth in Grounds of Rejections 1—7. Claims 18, 27, 29, and 38^11 fall with claim 15. 37 C.F.R. § 41.37(c)(l)(iv). TIME PERIOD No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a)(l)(iv). AFFIRMED 19 Copy with citationCopy as parenthetical citation