Ex Parte 6030790 et alDownload PDFBoard of Patent Appeals and InterferencesMar 27, 200990007412 (B.P.A.I. Mar. 27, 2009) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE ____________________ BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES ____________________ Ex parte PHARIS-BIOTEC GMBH, Appellant ____________________ Appeal 2007-4005 Reexamination Control 90/007,412 U.S. Patent 6,030,790 Technology Center 3900 ____________________ Decided: March 30, 20091 ____________________ Before CAROL A. SPIEGEL, ROMULO H. DELMENDO, and ERIC B. GRIMES, Administrative Patent Judge. SPIEGEL, Administrative Patent Judge. DECISION ON APPEAL I. Statement of the Case Appellant appeals under 35 U.S.C. §§ 134 and 306 from an Examiner's final rejection of claims 9-16. On September 20, 2006, the Court of Appeals for the Federal Circuit (CAFC) held claims 17 and 20-25 unpatentable in a related litigation, Nichols Institute Diagnostics, Inc. v. 1 The two month time period for filing an appeal or commencing a civil action, as recited in 37 C.F.R. § 1.304, begins to run from the decided date shown on this page of the decision. The time period does not run from the Mail Date (paper delivery) or Notification Date (electronic delivery). Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 2 Scantibodies Clinical Laboratories, Inc., No. 2006-1087, 2006 WL 2686734 (Fed. Cir. 2006).2 Claims 1-8, 18-19, 26-29, 38, and 39, the only other pending claims, have been expressly withdrawn from appeal.3 We have jurisdiction under 35 U.S.C. §§ 134 and 306. We AFFIRM. The subject matter on appeal is directed to a two-side or "sandwich" immunoassay for detecting active human parathyroid hormone ("hPTH") in a sample wherein first and second antibodies or antibody fragments selectively bind to non-overlapping epitopes contained within specific regions of hPTH defined by the amino acids spanning each region (also called peptides).4 The first antibody or antibody fragment binds to an epitope contained within a region selected from hPTH 1-5, hPTH 1-6, hPTH 1-7, hPTH 1-8, hPTH 1-9, and hPTH 1-10, i.e., peptides having SEQ ID NOs. 1-6. The second antibody or fragment binds to an epitope contained within region hPTH 24-37. Binding of both the first and second antibodies or antibody fragments indicates the presence of active hPTH in the sample. Claim 9 is illustrative and reads (App. Br. A-2): 9. An immunological method of detecting active human parathyroid hormone (hPTH) in a sample comprising: contacting the sample with a first antibody or antibody fragment which selectively binds a peptide of hPTH selected from the group consisting of peptides having SEQ. ID. Nos. 1-6, 2 We cite to the decision provided in Evidence Appendix C of the Appeal Brief, filed 11 December 2006, ("App. Br.") as "Nichols." 3 Transcript of Oral Hearing held 1 October 2008 ("Tr.") at 3. 4 Amino acids are conventionally numbered from the N-terminus to the C- terminus of a peptide or protein. Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 3 wherein the first antibody or antibody fragment binds hPTH in the sample; contacting the sample with a second antibody or antibody fragment which selectively binds hPTH at an epitope contained within amino acids 24 to 37; wherein the second antibody or antibody fragment binds to hPTH bound by the first antibody or antibody fragment; and detecting the binding of the first and second antibodies or antibody fragments, wherein the binding of first and second antibodies or antibody fragments indicates the presence of active hPTH in the sample. The Examiner has relied on the following prior art5 of record as evidence of unpatentability: Woods 4,469,787 Sep. 4, 1984 Forssmann 5,744,444 Apr. 28, 1998 Addermann 6,030,790 Feb. 29, 2000 Hilliker WO 94/03201 Feb. 17, 1994 M. Mägerlein, "Immunological Detection of Human Parathyroid Hormone 1-37 (hPTH 1-37), the Physiologically Circulating Fragment of hPTH," European Journal of Pharmaceutical Sciences, 2 (1994): 154, Abstract P142 ("the Magerlein abstract"). M. Mägerlein, "A New Immunoenzymometric Assay for Bioactive N- Terminal Human Parathyroid Hormone Fragments and Its Application in Pharmacokinetic Studies in Dogs," Arzneim.-Forsch./Drug Res. 48 (1998): 197-204 ("Magerlein I"). M. Mägerlein, "Production of Sequence Specific Polyclonal Antibodies to Human Parathyroid Hormone 1-37 by Immunization with Multiple Antigenic Peptides," Arzneim.-Forsch./Drug Res. 48 (1998): 783-787 ("Magerlein II"). 5 No references to et al. are made in this decision. Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 4 ANTIBODIES: A LABORATORY MANUAL, E. Harlow, Cold Spring Harbor Laboratory (1988): 579-581 ("Harlow"). The Examiner rejected (Advisory6 3-28; Ans.7 4-7): 1. claims 26-29, 38, and 39 as unpatentable under 35 U.S.C. § 112, first paragraph (lack of original descriptive support); 2. claims 26-29, 38, and 39 as unpatentable under 35 U.S.C. § 305 (improperly enlarging the scope of a patent claim), 3. claims 1-8 as unpatentable under 35 U.S.C. § 102(b) or, alternatively under 35 U.S.C. § 103(a), over the Magerlein abstract alone or in light of Magerlein II, 4. claims 1-8 as unpatentable under 35 U.S.C. § 103(a) over the Magerlein abstract, Magerlein II, and Woods, 5. claims 1-8 as unpatentable under 35 U.S.C. § 103(a) over the Magerlein abstract, Magerlein II, Woods, Forssmann, and Hilliker, 6. claims 17-25 as unpatentable under 35 U.S.C. § 102(b) or, alternatively under 35 U.S.C. § 103(a), over the Magerlein abstract in light of Magerlein II and Harlow, 7. claims 17-25 as unpatentable under 35 U.S.C. § 103(a) over the Magerlein abstract, Magerlein II, and Woods, 8. claims 20-29, 38, and 39 as unpatentable under 35 U.S.C. § 102(b) or, alternatively under 35 U.S.C. § 103(a), over the Magerlein abstract in light of Harlow, Magerlein I, and Magerlein II, 6 The Advisory Action mailed 19 September 2006 ("Advisory"). 7 Examiner's Answer mailed 28 February 2007 ("Ans."). Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 5 9. claims 26-29, 38, and 39 as unpatentable under 35 U.S.C. § 103(a) over the Magerlein abstract, Harlow, Magerlein I, Magerlein II, and Woods, 10. claims 9-16 as unpatentable under 35 U.S.C. § 102(b) or, alternatively under 35 U.S.C. § 103(a), over the Magerlein abstract in light of Harlow, 11. claims 9-16 as unpatentable under 35 U.S.C. § 103(a) over the Magerlein abstract, Harlow, and Woods, and 12. claims 9-16 as unpatentable under 35 U.S.C. § 103(a) over the Magerlein abstract, Harlow, Woods, Forssmann, and Hilliker. We summarily sustain rejections 1-9 in view of the CAFC's decision in Nichols and of Appellant's withdrawal of the appeal of the final rejections of claims 1-8, 18-19, 26-29, 38, and 39. We now turn to rejections 10-12 of immunoassay claims 9-16. Since Appellant has argued the patentability of claims 9-16 as a single group of claims, we decide this appeal on the basis of claim 9. 37 C.F.R. § 41.37(c)(1)(vii). The Examiner found that the Magerlein abstract discloses a sandwich immunoassay for detecting the physiologically circulating fragment of hPTH in serum using a combination of two antibodies from ten antisera raised against "epitope mapped" 9-10 amino acid peptides with overlapping sequences representing hPTH 1-37 (Advisory 23-24). Given the small number of possible combinations of two antibodies capable of binding non- overlapping epitopes, the Examiner found that the claimed immunoassay was anticipated by the sandwich hPTH immunoassay disclosed in the Magerlein abstract (Advisory 25). Alternatively, the Examiner concluded it would have been obvious to combine two antibodies in a sandwich Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 6 immunoassay to specifically detect the physiologically circulating fragment of hPTH in serum as stated by the Magerlein abstract (Advisory 25). The Examiner relied on Harlow as evidence of the method steps inherent in a sandwich immunoassay and on Woods as teaching the functional equivalency of whole antibodies and antibody fragments in conventional sandwich immunoassays (Advisory 25-27; Ans. 6-7). The Examiner further relied on Forssmann as teaching that hPTH 1-37 is the shortest fragment of hPTH 1-84 that shows full biological activity in serum; and, on both Forssmann and Hilliker as teaching that removing the first one or two N-terminal amino acids (hPTH 1 or hPTH 1-2) from hPTH 1-34, hPTH 1-37, and hPTH 1-84 reduces the biological activity of hPTH (Advisory 27). The Examiner concluded that since the N-terminal amino acids of hPTH 1-37 are critical for its biological activity, it would have been obvious to select first and second antibodies specific for epitopes found in the N- terminal (hPTH peptides of SEQ ID NOs. 1-6) and C-terminal (hPTH 24-37) regions of hPTH 1-37, respectively, for use in the Magerlein abstract sandwich immunoassay for detecting the physiologically circulating fragment of hPTH in serum (Advisory 26-28). Appellant essentially argues that the Magerlein abstract taken alone, or together with Harlow, Woods, Forssmann, and/or Hilliker, does not teach or suggest a sandwich immunoassay for detecting active hPTH using first and second antibodies which distinguish between active and inactive hPTH (App. Br. 34). Appellant further argues that its rebuttal evidence of commercial success is sufficient to overcome a prima facie conclusion of Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 7 obviousness even if one existed (App. Br. 34). Appellant relies on declarations by Joseph O. Falkinham (dated May 8, 2006, "the Falkinham Decl.") and by Donna Ketter (dated July 7, 2006, "the Ketter Decl.") in support of its position. Thus, there are three issues before us. The first issue is whether Appellant has shown that the Examiner erred in finding that the Magerlein abstract explicitly or inherently discloses a sandwich immunoassay for detecting active hPTH in a sample. The second issue is whether Appellant has shown the Examiner erred in concluding that the claimed sandwich immunoassay for detecting active hPTH is prima facie obvious over the teachings of the Magerlein abstract taken alone, or in combination with Harlow, Woods, Forssmann, and/or Hilliker. Contingent on answering the second issue in the negative, the third issue is whether Appellant's rebuttal evidence of commercial success, the Ketter Declaration, is sufficient to overcome the Examiner's prima facie conclusion of obviousness. II. Findings of Fact (FF) The following findings of fact are supported by a preponderance of the evidence of record. [1] According to Hilliker, "[i]t is . . . well established that the first 34 N- terminal amino acids, (1-34)PTH, of the 84 amino acids, which make up PTH, are responsible for nearly all of the biological activity of the native hormone"(Hilliker 2). Further according to Hilliker, "[r]emoval of the first one or two amino acids is known to reduce the activities of PTH and (1-34) PTH . . . in vitro"(Hilliker 2). Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 8 [2] According to Forssmann, "the shortest hPTH fragment exhibiting full biological activity, which is formed by the primary cleavage of the hPTH-(1-84) in the human body, is the hPTH-(1-37)" (Forssmann 3:66-4:3). [3] Further according to Forssmann, "removal of amino-terminal amino acids from the hPTH fragment-(1-37) reduces its biological activity" (Forssmann abstract). [4] The Magerlein abstract, in its entirety, reads: Human parathyroid hormone, an 84 amino acid peptide, is one of the major factors in the homoeostasis of calcium metabolism. The metabolism of hPTH generates numerous C- terminal fragments which are of unknown biological significance. Since the N-terminal fragment of hPTH 1-37 was proposed as the physiologically circulating form of hPTH we developed an immunological assay in order to measure this fragment in human serum. We produced monoclonal antibodies (Mab) to hPTH 1- 37 by hybridoma cells in serum free cell culture. To generate sequence-specific polyclonal antibodies to hPTH 1-37 we synthesized multiple antigenic peptide systems (MAP) representing parts of the primary structure of hPTH 1-37. We obtained ten polyclonal antisera raised in rabbits: sera K1-K3 (from hPTH 1-10 MAP), including the [sic, α] –helical region between the residues 5-9; sera K4-K6 (from hPTH 9-18 MAP), representing an undefined region between residues 10-16 and sera K7-K10 (from hPTH 27-34 MAP), constituting the C-terminal [sic, α-] helix (residues 17-34). All polyclonal and monoclonal antibodies were characterized by epitope mapping. For this purpose peptides (9-10 amino acid residues) with Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 9 overlapping sequences, representing the entity [sic, entirety?] of hPTH 1-37, were synthesized. Antigenic determinants are found as follows: (1) sera K1-K3 show a predominant binding sequence at hPTH 1-5, (2) sera K4-K6 preferentially bind to residues 9-14, (3) serum K7 recognizes residues 24-30, (4) sera K8 and K9 bind to residues 28-36 and (5) serum K10 recognizes residues 30-37. (6) All Mabs recognize the hPTH fragment 16-24. In summary, the different regions of hPTH 1-37 are covered by the produced antibodies. Furthermore, the combinations of two antibodies in a two-side assay are tested. These experiments provide the possibility to specifically detect the physiologically circulating fragment of human PTH in serum. [5] Two-antibody sandwich immunoassays conventionally (a) use a first antibody immobilized on a solid phase to "capture" analyte in a test sample and a second "label" antibody which binds analyte at a second, non-overlapping epitope and (b) measure the amount of bound "label" to quantitate the amount of analyte in the sample. Either two monoclonal antibodies that recognize discrete sites or one batch of affinity-purified polyclonal antibodies can be used. [Harlow 579.]. [6] The first step of appealed immunoassay claim 9 reads "contacting the sample with a first antibody … which selectively binds a peptide of hPTH selected from the group consisting of peptides having SEQ. ID. Nos. 1-6, wherein the first antibody … binds hPTH in the sample" (App. Br. A-2). Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 10 [7] The '790 specification ("Spec.") defines SEQ. ID. Nos. 1-6 as (1) hPTH 1-10, (2) hPTH 1-9, (3) hPTH 1-8, (4) hPTH 1-7, (5) hPTH 1- 6, and (6) hPTH 1-5, respectively (Spec. cols. 1-2). [8] Claim 17 of the '790 patent reads (App. Br. A-3): A composition comprising an antibody or antibody fragment and a suitable carrier, wherein the antibody or antibody fragment selectively binds a peptide of human parathyroid hormone (hPTH) selected from the group consisting of peptides having SEQ. ID. Nos. 1-6. [9] The '790 specification does not define the term "selectively binds." [10] However, the antibodies described in the '790 patent are said to be capable of (i) discriminating between biologically active and inactive forms of hPTH, (ii) discriminating between hPTH lacking the first two amino acids and hPTH having the first two amino acids, and (iii) binding to the first two amino acids of hPTH (Spec. 2:21-28; 4:63- 5:4). [11] Dr. Falkinham testified that an antiserum which "predominantly binds" to a specified region of an antigen also exhibits substantial binding outside of the specified region, whereas an antibody that "selectively binds" to a specified region of an antigen would not exhibit substantial binding outside of the specified region (Falkinham Decl. ¶ 5). [12] In Dr. Falkinham's opinion, "there would be no way for one of ordinary skill to conclude that selective antibodies could be found, let alone are actually present in the K1-K3 antisera" disclosed in the Magerlein abstract (Falkinham Decl. ¶ 8). Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 11 [13] According to Magerlein I, which was published after the effective filing date of the '790 patent, "antisera K1-K3 did bind no truncated hPTH-fragments lacking the first two or more N-terminal amino acids (e.g., K2, Fig. 1)" in an epitope-mapping ELISA which measured antisera binding to various hPTH fragments coated onto a microtiter plate (Magerlein I 201, §§ 2.5 and 3; Fig. 1). [14] Further according to Magerlein I, a two-antibody immunoassay using an anti-hPTH 1-37 Mab as the "capture" antibody and affinity- purified K2 polyclonal antiserum as the "label" antibody did not detect biologically inactive N-terminally truncated hPTH fragments (Magerlein I 201, §§ 2.6 and 3; Fig. 2). [15] Dr. Falkinham testified that affinity purified K2 antiserum would be considered to "selectively bind" in accordance with the requirements of claim 17 (Falkinham Decl. ¶ 11). [16] In Nichols, the CAFC found that the antibody composition of claims 17 and 20-25 of the '790 patent was anticipated by the Magerlein abstract because the K2 antiserum disclosed in the abstract contained the claimed antibody and because it was well known how to isolate the claimed antibody from the other antibodies in the disclosed antiserum (Nichols 2 and 8-9). [17] The CAFC held that claims 17 and 20-25 were anticipated, even though the Magerlein abstract did not expressly disclose the "selective" binding capability of the claimed antibody, because it "was undisputed that once the antibody is isolated from the sera, Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 12 using well-known purification methods, the isolated antibody necessarily will exhibit the claimed 'selective' binding" (Nichols 9). [18] According to the CAFC, it is immaterial that the inventors of the '790 patent did not know the significance of the claimed antibody until after the abstract was published, i.e., that it could be used to detect biologically active hPTH (Nichols 7), because "inherent anticipation does not require a person of ordinary skill in the art to recognize the inherent disclosure in the prior art at the time the prior art is created" (id. 10, citations omitted). [19] Ms. Ketter, Controller for Nichols Institute Diagnostics ("NID"), testified that NID sold two assays for measuring hPTH – NA Intact- PTH and NA Bio-Intact PTH (Ketter Decl. ¶ 2). [20] According to Ms. Ketter, sales of NA Intact-PTH have declined steadily since the introduction of NA Bio-Intact PTH and the sales of NA Bio-Intact PTH are into the multi-million dollars per year (Ketter Decl. ¶ 3). [21] Further according to Ms. Ketter, "[t]he increase in sales of NA Bio- Intact PTH and corresponding decrease in sales of NA Intact-PTH results in part from customers switching from NA Intact-PTH to NA Bio-Intact PTH. This knowledge comes to me from customer activity analysis and customer feedback." [Ketter Decl. ¶ 4.] III. Discussion A. Legal principles Anticipation requires a prior art reference to describe every limitation in a claim either explicitly or inherently. In re Schreiber, 128 F.3d 1473, Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 13 1477 (Fed. Cir. 1997). "Inherent anticipation requires that the missing descriptive material is 'necessarily present,' not merely probably or possibly present, in the prior art." In re Robertson, 169 F.3d 743, 745 (Fed. Cir. 1999). A specific example is not required to establish anticipation. In re Petering, 301 F.2d 676 (CCPA 1962); In re Schaumann, 572 F.2d 312, 316 (CCPA 1978); Sanofi-Synthelabo v. Apotex Inc., 470 F.3d 1368, 1377 (Fed. Cir. 2006). However, when a generic disclosure is the basis for anticipation, one skilled in the art must be able to “at once envisage†the claimed structure in the disclosure. Petering, 301 F.2d. at 681. In order to establish a prima facie case of obviousness, the Examiner must show that each and every limitation of the claim is described or suggested by the prior art or would have been obvious based on the knowledge of those of ordinary skill in the art. In re Fine, 837 F.2d 1071, 1074 (Fed. Cir. 1988). “[R]ejections on obviousness grounds cannot be sustained by mere conclusory statements; instead, there must be some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness.†In re Kahn, 441 F.3d 977, 988, (Fed. Cir. 1996) (quoted with approval in KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007)). A prima facie case of anticipation under 35 U.S.C. § 102 and/or obviousness under 35 U.S.C. § 103 may be supported by evidence which reasonably shows that the characteristics missing from a prior art disclosure necessarily flow from the teaching of the prior art. Ex parte Levy, 17 USPQ2d 1461, 1464 (Bd. Pat. App. & Int. 1990). Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 14 When the Examiner has met the initial burden of showing a prima facie case of unpatentability, the burden then shifts to Appellant to rebut. In re Harris, 409 F.3d 1339, 1343-44 (Fed. Cir. 2005). Then, patentability is determined in view of the entire record. Id. Moreover, obviousness requires analysis of secondary considerations of nonobviousness, while anticipation does not. Compare King Instrument Corp. v. Otari Corp., 767 F.2d 853, 857 (“In a §103 obviousness analysis, Graham [v. John Deere Co., 383 U.S. 1)] requires that the trier assess certain underlying facts: (1) the scope and content of the prior art, (2) the level of ordinary skill in the art, (3) the differences between the claimed invention and the prior art, and (4) the so- called ‘secondary considerations.’â€), with Hakim v. Cannon Avent Group, PLC, 479 F.3d 1313, 1319 (“‘Anticipation’ means that the claimed invention was previously known, and that all of the elements and limitations of the claim are described in a single prior art reference.â€). Evidence of commercial success or other secondary considerations is only significant if there is a nexus between the claimed invention and the commercial success. In re DBC LLC, 545 F.3d 1773, 1384 (Fed. Cir. 2008). B. Analysis 1. Anticipation The Magerlein abstract discloses a two-antibody immunoassay for specifically detecting the physiologically circulating fragment of hPTH in serum using a small number of antisera and Mabs which bind to different regions of hPTH 1-37 (FF 5). We find that one of ordinary skill in the art would have immediately envisaged an immunoassay using first and second antibodies which bind to non-overlapping epitopes of hPTH 1-37, i.e., Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 15 epitopes contained in the N- and C-termini of hPTH 1-37, for use in a conventional two-antibody immunoassay (FF 6). In other words, given a thirty-seven amino acid analyte, the farther apart the antibody binding sites, the better to avoid steric hindrance. Of the ten antisera disclosed by the Magerlein abstract, antisera K1-K3 predominantly bind to the N-terminus of hPTH 1-37, i.e., to peptide hPTH 1-5 or SEQ ID No.6 of the '790 patent (FF 5 and 8). Of the ten antisera disclosed by the Magerlein abstract, antiserum K10 recognizes the C-terminus of hPTH 1-37 (FF 5). Thus, we find that one of ordinary skill in the art would have immediately envisaged a two- antibody immunoassay for specifically detecting the physiologically circulating fragment of hPTH in serum using first and second antibodies contained in antisera K1-K3 and K10, respectively, in light of the Magerlein abstract. We further find that antisera K1-K3 inherently do not bind to truncated hPTH 1-37 lacking the first two or more N-terminal amino acids (FF 14). In other words, antisera K1-K3 will detect active, but not inactive, hPTH 1-37. Relying on the Falkinham Declaration, ¶¶ 8, 10, and 11, Appellant argues that antisera K1-K3 "predominantly bind," but do not "selectively bind," to hPTH 1-6 as required by claim 9 (App. Br. 15-16). However, Dr. Falkinham testified that affinity-purified K2 antiserum would "selectively bind" to hPTH 1-5 (FF 16). This argument is unpersuasive of Examiner error in finding that the immunoassay of claim 9 is anticipated by the Magerlein abstract. Claim 9 requires a first and a second antibody, each of which "select" for a particular binding in the context of a two-antibody immunoassay. The first and the Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 16 second antibody encompass both monoclonal and polyclonal antibodies and neither antibody is required to be a purified antibody. The '790 patent does not specifically define the term "selectively binds" (FF 10). While Dr. Falkinham does not consider a polyclonal antiserum which "predominantly binds" to hPTH 1-5 to "selectively bind" thereto, Dr. Falkinham has not cited to any standard textbook or technical dictionary in support of his narrow interpretation of "selectively binds." Claims in reexamination “will be given their broadest reasonable interpretation...†In re Yamamoto, 740 F.2d 1569, 1571 (Fed. Cir. 1984). To the extent any of antisera K1-K3 bind to hPTH having the first two amino acids but not to truncated hPTH lacking the first two or more N-terminal amino acids, any of antisera K1-K3 (i) discriminate between biologically active and inactive forms of hPTH, (ii) discriminate between hPTH lacking the first two amino acids and hPTH having the first two amino acids, and (iii) bind to the first two amino acids of hPTH and, therefore, "selectively bind" to a peptide selected from the group consisting of peptides having SEQ ID NOs. 1-6, giving that term its broadest reasonable interpretation consistent with the '790 specification (FF 8, 11, and 14). Thus, Appellant has not shown that the Examiner erred in finding that the Magerlein abstract discloses the two-antibody sandwich immunoassay of claim 9. Secondary considerations of commercial success are irrelevant to a finding of anticipation. Therefore, we sustain the rejection of claims 9-16 under § 102 as anticipated by the Magerlein abstract. 2. Obviousness Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 17 In the alternative, according to the Magerlein abstract, "[s]ince the N- terminal fragment of hPTH 1-37 was proposed as the physiologically circulating form of hPTH we developed an immunological [two-side] assay in order to measure this fragment in human serum" (FF 5). Two-antibody sandwich immunoassays are well-known in the art and use first and second antibodies which bind to epitopes contained in discrete, non-overlapping regions of a target antigen (FF 6). Monoclonal or affinity purified polyclonal antibodies can be used (FF 6). Therefore, it would have been obvious to one of ordinary skill in the art to select a combination of two of the antisera disclosed in the Magerlein abstract which bind to two different epitopes contained in discrete, non-overlapping regions of hPTH 1-37 and to affinity-purify the antisera for use in a two-antibody immunoassay to detect analyte, i.e., the physiologically circulating fragment of hPTH in human serum, following well-known procedures as disclosed by Harlow (FF 6). It would have been obvious to use one affinity-purified K1-K3 antiserum, which inherently distinguishes active from inactive hPTH by virtue of binding to the N-terminus of an hPTH having hPTH 1-2 present, while not binding to the N-terminus of a truncated hPTH (see Forssmann and Hilliker (the first couple of amino acids are required for full biological activity (FF 2 and 4)). It also would have been obvious to use a second affinity-purified antiserum that binds to an epitope found in the C-terminus of hPTH 1-37, e.g., an epitope contained in hPTH 24-37, in view of Forssmann's teaching that the shortest hPTH fragment with full biological activity is hPTH 1-37 (FF 3). Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 18 Appellant reiterates the argument that the Magerlein abstract fails to teach or suggest first and second antibodies which "selectively bind" to the epitopes contained within defined regions of hPTH. These arguments are unpersuasive for the reasons given above in regard to the anticipation rejection. In addition, Appellant argues that none of Harlow, Woods, Forssmann, and Hilliker individually teaches or suggests all of the limitations of claim 9 (App. Br. 18, 19, and 25-30). In determining whether obviousness is established by combining the teachings of the prior art, “the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art.†In re Keller, 642 F.2d 413, 425 (CCPA 1981). However, the combined teachings of the applied references teach or suggest using a conventional two-antibody immunoassay (as explained by Harlow) for detecting biologically active hPTH using two of a small number of antisera disclosed by the Magerlein abstract (which Harlow suggests should be further affinity purified) paired to bind discrete, non-overlapping epitopes (Harlow). Alternatively, Forssmann and Hilliker provide motivation to select antibodies which bind the first and second amino acids of hPTH but do not bind to N-terminus truncated hPTH and provide a reasonable expectation of success that such antibodies will discriminate between biologically active circulating hPTH and fragments thereof at least 34-37 amino acids in length and inactive hPTH and fragments thereof. It is not necessary to discuss Woods since Appellant does not dispute that antibody fragments which bind analyte are functionally equivalent to their parent antibodies when used in immunoassays. Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 19 Therefore, the Examiner has provided a sufficient factual basis to conclude that the immunoassay of claim 9 is prima facie obvious over the teachings of the Magerlein abstract taken alone or in combination with the teachings of Harlow, Woods, Forssmann, and/or Hilliker and to shift the burden to Appellant to prove otherwise. 3. Secondary considerations of commercial success Appellant argues that the shift in sales between NA Intact-PTH and NA Bio-Intact PTH assays testified to by Ms. Ketter and graphically illustrated at page 19 of a slide presentation entitled "Welcome to Nichols Institute Diagnostics" (App. Br. Exh. 11) demonstrates a nexus between the commercial success of the NA Bio-Intact PTH assay and the claimed antibodies embodied by that assay, i.e., antibodies which selectively bind an N-terminal peptide of hPTH and, therefore, distinguish biologically active circulating hPTH from inactive circulating hPTH (App. Br. 22-23). Appellant also argues that a STIPULATION AND ORDER RE EXTENSION OF STAY OF ENFORCEMENT OF JUDGMENT in Nichols Inst. Diagnostics, Inc. v. Scantibodies Clinical Lab., Inc., No. 02-CV-46 (S.D. Cal. dated January 31, 2006) ("Stipulation," App. Br. Exh. 12) staying enforcement of a more than two million dollar judgment entered against the defendants is further evidence of commercial success (App. Br. 25). As an initial matter, we note that none of the asserted rebuttal evidence addresses use of antibody fragments versus whole antibodies in the method of claim 9. Neither the Ketter Declaration nor the slide show (Exh. 11) establishes the required nexus between the claimed invention and the sales Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 20 of NA Bio-Intact PTH. Neither the Ketter Declaration nor the slide show (Exh. 11) contains a factual basis for concluding that the NA Bio-Intact PTH assay is the assay of any of claims 9-16. The Ketter Declaration contains no details of the NA Bio-Intact PTH assay. The slide show highlights the "Nichols Advantage® System" (Exh. 11 at 8 and 11-17) which performs a number of automated methods with the stated goals of continuing developing markets and expanding its menu of available assays (Exh. 11 at 17 and 19). The Ketter Declaration fails to exclude other possible factors which may have resulted in increased NA Bio-Intact PTH sales and decreased NA Intact PTH sales, e.g., extensive advertising and position as a market leader before the introduction of the claimed immunoassay, see Pentec, Inc. v. Graphic Controls Corp., 776 F.2d 309, 317 (Fed. Cir. 1985), or recent changes in related technology or consumer demand. See In re Fielder, 471 F.2d 640, 642-43 (CCPA 1972). For example, there may be consumer demand for a battery of tests aimed at diagnosing specific diseases or metabolic areas, e.g., bone and mineral metabolism (see e.g., Exh. 11 at 17). Arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602 (CCPA 1065). The Stipulation (Exh. 12) is not probative of commercial success for a number of reasons. Initially, we note that the Stipulation involves the same civil case appealed to the CAFC in Nichols (Nichols 1). In addition, in PTO examinations and reexaminations, the standard of proof, i.e., by a preponderance of the evidence, is substantially lower than in a civil case. In re Caveney, 761 F.2d 671, 674 (Fed. Cir. 1985). Furthermore, there is no presumption of validity. In re Etter, 756 F.2d 852, 856 (Fed. Cir. 1985). Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 21 Moreover, claims in reexamination "will be given their broadest reasonable interpretation." In re Yamamoto, 740 F.2d 1569, 1571 (Fed. Cir. 1984). Thus, considering an issue at the district court is not equivalent to the PTO considering the issue because the court and the PTO use different standards of proof. Furthermore, Appellant has not submitted evidence that the stay has been lifted and the judgment enforced or that licenses for the claimed invention have been taken out by a substantial portion of its marketplace competitors, etc. Therefore, Appellant's rebuttal arguments and evidence of commercial success is insufficient to overcome the Examiner's prima facie conclusion of obviousness. C. Conclusion Appellant has not shown that the Examiner erred in finding that the Magerlein abstract explicitly or inherently discloses a sandwich immunoassay for detecting active hPTH in a sample. Appellant has not shown the Examiner erred in concluding that the claimed sandwich immunoassay for detecting active hPTH is prima facie obvious over the teachings of the Magerlein abstract taken alone, or in combination with Harlow, Woods, Forssmann, and/or Hilliker. Appellant's rebuttal evidence of commercial success, the Ketter Declaration, is insufficient to overcome the Examiner's prima facie conclusion of obviousness. IV. Order Upon consideration of the record, and for the reasons given, it is ORDERED that the Examiner's rejections of claims 1-29, 38, and 39 are AFFIRMED. Appeal 2007-4005 Reexamination Control 90/007,412 Patent 6,030,790 22 Requests for extensions of time in this ex parte reexamination proceeding are governed by 37 C.F.R. § 1.550(c). See 37 C.F.R. § 41.50(f). AFFIRMED MAT Patent Owner: Dickstein Shapiro, LLP 1825 Eye Street NW Washington DC 20006-5403 Third Party Requester: Peng Chen MORRISON & FOERSTER LLP 12531 High Bluff Drive, Suite 100 San Diego, CA 92130-3014 Copy with citationCopy as parenthetical citation