Ex Parte LazarDownload PDFBoard of Patent Appeals and InterferencesSep 20, 201110098851 (B.P.A.I. Sep. 20, 2011) Copy Citation UNITED STATES PATENT AND TRADEMARKOFFICE 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. 10/098,851 03/15/2002 James G. Lazar 38521.00500US 3074 38647 7590 09/21/2011 MILBANK, TWEED, HADLEY & MCCLOY LLP INTERNATIONAL SQUARE BUILDING 1850 K STRET, N.W., SUITE 1100 WASHINGTON, DC 20006 EXAMINER JUNG, UNSU ART UNIT PAPER NUMBER 3768 MAIL DATE DELIVERY MODE 09/21/2011 PAPER Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES __________ Ex parte JAMES G. LAZAR __________ Appeal 2010-008406 Application 10/098,851 Technology Center 1600 __________ Before DEMETRA J. MILLS, FRANCISCO C. PRATS, and MELANIE L. McCOLLUM, Administrative Patent Judges. McCOLLUM, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to a signal amplification method. The Examiner has rejected the claims as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. STATEMENT OF THE CASE Claims 1, 2, 6-8, 12-18, 21-23, and 47 are pending (App. Br. 2). The claims subject to each rejection have not been argued separately and therefore stand or fall together. 37 C.F.R. § 41.37(c)(1)(vii). We will focus on claim 1, which reads as follows: Appeal 2010-008406 Application 10/098,851 2 1. A method of signal amplification for detection of a target analyte comprising: (a) reacting a target analyte with a conjugated antibody, wherein said antibody is conjugated to a binding molecule, and said antibody is reactive with the target analyte, thereby forming an antibody complex; (b) reacting the binding molecule of the antibody complex with a conjugated binding partner, forming a binding pair, wherein said binding partner is conjugated to a reagent; and (c) reacting a detectably-labeled reagent-specific binding entity with the reagent of the binding pair to form a detectable complex, wherein detection of the complex provides signal amplification. Claims 1, 6, 12, 13, 17, 18, 21, 22, and 47 stand rejected under 35 U.S.C. § 103(a) as obvious over Martinelli1 in view of Lazar2 (Ans. 4). Claims 2, 7, and 8 stand rejected under 35 U.S.C. § 103(a) as obvious over Martinelli in view of Lazar and Wogoman3 (Ans. 7). Claim 14 stands rejected under 35 U.S.C. § 103(a) as obvious over Martinelli in view of Lazar and Mantero4 (Ans. 8). Claims 15 and 16 stand rejected under 35 U.S.C. § 103(a) as obvious over Martinelli in view of Lazar and Chiswell5 (Ans. 9-10). Claim 23 stands rejected under 35 U.S.C. § 103(a) as obvious over Martinelli in view of Lazar and Wagner6 (Ans. 11). 1 Martinelli et al., US 6,083,689, Jul. 4, 2000. 2 Lazar et al., Hybrid Capture®: A Sensitive Signal Amplification-based Chemiluminescent Test for the Detection and Quantitation of Human Viral and Bacterial Pathogens, 22 J. CLIN. LIGAND ASSAY 139-151 (1999). 3 Wogoman, US 4,990,075, Feb. 5, 1991. 4 Mantero et al., DNA Enzyme Immunoassay: General Method for Detecting Products of Polymerase Chain Reaction, 37 CLIN. CHEM. 422-429 (1991). 5 Chiswell, US 4,716,106, Dec. 29, 1987. 6 Wagner et al., US 5,079,150, Jan. 7, 1992. Appeal 2010-008406 Application 10/098,851 3 Appellant argues: The rejection of all of the pending claims is erroneous for the following reasons . . . : (i) the proposed modification of the Martinelli reference (adding the “universal nucleic acid detection” technology of Lazar) impermissibly changes the principle of operation of both the Martinelli and Lazar methods; (ii) the Examiner has not provided a valid reason to explain why one of ordinary skill in the art would have made the Examiner’s proposed combination; (iii) the Examiner’s conclusion of obviousness is based on impermissible hindsight reconstruction; and (iv) the references, read as a whole, teach away from making the combination. (App. Br. 15.) ISSUE Does a preponderance of the evidence support the Examiner’s combination of Martinelli and Lazar? FINDINGS OF FACT 1. Martinelli discloses “immunoassay methods that use an antibody-variant DNA conjugate as a tracer antibody, wherein the variant DNA is a substrate for an RNA-dependent RNA polymerase (Martinelli, col. 2, ll. 31-35). 2. Martinelli also discloses that the “antibody of the conjugate can be directed to either analyte under assay or to an anti-analyte antibody used in an immunoassay” (id. at col. 2, ll. 38-40). 3. In addition, Martinelli discloses that, “[a]fter incubation and separation of unbound antibody-variant DNA conjugate from that bound to the analyte under assay, the variant DNA template, bound to the analyte, is transcribed, and the RNA transcript is replicated by contact with an Appeal 2010-008406 Application 10/098,851 4 appropriate amount of an RNA-dependent RNA polymerase, whose substrate is the variant DNA” (id. at col. 2, ll. 40-46). 4. Martinelli also discloses that the “detection of RNA replication products produced in the assay, indicates the presence of the analyte under assay” (id. at col. 2, ll. 47-48). 5. In addition, Martinelli discloses: Another embodiment wherein the antibody-variant DNA conjugate can be considered to be a universal type of immunoassay reagent is that wherein the variant DNA is linked to avidin, and biotinylated anti-analyte antibodies are used. In that embodiment, the universal immunoassay reagent is actually the variant DNA linked to avidin, preferably the variant DNA linked to streptavidin. The variant DNA-antibody conjugate in that embodiment is prepared during the immunoassay procedure. (Id. at col. 8, ll. 43-52.) 6. Lazar discloses that “Hybrid Capture® is a universal nucleic acid detection technology that utilizes long genomic probes and antibodies specific for RNA:DNA hybrids to achieve a high level of signal amplification by virtue of the fact that each copy of target can bind hundreds or thousands of enzyme labels” (Lazar 139). 7. In particular, Lazar discloses: Specimen DNA is denatured and then hybridized in solution to genomic RNA probes forming RNA:DNA hybrids. Hybrids are captured onto an antibody-coated solid phase and reacted with an alkaline phosphatase-labeled conjugate. The alkaline phosphatase acts upon a dioxetane substrate to generate light that is measured in a luminometer. (Id. at 140 (italics omitted).) Appeal 2010-008406 Application 10/098,851 5 8. In addition, Lazar discloses: Target amplification protocols increase the total number of nucleic acid molecules, thus permitting the use of less sensitive signal detection methods. Though amplification techniques such as the polymerase chain reaction (PCR) and ligase chain reaction (LCR) are remarkably sensitive, extreme care must be taken to avoid cross-contamination during sample processing. In addition, quantitation of the original target is a challenge for the user and is usually accomplished by the inclusion of multiple internal and external controls. Some steps involved in target amplification have unascertained or variable efficiencies, especially in·the presence of crude clinical material, making it difficult to accurately correlate the final copy numbers to the original amounts of target. (Id. at 139.) 9. In contrast, Lazar discloses: Signal amplification methods increase the signal of the system without changing the total number of target molecules. In methods involving signal amplification, the nucleic acid of interest is measured directly, and the resulting signal is directly proportional to the concentration of the specific nucleic acid in the sample. This type of direct detection method does not require complex enzymatic reactions, and therefore, accurate quantitation is preserved in the presence of relatively crude specimens. (Id.) PRINCIPLES OF LAW Obviousness “analysis need not seek out precise teachings directed to the specific subject matter of the challenged claim.” KSR Int’l v. Teleflex Inc., 550 U.S. 398, 418 (2007). Instead, it proper to “take account of the inferences and creative steps that a person of ordinary skill in the art would Appeal 2010-008406 Application 10/098,851 6 employ.” Id. “A person of ordinary skill is also a person of ordinary creativity, not an automaton.” Id. at 421. A reference may be said to teach away when a person of ordinary skill, upon reading the reference, would be discouraged from following the path set out in the reference, or would be led in a direction divergent from the path that was taken by the applicant. The degree of teaching away will of course depend on the particular facts; in 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). ANALYSIS Martinelli discloses a method for detection of a target analyte comprising: reacting a target analyte with a conjugated antibody, wherein said antibody is conjugated to a binding molecule (biotin), and said antibody is reactive with the target analyte, thereby forming an antibody complex; and reacting the binding molecule of the antibody complex with a conjugated binding partner (avidin), forming a binding pair, wherein said binding partner is conjugated to a reagent (variant DNA) (Findings of Fact (FF) 1-5). Lazar discloses reacting a detectably-labeled reagent-specific binding entity (alkaline phosphatase-labeled conjugate) with a reagent (RNA:DNA hybrids) to form a detectable complex, wherein detection of the complex provides signal amplification (FF 6-7). For the reasons discussed below, we conclude that it would have been obvious to combine these teachings to provide the method of claim 1. As noted by the Examiner, Lazar teaches that signal amplification methods are advantageous because they “increase the signal of the system Appeal 2010-008406 Application 10/098,851 7 without changing the total number of target molecules,” “the resulting signal is directly proportional to the concentration of the specific nucleic acid in the sample,” and they do “not require complex enzymatic reactions, and therefore, accurate quantitation is preserved in the presence of relatively crude specimens” (FF 8-9). In view of these teachings, we agree with the Examiner that it would have been obvious “to employ the universal nucleic acid detection technology of Lazar . . . in the method of Martinelli et al. in order to . . . increas[e] the signal of the resulting complex in the binding assay of Martinelli et al. without changing the total number of target molecules” (Ans. 6). In addition, we agree that, [w]hile the RNA transcription amplification method of Martinelli et al. may provide exponential signal production, the detection method of forming DNA:RNA hybrids followed by the use of specific antibodies against the hybrids has a further advantage of being simple compared to the more complicated process of facilitating RNA transcripts, which involve complex enzymatic reactions. (Id. at 21.) Thus, we do not agree with Appellant that “the Examiner has not provided a valid reason to explain why one of ordinary skill in the art would have made the Examiner’s proposed combination” (App. Br. 15). For substantially the same reasons, we also do not agree with Appellant that “the Examiner’s conclusion of obviousness is based on impermissible hindsight reconstruction” (id.). In this regard, Appellant argues that “the only reason to employ a ‘binding pair’ comprising the ‘binding molecule’ and its reagent-conjugate ‘binding partner’ is found in the instant specification” (id. at 26). We do not agree. Instead, Martinelli provides the reason to employ a “binding pair” comprising the “binding Appeal 2010-008406 Application 10/098,851 8 molecule,” biotin, and its “binding partner,” avidin, that is, to form “a universal type of immunoassay reagent” (FF 5). As indicated by the Supreme Court, “any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. at 420. In addition, we do not agree with Appellant that “the references, read as a whole, teach away from making the combination” (App. Br. 15). Martinelli may well be “unequivocally focused on signal amplification by enzyme-based systems, using replicable DNA templates, to enhance the sensitivities of immunoassays” (id. at 28-29). However, Lazar teaches advantages of its amplification technique (FF 9). Appellant has not adequately explained why Martinelli’s teaching of a particular amplification method would discourage one of ordinary skill in the art from using Lazar’s amplification method. Even if using Lazar’s amplification method would result in less amplification than Martinelli’s method, Lazar’s amplification method “does not require complex enzymatic reactions” and “accurate quantitation is preserved” (FF 9). “The fact that the motivating benefit comes at the expense of another benefit . . . should not nullify its use as a basis to modify the disclosure of one reference with the teachings of another. Instead, the benefits, both lost and gained, should be weighed against one another.” Medichem S.A. v. Rolabo S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006). In the present case, Appellant has not provided sufficient evidence to demonstrate that any loss in the amount of signal amplification would cause one of ordinary skill in the art to avoid the claimed combination. Appeal 2010-008406 Application 10/098,851 9 Furthermore, we do not agree with Appellant that “the proposed modification of the Martinelli reference . . . impermissibly changes the principle of operation of both the Martinelli and Lazar methods” (App. Br. 15). In particular, we do not agree that the Examiner’s combination is either using Martinelli’s variant DNA itself to form RNA:DNA hybrids (Reply Br. 3-5) or bodily incorporating Lazar’s genomic DNA into Martinelli’s conjugate (App. Br. 16-20). Both approaches seem to treat the skilled artisan as an automaton. Instead, we conclude that, based on the teachings in Lazar, one of ordinary skill in the art would have used an appropriately sized DNA in forming Martinelli’s conjugate, such that an RNA:DNA hybrid thereof would react with a sufficient number of Lazar’s labels to provide sufficient signal amplification. CONCLUSION The evidence supports the Examiner’s combination of Martinelli and Lazar. We therefore affirm the obviousness rejection of claim 1. Claims 6, 12, 13, 17, 18, 21, 22, and 47 fall with claim 1. 37 C.F.R. § 41.37(c)(1)(vii). In rejecting claims 2, 7, 8, 14-16, and 23, the Examiner additionally relies on Wogoman, Mantero, Chiswell, or Wagner (Ans. 7-12). Appellant does not point out any deficiencies in the Examiner’s reliance on these references. Thus, having found no deficiencies in the combination of Martinelli and Lazar, we affirm the obviousness rejections of claims 2, 7, 8, 14-16, and 23 for the reasons stated in the Examiner’s Answer. Appeal 2010-008406 Application 10/098,851 10 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 dm Copy with citationCopy as parenthetical citation