Ex Parte OZINSKY et alDownload PDFPatent Trial and Appeal BoardOct 22, 201813769195 (P.T.A.B. Oct. 22, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 13/769, 195 02/15/2013 25225 7590 10/24/2018 MORRISON & FOERSTER LLP 12531 HIGH BLUFF DRIVE SUITE 100 SAN DIEGO, CA 92130-2040 FIRST NAMED INVENTOR Adrian OZINSKY 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 ATTORNEY DOCKET NO. CONFIRMATION NO. 655652004000 3413 EXAMINER LEITH, NANCY J ART UNIT PAPER NUMBER 1636 NOTIFICATION DATE DELIVERY MODE 10/24/2018 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): PatentDocket@mofo.com EOfficeSD@mofo.com pair_mofo@firsttofile.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte ADRIAN OZINSKY, ROLF KUESTNER, and GREGORY ZORNETZER1 Appeal2017-001038 Application 13/7 69,195 Technology Center 1600 Before DONALD E. ADAMS, ULRIKE W. JENKS, and TA WEN CHANG, 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 method to determine the presence or absence of, quantify and/or identify at least one RNA species in a sample, which have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. STATEMENT OF THE CASE RNases Hare enzymes that are able to bind a single-stranded RNA hybridized to a complementary single-stranded DNA and then degrade the 1 Appellants identify the Real Party in Interest as Institute for Systems Biology. (Appeal Br. 1.) 1 Appeal2017-001038 Application 13/769,195 RNA portion of the RNA:DNA hybrid. (Carter2 1:45-50.) The Specification states that "[t]he present invention takes advantage of the reversible nuclease activity of RNase H due to the presence or absence of magnesium ion to utilize DNA probes in a prepared oligomer library as indices for the presence and/or amount of RNA complementary to them." (Spec. ,r 5.) According to the Specification, the invention provides an easily multiplexed and miniaturized method for detecting, quantitating, and identifying RNA species in a sample. (Id. ,r 6.) Claims 1, 4--16, 21, and 22 are on appeal. Claim 1 is illustrative and reproduced below: 1. A method to determine the presence or absence of and/or to quantify and/or to identify at least one RNA species in a sample, comprising the steps of: a) exposing the sample to at least one DNA probe comprising a sequence complementary to said at least one RNA species of interest to form DNA:RNA hybrids with any said RNA species of interest in the sample; b) incubating the DNA:RNA hybrids formed in a) with RNase H under conditions that inhibit the nuclease activity of the RNase H but do not inhibit its DNA:RNA binding activity thereby forming a complex whereby said RNase His bound to said hybrids designated RNase H-bound DNA:RNA; c) separating RNase H-bound DNA:RNA from unbound DNA and RNA; d) incubating the RNase H-bound DNA:RNA under conditions wherein the nuclease activity is restored so as to hydrolyze the RNA of the DNA:RNA hybrids and release the DNA probe; and e) determining the presence or absence and/ or amount and/or identity of the released DNA probe, thereby determining the presence or absence and/ or quantity and/ or identity of said at least one RNA species in the sample; 2 Carter et al., US 7,560,232 B2, issued July 14, 2009. 2 Appeal2017-001038 Application 13/769,195 wherein multiple RNA species of interest are detected and/or quantified and/or identified in a multiplexed assay and wherein step a) employs DNA probes complementary to each said multiple RNA species of interest and wherein in step e) the presence and/or quantity and/or identity of DNA probe complementary to each of said multiple RNA species of interest is determined. (Appeal Br. 10 (Claims App.).) The Examiner rejects claims 1, 6, 8, and 11-14 under pre-AIA 35 U.S.C. § I03(a) as being unpatentable over Carter. (Ans. 3.) The Examiner rejects claims 4, 5, and 9 under pre-AIA 35 U.S.C. § I03(a) as being unpatentable over Carter and Galas. 3 (Ans. 6.) The Examiner rejects claim 10 under pre-AIA 35 U.S.C. § I03(a) as being unpatentable over Carter and Shachar. 4 (Ans. 7-8.) The Examiner rejects claims 15 and 16 under pre-AIA 35 U.S.C. § I03(a) as being unpatentable over Carter, Cheung, 5 and Ohtani. 6 (Ans. 8- 9.) The Examiner rejects claims 7, 21, and 22 under pre-AIA 35 U.S.C. § I03(a) as being unpatentable over Carter, Bibikova,7 and Park. 8 (Ans. 10.) 3 Galas et al., WO 2011/097528 Al, published Aug. 11, 2011. 4 Shachar et al., US 2010/0262375 Al, published Oct. 14, 2010. 5 Cheung et al., US 2011/0294674 Al, published Dec. 1, 2011. 6 Naoto Ohtani et al., Heat Labile Ribonuclease HI from a Psychrotrophic Bacterium: Gene Cloning, Characterization and Site-Directed Mutagenesis, 14 PROTEIN ENGINEERING 97 5 (2001 ). 7 Marina Bibikova et al., Technical Brief, Gene Expression Profile in Formalin-Fixed, Paraffin-Embedded Tissues Obtained with a Novel Assay for Microarray Analysis, 50 CLINICAL CHEMISTRY 2384 (2004). 8 Young Nyun Park et al., Technical Advance, Detection of Hepatitis C Virus RNA Using Ligation-Dependent Polymerase Chain Reaction in Formalin-Fixed, Paraffin-Embedded Liver Tissues, 149 AM. J. PATHOLOGY 1485 (1996). 3 Appeal2017-001038 Application 13/769,195 DISCUSSION Issue The Examiner finds that Carter discloses all of the steps of claim 1, which is the only independent claim, except that Carter does not suggest "incubating the RNase H bound DNA:RNA under conditions where the nuclease activity of the RNase His restored, so that the RNA is hydrolyzed, and the DNA probe released." (Ans. 4, 5.) The Examiner concludes that it would have been obvious to a skilled artisan to manipulate the RNase Hin the reaction to first inhibit the nuclease activity so that the RNA:DNA hybrid can be formed, and then to allow an increase in the nucleolytic activity of the RNase H through manipulation of the reaction conditions, so as to degrade the RNA, which will allow the labeled DNA probe to be detected without the interference from RNA molecules. One of ordinary skill in the art knowing that the RNase H activities can be manipulated through the reaction conditions, such as the magnesium ion levels, would have a reasonable expectation of success in doing so. (Id. at 5-6.) Appellants contend among other things that Carter does not suggest restoring the RNase H activity, as required by step d) of claim 1. (Appeal Br. 3.) The issue with respect to the rejections on appeal is whether Carter suggests a method to determine the presence or absence of and/or to quantify and/or to identify at least one RNA species in a sample comprising the steps of "incubating RNase H-bound DNA:RNA under conditions wherein the nuclease activity is restored so as to hydrolyze the RNA of the DNA:RNA hybrids and release the DNA probe" and then "determining the presence or absence and/or amount and/or identity of the released DNA probe, thereby 4 Appeal2017-001038 Application 13/769,195 determining the presence or absence and/or quantity and/or identity of said at least one RNA species in the sample." Analysis On balance, we find Appellants have the better position. The Examiner acknowledges that "Carter fails to disclose or suggest incubating the RNase H bound DNA:RNA under conditions where the nuclease activity of the RNase His restored, so that the RNA is hydrolyzed, and the DNA probe released." (Ans. 5.) However, the Examiner finds that "Carter discloses that the presence or absence of magnesium ions in the RNase H buffer can be used to manipulate whether the nucleolytic activity of the RNase His present" and also teaches that "an active RNase H can be added to degrade the RNA:DNA hybrids to liberate ribonucleotides." (Id. at 4.) In light of the above and given Carter's teaching of a method for detecting and/or quantifying an RNA of interest in a sample comprising a step of "incubating ... DNA:RNA hybrids with an RNase H under conditions that inhibit the nuclease activity of the RNase H," the Examiner concludes that it would have been obvious to a skilled artisan to first inhibit and then allow an increase in the nucleolytic activity of the RNase H by varying reaction conditions, such as magnesium ion levels, in order to degrade RNA and allow labeled DNA probe to be detected without interference from RNA molecules. (Id. at 5---6.) The Examiner also finds that a skilled artisan would have a reasonable expectation of success in arriving at the claimed invention in view of Carter's disclosure that "RNase H activities can be manipulated through the reaction conditions, such as ... magnesium ion levels." (Id. at 6.) 5 Appeal2017-001038 Application 13/769,195 While we understand the Examiner's position, we are not persuaded. We agree with the Examiner that Carter teaches that RNase H nucleolytic activity is dependent on access to divalent cations such as magnesium ions. (Carter 8:21-24, 10:61-11 :7.) However, this teaching is provided in the context of the desirability of suppressing RNase H nucleolytic activity. Likewise, while Carter teaches a preferred embodiment in which a protein having RNase H activity is added to degrade RNA:DNA hybrids, the embodiment does not involve incubating DNA:RNA hybrids with RNase H under conditions that first inhibit and then restore RNase H nucleolytic activity, nor does the embodiment involve determining the presence, quantity, and/or identity of RNA in the sample using DNA probes released through RNase H nucleolytic activity. Instead, in that embodiment Carter teaches hybridizing RNA in the sample with immobilized DNA probes, degrading the hybrids using RN ase H to release mono- and oligoribonucleotides, generating ATP from liberated AMP nucleotides, and then detecting the presence of the RNA sequence of interest through an ATP detection reaction. (Id. at 4:51---65.) We are cognizant that the rejection of claim 1 is one of obviousness rather than anticipation; thus, "picking and choosing" disclosures in Carter that are not directly related to each other for combination may be proper. In reArkley, 455 F.2d 586,587, 172 USPQ 524,526 (CCPA 1972). In this case, however, we find that the Examiner has not sufficiently articulated a reason that a skilled artisan would have combined the disclosures in Carter to supply the limitation not explicitly disclosed to arrive at the claimed invention. For instance, the Examiner cites no evidentiary support for the conclusion that, based on Carter's disclosures, a skilled artisan would have 6 Appeal2017-001038 Application 13/769,195 first inhibited and then allowed an increase in the nucleolytic activity of the RNase H "in order to ... allow labeled DNA probe to be detected without the interference from RNA molecules." (Ans. 5---6.) Neither has the Examiner argued or shown that claim 1 is merely the combination of familiar elements according to known methods to yield predictable results, or may be arrived at by a simple substitution of known equivalents. "[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." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,418 (2007) (quoting In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006). Accordingly, we reverse the Examiner's rejection of claim 1 as obvious over Carter. We also reverse the rejection of claims 4--16, 21, and 22, which depend directly or indirectly from claim 1, for the same reasons. In re Fine, 837 F .2d 1071, 107 6 (Fed. Cir. 198 8) ("Dependent claims are nonobvious under section 103 if the independent claims from which they depend are nonobvious. "). SUMMARY For the reasons above, we reverse the Examiner's decision rejecting claims 1, 4--16, 21, and 22. REVERSED 7 Copy with citationCopy as parenthetical citation