Ex Parte Wedler et alDownload PDFPatent Trials and Appeals BoardMay 17, 201914397733 - (D) (P.T.A.B. May. 17, 2019) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. 14/397,733 94822 7590 Seyfarth Shaw LLP Patent Docketing FILING DATE 10/29/2014 05/21/2019 975 F. Street N.W. Washington, DC 20004 FIRST NAMED INVENTOR Roiger Wedler 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. 102960-000054 2154 EXAMINER HILL, KEVIN KAI ART UNIT PAPER NUMBER 1633 NOTIFICATION DATE DELIVERY MODE 05/21/2019 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): wdcip@seyfarth.com bosippto@seyfarth.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte HOLGER WEDLER, ERIKA WEDLER, DIRK LOEFFERT, and DOMINIC O'NEIL 1 Appeal 2018-003615 Application 14/397,733 Technology Center 1600 Before ULRIKE W. JENKS, JOHN E. SCHNEIDER, and RYAN H. FLAX, Administrative Patent Judges. FLAX, Administrative Patent Judge. DECISION ON APPEAL This is a decision under 35 U.S.C. § 134(a) involving claims directed to a method for enriching one or more target sequences of DNA in a composition. Claims 22-38 are on appeal as rejected under 35 U.S.C. § 103. We have jurisdiction under 35 U.S.C. § 6(b ). We affirm-in-part. 1 Appellants identify the Real Party in Interest as "Qiagen GmbH." Br. 3. Appeal2018-003615 Application 14/397, 733 STATEMENT OF THE CASE Independent claim 22 is representative and is reproduced below: 22. A method for enriching one or more target sequences of a deoxyribonucleic acid (DNA) in a composition, comprising the steps of: (a) providing a composition comprising one or more deoxyribonucleic acid (DNA) molecules, (b) hybridizing to said one or more DNA molecules, one or more target specific ribonucleic acid (RNA) hybridization probes, thereby forming one or more RNA/DNA hybrids, (c) capturing the RNA/DNA hybrids with one or more antibodies being specific for such RNA/DNA hybrids, thereby forming one or more RNA/DNA/antibody hybrids, ( d) isolating the one or more RNA/DNA/antibody hybrids, ( e) amplifying the one or more DNA molecules of the one or more RNA/DNA/antibody hybrids, and (f) sequencing the DNA molecules of the amplification product. Br. 22 (Claims Appendix). The following rejections are appealed: Claims 22-34, 36, and 38 stand rejected under 35 U.S.C. § I03(a) over Hartley2 and Gnirke. 3 Answer 3. Claim 35 stands rejected under 35 U.S.C. § I03(a) over Hartley, Gnirke, and Metzker. 4 Answer 12. 2 US 5,106,727 (issued Apr. 21, 1992) ("Hartley"). 3 US 2010/0029498 Al (published Feb. 4, 2010) ("Gnirke"). 4 Michael L. Metzker, Sequencing technologies - the next generation, 11 NAT. REV., GENETICS 31--46 (2010) ("Metzker"). 2 Appeal2018-003615 Application 14/397, 733 Claim 37 stands rejected under 35 U.S.C. § I03(a) over Hartley, Gnirke, Metzker, and Kamberov. 5 Answer 14. The Examiner has withdrawn a rejection of claim 23 under 35 U.S.C. § 112, second paragraph. Answer 17. The Final Action included claim 16 with claim 23 in this rejection; we understand it to also be withdrawn as to claim 16, which is no longer in the application according to the Claims Appendix to Appellants' Brief. See Final Action 4; see also Br. The Final Action also included a rejection of claims 1, 2, 6-8, and 19-21 under 35 U.S.C. § 102(b) over Hartley (Final Action 6); however, this rejection is addressed by neither Appellants' Brief nor the Examiner's Answer, and these claims are no longer in the application according to the Claims Appendix to Appellants' Brief. See generally Br.; Answer. Therefore, we understand this rejection is also withdrawn. DISCUSSION "[T]he examiner bears the initial burden, on review of the prior art or on any other ground, of presenting aprimafacie case ofunpatentability. If that burden is met, the burden of coming forward with evidence or argument shifts to the applicant." In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992). Arguments made by Appellants in the Appeal Brief have been considered in this Decision (no Reply Brief was submitted); arguments not so-presented in the Brief are waived. See 37 C.F.R. § 4I.37(c)(l)(iv) (2015); see also Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative) ("Any bases for asserting error, whether factual or legal, that are not raised in the principal brief are waived."). 5 US 2004/0209298 Al (published Oct. 21, 2004) ("Kamberov"). 3 Appeal2018-003615 Application 14/397, 733 As applicable to the rejections on appeal and Appellants' arguments there-over, "[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007). Put another way, "when a patent claims a structure [or method] already known in the prior art that is altered by the mere substitution [ or addition] of one element for [ or to] another known in the field, the combination must do more than yield a predictable result." Id. "[T]he question is whether there is something in the prior art as a whole to suggest the desirability, and thus the obviousness, of making the combination, not whether there is something in the prior art as a whole to suggest that the combination is the most desirable combination available." In re Fulton, 391 F.3d 1195, 1200 (Fed. Cir. 2004) ( citation omitted). The Examiner determined claims 22-34, 36, and 38 would have been obvious over the combination of Hartley and Gnirke. Answer 3-12. Specifically, the Examiner found that, regarding independent claim 22, Hartley disclosed providing a sample with DNA (Hartley Abstract, 2:55:59, 3:12-22, 12:44--51), hybridizing the DNA with RNA (Hartley 13:19-20), capturing the RNA:DNA hybrids with antibodies to form RNA:DNA:antibody hybrids (Hartley 13:25-37; see also Gnirke Fig. 1, ,r,r 17, 68, 95, 108, 153), isolating those hybrids (Hartley Example 4, generally; see also Gnirke ,r 95), and then sequencing the DNA of those hybrids (Hartley 9:30-36). See Answer 3 et seq. (citing Hartley cols. 1-3, 7, 9, 12-13). The Examiner found Hartley did not disclose amplifying the DNA of the RNA:DNA:antibody hybrid before sequencing, but found it 4 Appeal2018-003615 Application 14/397, 733 would have been obvious to look to Gnirke' s similar teachings of providing a DNA sample, hybridizing the DNA with RNA, capturing the RNA:DNA hybrids with antibodies to form RNA:DNA:antibody hybrids, isolating these hybrids, amplifying the DNA of these hybrids, and then sequencing the DNA of the hybrids, for such subject matter. Answer 4 et seq. (citing Gnirke,T,T6,8, 10, 13, 17,31,32,40,41,43,48,86,96, 108,114,123,160, 189, 190, 198,281 (Example 4), Figures 1, 6, 7). The Examiner also made determinations regarding the dependent claims as obvious over Hartley and Gnirke. Answer 5-7 ( citing Hartley and Gnirke ). Regarding claim 35, recognizing that the former prior art combination did not "disclose wherein the DNA molecules are amplified directly on the isolated RNA/DNA/antibody hybrids," the Examiner determined this would have been obvious over the combination of Hartley, Gnirke, and Metzker. Answer 12-14. Specifically, the Examiner found that, although Hartley and Gnirke taught all other claim elements, Metzker was also directed to methods of amplifying/characterizing DNA and taught that DNA could be amplified directly on a solid support hosting an isolated RNA:DNA hybrid, such as the solid beads taught by Hartley and Gnirke. Answer 12-14 (citing Metzker generally, but Figure 1 specifically). Regarding claim 3 7, recognizing that the former combination of prior art did not "teach/disclose wherein RNA is enzymatically digested prior to sequencing," the Examiner determined this subject matter would have been obvious over the combination of Hartley, Gnirke, Metzker, and Kamberov. Answer 14--16. The Examiner found that Kamberov disclosed using RNase H to enzymatically digest RNA and that it would be obvious to do so before 5 Appeal2018-003615 Application 14/397, 733 sequencing DNA as taught by Hartley and Gnirke. Answer 14--16 ( citing Kamberov ,r,r 67, 69, 84, 121,261). Except as otherwise noted below, we agree with and adopt the Examiner's findings of fact and rationale on obviousness. Appellants separately argue the claims in six groups. Therefore, we similarly address the rejected claims. We note that Appellants have defined the person of ordinary skill in the art as follows: "Applicant takes the position that a person with a level of ordinary skill in the art (OSIT A) is a person who has obtained a graduate degree in a biomedical science having laboratory experience in dealing with nucleic acids." Br. 11. This definition is not disputed by the Examiner and, other than the level of skill exemplified by the prior art of record, there is no other identified evidence of record for the definition of the skilled artisan. Therefore, for the purposes of this decision we adopt this definition of the skilled artisan and use it when considering the issue of obviousness. Group I- Claims 22-25, 29-33, 36, and 38 Appellants argue that the prior art combination fails to teach the claimed DNA amplification step before the claimed DNA sequencing step. Br. 11. Appellants argue Hartley teaches amplification of DNA only before any subsequent hybridization steps and does not disclose such amplification after a hybridization step. Id. Appellants argue the skilled artisan would not have been motivated to look to Gnirke for such a teaching because Gnirke discloses that amplification of DNA is not required and teaches benefits of not doing so. Id. at 11-12. Appellants argue Hartley's method does not need amplification or combination with Gnirke because it is so sensitive, i.e., 6 Appeal2018-003615 Application 14/397, 733 able to detect as little as 10 femtograms of DNA without amplification. Id. at 12. These arguments are not persuasive. Contrary to Appellants' contentions (and even the Examiner's finding), Hartley is not silent on amplification after hybridization and before sequencing. Hartley discloses, at Example 4, detecting RNA:DNA:antibody hybrids with ELISA amplification. Hartley 13:36-41. Hartley further discloses that an amplification of about 800-fold was observed in Example 4. Id. at 14:6-7. Hartley also teaches more broadly that RP A-amplified sequences may be purified and the purified products may be subject to further amplification by RP A, which is applicable to the process of Example 4. Id. at 7:58---64. Finally, Hartley discloses "[t]he invention also contemplates the characterization of such amplified molecules ... [f]or example, such amplified molecules can be sequenced ... ," which is also applicable to Example 4. Hartley 9:30-36. Thus, Hartley teaches or suggests the claimed hybridizing DNA to RNA and then to antibodies, isolating that hybrid, and then amplifying the target DNA, which can then be characterized by sequencing. The teachings of Gnirke are not necessarily required for such subject matter, however, Appellants' rationale for not making the combination is not persuasive. As identified by the Examiner, Hartley may teach a highly sensitive method for merely detecting DNA, but this does not mean that such low, femtogram-amounts of DNA could be readily characterized by the process without amplification. Furthermore, although Gnirke does state "that amplification of the nucleic acids is not required," it further states that, "[t ]he ability to select without amplification is important for applications 7 Appeal2018-003615 Application 14/397, 733 that are not compatible with amplification." Gnirke ,r 96. Thus, Gnirke is not dissuading the practitioner from amplifying DNA (to the contrary, Gnirke teaches such amplifying throughout its disclosure), but provides flexibility in case the ultimate DNA-characterization process would be hindered by amplification, which is not the case with Hartley's methods. Appellants argue that because Gnirke teaches amplifying hybridized DNA after elution from magnetic beads, the skilled artisan would not amplify DNA without eluting it from such beads, which means the prior art fails to teach amplification of the DNA in an RNA:DNA:antibody hybrid as claimed. Besides directly contradicting their just-discussed-argument regarding amplification, this is not persuasive. Only claim 35 requires that the DNA be amplified directly on the RNA:DNA:antibody hybrid, and even that claim does not require that the hybrid still be attached to a solid support. Amplifying DNA of a hybrid ( claim 22) is not synonymous with amplifying DNA on a hybrid (claim 35). Independent claim 22 requires amplifying the DNA "of the one or more RNA/DNA/antibody hybrids," but does not require the hybrid to be intact at the amplification, only that the amplified DNA is of that hybrid. Hartley teaches ELISA amplification and teaches or suggests other types of amplification of DNA of its disclosed RNA:DNA:antibody hybrid on magnetic beads, teaching that the beads are washed several times before amplification, but not disclosing removing the DNA. See Hartley 13:25-14: 12. Thus, Gnirke's alleged teaching of elution of DNA before its amplification is not determinative on this issue. Appellants also argue, regarding claims 23-25, 36, and 38, "that Hartley is silent on (A) sequencing with a next generation sequencing 8 Appeal2018-003615 Application 14/397, 733 procedure; (B) the target sequences being selected from exons such as exons of metabolic genes, regulatory genes or oncogenes; and (C) the amplification being done with primers that bind universal adapter sequences as recited in claims 23, 24, 25 or 38." Br. 14. Appellants argue Gnirke's disclosures of next generation sequencing, exons of cancer-related genes, and amplification with universal adapter sequences do not cure such deficiencies. Such argument( s) is not persuasive. The Examiner has identified where Gnirke teaches the relevant subject matter. See Answer 4--7. Gnirke's paragraphs 192 and 198, for example, disclose next generation sequencing. Gnirke ,r,r 192, 198. Gnirke's paragraphs 123 and 160, for example, disclose characterizing DNA for genes involved in cancer. Id. ,r,r 123, 160. Gnirke's paragraph 86, for example, discloses adapters for PCR amplification. Id. ,r 86. As discussed above, it would have been obvious to combine Gnirke and Hartley as they are directed to largely the same methodology for essentially the same purpose. For the reasons above, we are unpersuaded the Examiner erred in determining the claims of Appellants' Group I would have been obvious. Group II-Claim 26 Appellants argue Hartley does not teach or suggest using a DNA fragment library and this defect is not cured by Gnirke. Br. 15. Appellants argue it would not have been obvious to use fragmented DNA in Hartley's methods because Hartley discloses a need for sufficient starting material and a desire for a simple, inexpensive process without needing special equipment. Id. Appellants argue adding a fragmentation step for Hartley's 9 Appeal2018-003615 Application 14/397, 733 non-fragmented DNA adds extra procedures, and imply it would also add expense. Id. at 16. This argument is not persuasive. As discussed above, as determined by the Examiner, it would have been obvious to combine the teachings of Hartley and Gnirke. Once so- combined, commencing the DNA characterization processing may utilize either Hartley's DNA sample source, e.g., a sample of cloned, potentially amplified, HPV 16 DNA, or Gnirke's DNA sample source, e.g., a "pond" library of fragmented genomic DNA. The skilled artisan would reasonably expect to successfully hybridize DNA and RNA, and then hybridize RNA:DNA with antibody, and then isolate and amplify the sample, followed by sequencing, as taught by the references using their methods. We are unpersuaded by Appellants' attorney argument that such a combination would add extra steps or expense to Hartley's process and, thus, be undesirable. "Attorneys' argument is no substitute for evidence." Johnston v. IVAC Corp., 885 F.2d 1574, 1581 (Fed. Cir. 1989). For the reasons above, we are unpersuaded the Examiner erred in determining the claims of Appellants' Group II would have been obvious. Group III- Claims 27 and 28 Appellants argue "claims 27 and 28 further differ[] from Hartley at least in that Hartley does not teach or suggest starting with a DNA fragment library with identical flanking sequences, and the deficiency is not cured by Gnirke." Br. 16. Further, Appellants argue: in the DNA fragments used in the method of Gnirke, the universal adapters at the 5' end of the DNA fragments are different from the universal adaptors at the 3' end of the DNA fragments (see Figs. 1, 6 and 7, Gnirke), so the universal adapters or flanking sequences in the DNA fragments used by Gnirke are 10 Appeal2018-003615 Application 14/397, 733 not identical. Even if the person of ordinary skill in the art were to use the DNA fragment library disclosed by Gnirke as the starting material in Hartley's process, the person would not have arrived at the methods of claims 27 and 28. Id. at 17. The Examiner's response to this argument is that Gnirke teaches "the [DNA] fragments have been ligated to adapter oligonucleotides in order to generate a fragment library with identical flanking sequences ([0040-41]; 2.1 Pond Library Preparation)" and "Gnirke et al disclose the steps of subjecting the DNA to end repair in order to generate double-stranded blunt end fragments or ends with an A-overhang, prior to adapter ligation (2.1 Pond Library Preparation)." Answer 11-12. Considering both Appellants' and the Examiner's positions on this issue, we conclude Appellants hold the stronger position. Looking to Gnirke' s paragraphs 40-41 and disclosure relating to Pond Library Preparation (i1 187), as cited by the Examiner, we find no teaching of the claimed "fragment library with identical flanking sequences." The Examiner has not clearly identified how or why the cited prior art teaches such subject matter, other than the aforementioned citations. Although Gnirke certainly does teach a DNA fragment library, it is not apparent on the record before us that such fragments include "identical flanking sequences." For the reasons above, we are persuaded the Examiner erred in determining the claims of Appellants' Group II, that is, claims 27 and 28, would have been obvious. Group IV-Claim 34 Appellants argue "Hartley does not teach or suggest washing the RNA/DNA/antibody hybrids after the RNA/DNA/antibody hybrids are 11 Appeal2018-003615 Application 14/397, 733 isolated as recited in claim 34" and "Gnirke does not disclose isolating any RNA/DNA/antibody hybrids, and does not disclose washing any RNA/DNA/antibody hybrids after isolation of RNA/DNA/antibody hybrids." Br. 18. Appellants' argument is not persuasive. Hartley discloses purifying target nucleic acid and Gnirke discloses that the "catching" of DNA with an RNA bait and then an antibody, using a moiety and binding molecule, separates the hybridized sequences from the mixture, thereby isolating the RNA:DNA:antibody hybrid. Hartley cols. 7, 12-13; Gnirke ,r 95. Hartley discloses that such captured RNA:DNA:antibody beads are washed several times, then amplified. Hartley cols. 13-14. This teaches or suggests the claimed subject matter. For the reasons above, we are unpersuaded the Examiner erred in determining the claims of Appellants' Group IV would have been obvious. Group V- Claim 35 As noted above, claim 35 is rejected over the prior art combination of Hartley, Gnirke, and Metzker. Appellants argue "Hartley in view of Gnirke does not teach or suggest amplifying the DNA directly on the RNA/DNA/antibody hybrids" and Metzker, relied upon by the Examiner for teaching amplifying DNA on a solid support, "does not disclose or suggest any isolated RNA/DNA/antibody hybrids, let alone disclosing or suggesting amplifying DNA molecules directly on isolated RNA/DNA/antibody hybrids." Br. 18. Appellants' argument is not persuasive. Hartley discloses capturing DNA with RNA via hybridization and then capturing the RNA:DNA hybrid with antibodies on magnetic beads, thus forming an RNA:DNA:antibody hybrid. See Hartley col. 13. This is 12 Appeal2018-003615 Application 14/397, 733 followed by washing and ELISA amplification, and Hartley also suggests following with further amplification by RP A and characterizing by sequencing. See Hartley cols. 7, 9, 13-14. Hartley does not disclose or require de-hybridizing the RNA:DNA:antibody before doing these steps. Neither does Gnirke. Metzker teaches that amplification, such as taught by Hartley, can be performed while such a hybrid is on a solid substrate, such as Hartley's magnetic beads. See Metzker Figure 1 and related disclosure. This teaches or suggests the claimed subject matter. For the reasons above, we are unpersuaded the Examiner erred in determining the claims of Appellants' Group V would have been obvious. Group VI-Claim 37 As noted above, claim 37 is rejected over the prior art combination of Hartley, Gnirke, Metzker, and Kamberov. Appellants argue "Hartley in view of Gnirke and Metzker does not teach or suggest enzymatically digesting RNA after amplifying the DNA molecules in the RNA/DNA/antibody hybrids prior to sequencing the DNA" and "Kamberov does disclose digesting RNA in a RNA/DNA duplex with RNase Hin paragraphs [0067] and [0069]," but "a person of ordinary skill in the art would not have been motivated to modify the process of Hartley in view of Gnirke and Metzker for amplifying DNAs with unknown sequences using random primers, using the disclosures of Kamberov pertaining to the linear transcription based amplification methods for making cDNA from RNA" and "Kamberov is also silent on digesting RNA in an RNA/DNA/antibody hybrid." Br. 20-21. 13 Appeal2018-003615 Application 14/397, 733 In response, the Examiner restates that Kamberov discloses RNA from an RNA/DNA hybrid is enzymatically digested, e.g., with RHase H. Answer 14 (citing Kamberov ,r,r 67, 69,261). Based on this, the Examiner concludes: Id. It would have been obvious to one of ordinary skill in the art to modify the method of Hartley et al and/ or Gnirke et al to comprise a step of enzymatically digesting the RNA from a RNA/DNA hybrid complex prior to sequencing with a reasonable expectation of success because those of ordinary skill in the art have long-recognized and practiced the step of enzymatically digesting the RNA from a RNA/DNA hybrid complex prior to sequencing, e.g. when synthesizing and amplifying cDNA. Considering both Appellants' and the Examiner's positions on this issue, we conclude Appellants hold the stronger position. We do not accept mere conclusory statements by Appellants' attorney to be evidence of non- obviousness nor do we accept mere conclusory statements by the Examiner to be evidence of obviousness. See In re Lindell, 385 F.2d 453, 456 (CCPA 1967) ("Appellant's opinion on the ultimate legal issue is not evidence in the case."); In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006) ("[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."). Here, we conclude that the Examiner has not explained why the skilled artisan, having the cited prior art in hand, would use Kamberov' s enzymatic digestion during the processes described by Hartley and Gnirke, as claimed. Neither 14 Appeal2018-003615 Application 14/397, 733 Hartley nor Gnirke expresses a need to do so and the Examiner has not sufficiently identified one. For the reasons above, we are persuaded the Examiner erred in determining the claim of Appellants' Group VI, that is, claim 3 7, would have been obvious. SUMMARY The obviousness rejection over Hartley and Gnirke is affirmed as to claims 22-26, 29-34, 36, and 38. But, it is reversed as to claims 27 and 28. The obviousness rejection of claim 35 over Hartley, Gnirke, and Metzker is affirmed. The obviousness rejection of claim 37 over Hartley, Gnirke, Metzker, and Kamberov is reversed. 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)(l)(iv). AFFIRMED-IN-PART 15 Copy with citationCopy as parenthetical citation