Ex Parte Mohammed et alDownload PDFPatent Trial and Appeal BoardJan 30, 201411134133 (P.T.A.B. Jan. 30, 2014) 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. 11/134,133 05/19/2005 Mansoor S. Mohammed 034827-3303 1327 22428 7590 01/31/2014 FOLEY AND LARDNER LLP SUITE 500 3000 K STREET NW WASHINGTON, DC 20007 EXAMINER POHNERT, STEVEN C ART UNIT PAPER NUMBER 1634 MAIL DATE DELIVERY MODE 01/31/2014 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 PATENT TRIAL AND APPEAL BOARD ________________ Ex parte MANSOOR S. MOHAMMED, NATASA DZIDIC, CHRISTOPHER MCCASKILL, and JAEWEON KIM1 ________________ Appeal 2012-007014 Application 11/134,133 Technology Center 1600 ________________ Before TONI R. SCHEINER, JOHN G. NEW, and SUSAN L.C. MITCHELL, Administrative Patent Judges. NEW, Administrative Patent Judge. DECISION ON APPEAL 1 The real party-in-interest is Quest Diagnostics Investments Incorporated. Appeal 2012-007014 Application 11/134,133 2 SUMMARY Appellants file this appeal under 35 U.S.C. § 134(a) from the Examiner’s Non-Final Rejection of claims 1-13, 15-29, 33-61, 64-68, and 70-73. Specifically, Claims 1, 2, 19, 34-35, and 60-61 stand rejected under 35 U.S.C. § 102(b) as anticipated by Mark Schena et al., Parallel human genome analysis: Microarray-based expression monitoring of 1000 genes, 93 PROC. NATL. ACAD. SCI. USA 10614 (1996) (“Schena”). Claims 1, 2, 19, 37, and 60-61 stand rejected under 35 U.S.C. § 102(b) as anticipated by Luo (US 2003/0044808 A1, March 6, 2003) (“Luo”). Claims 1-5, 19-29, 33-51, and 57-59 stand rejected under 35 US.C. § 103(a) as being obvious over the combination of Luo, Urdea (US 4,775,619, October 4, 1988) (“Urdea”) alone or in further combination with Brown et al. (U.S. 2002/0115841 A1, August 22, 2002) (“Brown”), Shafer (US 2004/0053275 A1, March 18, 2004) (“Shafer”), Getts (WO 03/012147 A1, February 13, 2003) (“Getts”), Shah et al. (US 2003/0124542 A1, July 3, 2003) (“Shah”), Singh (US 6,514,700 B1, February 4, 2003) (“Singh”), and/or Baker et al. (WO 01/87348 A2, November 22, 2001) (“Baker”). Claims 6-10, 52, and 64-67 stand rejected under 35 U.S.C. § 103(a) as being obvious over Luo in combination with Urdea alone or in combination with Shah and/or Shafer. Claims 11-13 and 15-18 stand rejected under 35 U.S.C. § 103(a) as being obvious over Luo in combination with Urdea alone or in combination with Shafer, Shah, Delenstarr et al. (US 2002/0068293 Al, June 6, 2002) (“Delenstarr”) and/or Getts. Appeal 2012-007014 Application 11/134,133 3 Claims 53-56 stand rejected under 35 U.S.C. § 103(a) as being obvious over Luo in combination with Pinkel et al. (WO 93/18186, September 16, 1993) (“Pinkel”). App. Br. 7. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. NATURE OF THE CLAIMED INVENTION Appellants’ invention is directed to methods of detecting and mapping chromosomal or genetic abnormalities associated with various diseases or with predisposition to various diseases or to detecting the phenomena of large scale copy number variants. In particular, the present invention provides advanced methods of performing array-based comparative hybridization that allow reproducibility between samples and enhanced sensitivity by using the same detectable label for both test sample and reference sample nucleic acids. Invention methods are useful for the detection or diagnosis of particular disease conditions such as cancer, and detecting predisposition to cancer based on detection of chromosomal or genetic abnormalities and gene expression level. Invention methods are also useful for the detection or diagnosis of hereditary genetic disorders or predisposition thereto, especially in prenatal samples. Moreover, invention methods are also useful for the detection or diagnosis of de novo genetic aberrations associated with post-natal developmental abnormalities. Abstract. Appeal 2012-007014 Application 11/134,133 4 GROUPING OF CLAIMS Appellants contend that the same arguments in favor of patentability apply to independent claims 1, 60, and 70.2 App. Br. 16. We therefore select claim 1 as representative of this group. Claim 1 recites: 1. A method for performing comparative hybridization, said method comprising, (i) simultaneously hybridizing test and reference nucleic acids to a single nucleic acid array wherein said array comprises a plurality of individual spots, wherein each spot comprises a plurality of substantially identical nucleic acid probes, and (ii) after step (i), comparing the relative amount of test and reference nucleic acids at a plurality of individual spots as an indication of the comparative hybridization, wherein said test and reference nucleic acids are labeled with an indistinguishable detectable label and a signal from said detectable label is used to determine the amount of hybridization of the test and reference nucleic acids to an individual spot. App. Br. 44. 2 Appellants state that claims 68 and 70-73 are on appeal, but make no separate arguments for them. We consequently affirm the Examiner’s rejection of these claims. Appeal 2012-007014 Application 11/134,133 5 ISSUES AND ANALYSES A. Rejection of claim 1 under 35 U.S.C. § 102(b) as anticipated by Schena Issue Appellants argue that the Examiner erred in finding that Schena anticipates all of the limitations of claim 1. App. Br. 8. We therefore address the issue of whether the Examiner so erred. Analysis Appellants argue that (1) the Examiner erred in interpreting the disclosures of Schena; and (2) that Schena does not disclose making comparisons at individual spots on the array. App. Br. 10-11. According to Appellants, the Examiner erred in finding that the Jurkat cell cDNA and the Arabidopsis cDNA correspond to the test and reference samples, respectively, of claim 1. App. Br. 10. Appellants argue that the Examiner failed to identify where in Schena the hybridization of these two nucleic acid samples are compared and, furthermore, that any direct comparison of the Arabidopsis and Jurkat cell cDNAs would be meaningless because they are drawn from plant and human samples, respectively. Id. Appellants argue further that claim 1 requires: “after step (i), comparing the relative amount of test and reference nucleic acids at a plurality of individual spots as an indication of the comparative hybridization” and that claim 1 therefore requires comparison on a spot-by- spot basis; an element which, Appellants claim, Schena does not disclose. App. Br. 11. Appellants contend that, even if some comparison of the Arabidopsis and Jurkat cDNA hybridization is performed, Schena would necessarily make that comparison across different spots on the array; viz., spots 1-10 for Arabidopsis cDNA and spots 11-1056 for Jurkat cell cDNA. Appeal 2012-007014 Application 11/134,133 6 Therefore, argue Appellants, Schena does not disclose the disputed limitation of claim 1. The Examiner responds that Schena discloses that Arabidopsis mRNA was “doped” in the reverse transcriptase reaction, and the reverse transcriptase reaction was hybridized to the arrays. Ans. 36. The Examiner finds that Schena further discloses scanning the array and thus determining the amount of the hybridized test and reference cDNA in the sample. Id. (citing Schena, p. 10614, 2nd col.; Figure 1). The Examiner finds that Figure 1 of Schena discloses that the color bar was calibrated in separate experiments in which known quantities of Arabidopsis control mRNA was used. Ans. 36. Therefore, finds the Examiner, Schena discloses that Arabidopsis mRNA was spiked into reverse transcription reactions and then hybridized to the arrays, and the known quantities of Arabidopsis mRNA were used to calibrate (or compare) the individual arrays so that a comparison could be made between the different arrays. Id. The Examiner further finds that claim 1 requires “simultaneously hybridizing test and reference nucleic acids to a single nucleic acid array wherein said array comprises a plurality of individual spots, wherein each spot comprises a plurality of substantially identical nucleic acid probes.” Id. The Examiner therefore finds that claim 1 recites no limitation requiring that the test and reference nucleic acid are hybridized to the same spot. Id. The Examiner finds that the rejected claims require a comparison of the relative amounts of test and reference nucleic acids to a plurality of individual spots. Id. The Examiner finds that the “wherein” clause of claim 1 merely indicates the indistinguishable label used allows for the determination of the amount of test and reference nucleic acids at an Appeal 2012-007014 Application 11/134,133 7 individual spot. Id. The Examiner finds that claim 1 does not require that the test and reference nucleic acids are hybridized at a single spot. Id. We are not persuaded by the Examiner’s reasoning. As an initial matter, we find that a plain reading of Schena discloses that the test samples recited in claim 1 correspond to the Jurkat cell mRNA (not cDNA) from either the heat shock- or phorbol ester-treated Jurkat cells and the reference samples are mRNA from the non-treated (control) Jurkat cells. Schena, p. 10614, col. 2 (“Jurkat mRNA was isolated as described by Schena et al. (4). …. Arabidopsis control mRNAs were made by in vitro transcription of cloned HAT4, HAT22, and YesAt-23 cDNAs (4, 8, 9) using an RNA Transcription Kit (Stratagene)”). The Arabidopsis cDNA in the library and the Arabidopsis mRNA probes were used as controls. Id. We disagree with the Examiner’s contention that Jurkat cell or Arabidopsis cDNA was employed as a test or reference sample; rather, we find that Schena discloses the hybridization of the Jurkat cell test and reference mRNAs (and Arabidopsis control mRNA) against a library of 1046 human cDNA clones made with mRNA from human peripheral blood lymphocytes transformed with the Epstein-Barr virus, and 10 Arabidopsis cDNA clones (as controls). Schena, p. 10614, cols. 1-2. However, we find that Schena explicitly teaches that the test and reference Jurkat mRNA probes were hybridized to separate arrays, which were then compared to determine differential gene expression between the test and reference samples. Schena, p. 10615, col. 2 (“Comparative expression analysis of heat shocked versus control cells in the two experiments revealed 17 array elements that displayed altered fluorescence ratios of ≥2.0-fold (Figs. 1 and 24)”). We are not persuaded by the Appeal 2012-007014 Application 11/134,133 8 Examiner’s argument that “[t]he claims do not require that the test and reference nucleic acids are hybridized at a single spot.” Ans. 38. We find, rather, that the limitation of claim 1 reciting “wherein said test and reference nucleic acids are labeled with an indistinguishable detectable label and a signal from said detectable label is used to determine the amount of hybridization of the test and reference nucleic acids to an individual spot” (emphasis added) necessarily requires determining the amount of both test and reference hybridization at an individual spot. The Examiner does not point to, nor can we find, any disclosure of Schena that teaches this requirement. Furthermore, claim 1 expressly requires “wherein said test and reference nucleic acids are labeled with an indistinguishable detectable label.” As Appellants stated on page 9 of their Brief and at oral argument, Schena explicitly teaches that the Jurkat cell test and reference mRNA probes are labeled with different labels: Control (37oC) and heat-treated (43°C) cells were harvested and lysed, and total mRNA from the two cell samples was labeled by reverse transcriptase incorporation of fluorescein- and Cy5- dCTP, respectively. In a second set of labeling reactions, the fluorescent groups were “swapped” such that samples from control and heat-treated samples were labeled with Cy5- and fluorescein-dCTP, respectively. Schena, p. 10615, cols. 1-2. Schena thus teaches that the test and reference nucleic acids are labeled with distinguishable detectable labels (fluorescein- and Cy5-dCTP). Therefore, because we find that Schena does not teach all of the limitations of claim 1, we cannot affirm the Examiner’s rejection of claim 1. Appeal 2012-007014 Application 11/134,133 9 B. Rejection of claim 1 under 35 U.S.C. § 102(b) as anticipated by Luo Issue Appellants argue that the Examiner erred in finding that Luo anticipates all of the limitations of claim 1. App. Br. 12. We therefore address the issue of whether the Examiner so erred. Analysis Appellants argue that the Examiner’s interpretation of “an array” is inconsistent with the Specification and a common-sense reading of Luo. App. Br. 13. According to Appellants, the Examiner first ignores the definitional requirement that an array be confined to “a defined area.” Appellants contend that, under the correct interpretation, each of Luo’s microtiter wells contains a single array because the array elements are contained in a defined area which segregates each sample from the other samples. Id. Appellants argue that although the arrays printed in each of Luo’s wells may be substantially identical, each well contains a different and separate “array” of capture nucleic acids. Id. Appellants argue that Luo thus discloses a plurality of arrays for the parallel processing of multiple samples and that Luo specifically distinguishes his multiple-array microtiter plates from the large-format single arrays typical of those printed, e.g., on microscope slides. App. Br. 13-14. Appellants argue that Luo therefore discloses hybridizing test and reference nucleic acids to two different arrays, each contained in an individual microtiter well, whereas claim 1 requires that the test and reference nucleic acids are hybridized to a single array. App. Br. 14. Appeal 2012-007014 Application 11/134,133 10 Appellants argue that the Examiner erred because Luo hybridizes the test and reference samples to different nucleic acid arrays, and not to the same array as required by the present claims. Therefore, argue Appellants, Luo does not disclose measuring the hybridization of both test and reference nucleic acids to the same (i.e., an individual) spot on a single array as required by claim 1. App. Br. 15. Appellants contend that Luo discloses, at most, comparing test and reference nucleic acid hybridization to different, but equivalent spots across two different arrays. Id. The Examiner responds that Luo discloses that the “KnowledgeWellTM bio grid array” refers to the microtiter plate formatted microarray platform of Applicant’s prior Application, and to the microarrays spotted thereon. Ans. 38 (citing Luo, ¶ [0047]). The Examiner finds that arrays composed of various types of material would be referred to by the type of material in the array, for example, “Bio Grid Array” more generally, but also “Gene Grid Array,” “Protein Grid Array,” “PNA Grid Array,” “Cell Grid Array,” or any other material that would be contained in an array. Ans. 38. The Examiner finds that Appellants’ microtiter plate formatted microarray platform may be, for example, in the footprint of a 96-, 384- or 1536-well microtiter plate. Id. The Examiner finds further that the base of the array, as described in Appellants’ prior application is a glass material and is overlaid with a bottomless plastic material in a grid having wells divided therein and being adhesively bound to the glass base to create wells with plastic walls and glass bottoms. Ans. 38-39. The Examiner also finds that limitation (ii) of the claim, as recited supra, does not specifically require the measuring of both test and reference Appeal 2012-007014 Application 11/134,133 11 nucleic acids at a specific spot, but rather, the comparison of a plurality of individual spots, and that Appellants are therefore reading limitations into the claim that are not explicit in the claim. Ans. 43. As an initial matter, we cannot agree with Appellants’ interpretation of Luo as disclosing that each individual well in the disclosed microtiter microassay plate constitutes an individual array. Appellants’ Specification describes the claim term “array” thus: The term “array” or “microarray” or “biochip” or “chip” as used herein refers to a plurality of elements arranged onto a defined area of a substrate surface. In practicing the methods of the invention, any known array and/or method of making and using arrays can be incorporated in whole or in part, or variations thereof…. Spec., ¶ [0077]. Luo discloses an embodiment of its invention thus: “The base … is a glass material and is overlaid with a bottomless plastic material in a grid having wells divided therein and being adhesively bound to the glass base to create wells with plastic walls and glass bottoms.” Luo, ¶ [0047]. Luo also discloses that: The labeled cDNA samples are then deposited 18 in to the KnowledgeWell™ bio grid array microtiter plate format assay platform 20, on the bottom inner glass surface of each well of which is immobilized an array of various known reagents including genes or portions thereof including DNA or RNA sequences, PNA, polynucleotides or polypeptide biopolymers such as known DNA fragments, cDNA or short oligonucleotides, proteins or polypeptides …. The labeled samples, once deposited in the wells, are then allowed to hybridize with the various immobilized reagents, and any resulting binding is measured by reading the signals from the label in a reader selected based on the label. Analysis is then performed from the various signals using software that acquires and processes the data into information useful for analysis. Appeal 2012-007014 Application 11/134,133 12 Luo, ¶ [0054]. We agree with the Examiner that the “labeled cDNA samples” (i.e., nucleic acid probes), that Luo discloses are deposited on the bottom glass surface of each well, correspond more closely with the “spots” of claim 1, which are also described as the “multiple elements” of the array in the definition provided by Appellants’ Specification. Since there is a plurality of these cDNA spots (one in each well) and a plurality of wells in Luo’s grid array microtiter plate, we find that the grid array microtiter plate disclosed by Luo, corresponds to the Specification’s definition of “array.” Nevertheless, we are not persuaded by the Examiner’s reasoning that claim 1 does not require that both test and reference nucleic acids be hybridized to the same individual spot. As we have related supra, we find that the claim explicitly so requires. The Examiner neither points to, nor can we find, any disclosure of Luo that requires binding by the test and reference nucleic acids to a single spot in the array. We therefore cannot affirm the Examiner’s rejection of claim 1. C. Rejection of claim 1 under 35 U.S.C. § 103(a) Issue Appellants argue that the Examiner erred in finding that Luo together with prior art reference Urdea alone or in further combination with Shafer, Getts, Shah, Singh, Baker and/or Brown teach or suggest the limitations of claim 1. App. Br. 15. We therefore address the issue of whether the Examiner so erred. Appeal 2012-007014 Application 11/134,133 13 Analysis Appellants argue, as they did supra, that Luo neither teaches nor suggests comparing the relative amount of test and reference nucleic acid hybridization at a plurality of individual spots on the single array. Ans. 17. We have related why we agree that Luo neither teaches nor suggests that the test and reference hybridize to a single spot in the array. The question therefore before us is whether any of the remaining references cure that deficiency. 1. Luo and Urdea Appellants argue that Urdea provides methods for detecting specific nucleic acid sequences hybridized to capture nucleic acids on a solid support. App. Br. 18. According to Appellants, Urdea teaches that a detectable label is present on the distal end of either the capture nucleic acid or the probe, such that the label is released via cutting by a restriction enzyme; detection of the “detectable label in the supernatant after treatment with the restriction enzyme implies hybridization of a soluble nucleic acid to the immobilized capture nucleic acid.” Id. Appellants argue that Urdea neither teaches nor suggests hybridizing two different nucleic acid samples (e.g., test and reference samples) to a single nucleic acid array, wherein each sample is labeled with the same detectable label. App. Br. 18-19. Appellants also contend that Urdea assesses the detectable label associated with only one nucleic acid sample; there is no indication in Urdea to assess two different samples hybridized to a single array. Appeal 2012-007014 Application 11/134,133 14 The Examiner responds that Urdea teaches or suggests the use of more than one cleavage site. Ans. 47. The Examiner finds that Urdea teaches that there can be at least one recognition site common to the probe and the sample polynucleotide, which can be digested with a restriction enzyme, thus releasing the probe from the support. Id. (citing Urdea, col. 7, ll. 41-44). We are persuaded by Appellants’ reasoning that Urdea does not teach or suggest hybridizing both test and reference nucleic acid samples to a single spot on the array. As such, it does not overcome the deficiency of Luo. We therefore decline to affirm the Examiner’s rejection of claim 1 on this ground. 2. Shafer Appellants argue that the Examiner relies on Shafer to demonstrate that detectable labels may be attached to nucleic acids via dendrimers and that labeling may be done either before or after array hybridization. App. Br. 19. Appellants contend that nothing in Shafer teaches or suggests a method in which two different nucleic acid samples (e.g., a test and a reference sample) are hybridized to a single nucleic acid array and the comparative hybridization assessed using an indistinguishable detectable label. We agree with Appellants that the teachings and suggestions of Shafer do not cure the deficiencies of Luo cited supra. We therefore reverse the Examiner’s rejection of claim 1 on this ground. Appeal 2012-007014 Application 11/134,133 15 3. Getts Appellants argue that Getts provides a method for probing target nucleic acids captured on a nucleic acid array by adding two labeled probes in series rather than simultaneously. App. Br. 20. According to Appellants, Getts teaches hybridizing target nucleic acids to an array and visualizing the complex using a detectably-labeled probe; the probe is then stripped from the array, with a confirmation measurement to ensure complete stripping, and the array-bound nucleic acids are visualized again using a second detectably-labeled probe. Id. Appellants contend that Getts neither teaches nor suggests hybridizing two different nucleic acid samples (e.g., test and reference samples) to a single nucleic acid array; nor, Appellants argue, does Getts suggest determining the comparative hybridization of two different nucleic acid samples at individual spots on an array using an indistinguishable detectable label. Id. According to Appellants, Getts merely provides a serial probe labeling technique as an alternative to the traditional simultaneous labeling methods. Id. We agree with Appellants that Getts does not cure the deficiencies of Luo cited supra. We therefore reverse the Examiner’s rejection of claim 1 on this ground. 4. Shah Appellants argue that the Examiner relies on Shah to demonstrate the standard technique of comparative genomic hybridization. App. Br. 20-21. According to Appellants, the basic technique involves hybridizing two nucleic acid samples (usually a test and reference sample) to a nucleic acid Appeal 2012-007014 Application 11/134,133 16 array. App. Br. 21. Each of the samples is detectably labeled to visualize and measure the amount of hybridization of the respective samples to individual array spots. Id. Appellants argue that Shah teaches that different detectable labels must be used in order to distinguish between the two samples during detection. Id. We agree with Appellants that the teachings and suggestions of Brown do not cure the deficiencies of Luo cited supra. We therefore reverse the Examiner’s rejection of claim 1 on this ground. 5. Singh and Baker The Examiner finds that the Office Action of January 25, 2011 fails to disclose a rejection in which Luo is used as a primary reference in a rejection with Singh and/or Baker and concludes that Appellants’ arguments are therefore moot. We agree with the Examiner that, lacking a rejection based on these grounds, Appellants’ argument is moot. However, because the deficiencies of Luo remain uncured, we do not affirm the Examiner’s rejection of claim 1 on the previously-stated ground. 6. Brown Appellants argue that the Examiner relies on Brown for teaching pH- sensitive linkers, and in particular linkers that are cleaved upon exposure to a hydroxyl radical (i.e., under basic condition). App. Br. 22. According to Appellants, the teachings of Brown are not materially different than those of Urdea and/or Baker which also disclose cleavable linkers, and that nothing in Brown remedies the fundamental deficiencies of Luo. Appeal 2012-007014 Application 11/134,133 17 We agree with the Examiner that the teachings and suggestions of Brown do not cure the deficiencies of Luo cited supra. We therefore reverse the Examiner’s rejection of claim 1 on this ground. 7. Delenstarr Appellants argue that the Examiner relies on Delenstarr as teaching that background signals may be subtracted from target signals to determine the amount of target signal on a nucleic acid array. App. Br. 36. Appellants argue that Delenstarr is not relevant to the use of a single, indistinguishable detectable label for assessing hybridization of two samples to a single spot. Id. We agree with Appellants that the teachings and suggestions of Delenstarr do not cure the deficiencies of Luo cited supra. We therefore reverse the Examiner’s rejection of claim 1 on this ground. D. Rejection of the remaining claims under 35 U.S.C. §§ 102(b) and 103(a) Appellants argue that the Examiner erred in rejecting the remaining claims for the same reasons as with respect to claim 1 argued supra. App. Br. 16, 24, 32, 40. We agree. With respect to the rejection of independent claim 60 under 35 U.S.C. § 102 as being anticipated by Luo, we reverse the Examiner’s rejection for the same reasons that we have related supra with respect to the rejection of claim 1 on this ground. With respect to the remaining claims depending on independent claims 1 and 60 we reverse the Examiner’s rejections for the same reasons that we have related supra with respect to the rejection of claim 1. Appeal 2012-007014 Application 11/134,133 18 DECISION The Examiner’s rejection of claims 1, 2, 19, 34-35, 37, and 60-61 under 35 U.S.C. § 102(b) is reversed. The Examiner’s rejection of claims 1-13 15-29, 33-59, and 64-67 under 35 U.S.C. § 103(a) is reversed. REVERSED cdc Copy with citationCopy as parenthetical citation