Ex Parte COLLARD et alDownload PDFPatent Trial and Appeal BoardAug 31, 201814629768 (P.T.A.B. Aug. 31, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. 14/629,768 92397 7590 OPKO Health, Inc. FILING DATE 02/24/2015 09/05/2018 4400 Biscayne Boulevard Miami, FL 33137 FIRST NAMED INVENTOR JOSEPH COLLARD 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. CURN00112 D01 7093 EXAMINER CHONG, KIMBERLY ART UNIT PAPER NUMBER 1674 NOTIFICATION DATE DELIVERY MODE 09/05/2018 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): patents@opko.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte JOSEPH COLLARD and OLGA KHORKOV A SHERMAN 1 Appeal2017-009105 Application 14/629,768 Technology Center 1600 Before JOHN G. NEW, CHRISTOPHER G. P AULRAJ, and RICHARD J. SMITH, Administrative Patent Judges. NEW, Administrative Patent Judge. DECISION ON APPEAL 1 Appellants state that the real party-in-interest is Cuma, Inc. App. Br. 1. Appeal2017-009105 Application 14/629,768 SUMMARY Appellants file this appeal under 35 U.S.C. § 134(a) from the Examiner's Final Rejection of claims 18, 19, 23, 25-27, 29, 32, and 33 2, which stand rejected as unpatentable under 35 U.S.C. §§ 102(e) and 103(a) as being anticipated by, and obvious over, Zhou (US 7,250,289 B2, July 31, 2007) ("Zhou"). Claims 18, 19, 23, 25-27, 29, 32, and 33 also stand rejected under 35 U.S.C. § 103(a) as being obvious over the combination of Zhou and T.T. Nikiforov et al., The Use of Phosphorothioate Primers and Exonuclease Hydrolysis for the Preparation of Single-Stranded PCR Products and Their Detection by Solid-Phase Hybridization, 3 PCR METHODS APPL. 285-91 ( 1994) ("Nikiforov"). We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. NATURE OF THE CLAIMED INVENTION Appellants' invention is directed to antisense oligonucleotides that modulate the expression of and/or function of Sialidase 4 (NEU4). Abstract. 2The Examiner also includes claims 31, 34, 35, and 36 in the Final Rejection. Final Act. 1. The Examiner only objects to these claims as being dependent upon a rejected base claim, but indicates that they would be allowable if rewritten in independent form, including all of the limitations of the base claim and any intervening claims. Id. at 3. Because the claims are objected to by the Examiner, but not expressly included in the grounds of rejection, we do not reach these claims. See 37 C.F.R. § 4I.31(c). 2 Appeal2017-009105 Application 14/629,768 REPRESENTATIVE CLAIM Claim 18 is representative of the claims on appeal and recites: A synthetic, modified oligonucleotide of 10 to 30 nucleotides in length comprising at least one modification wherein the at least one modification is selected from: at least one modified sugar moiety; at least one modified intemucleotide linkage; at least one modified nucleotide, and combinations thereof; wherein said oligonucleotide is an antisense compound which specifically hybridizes to a human natural antisense polynucleotide of the Sialidase 4 (NEU4) gene and upregulates the function and/or expression of a Sialidase 4 (NEU4) gene in vivo or in vitro as compared to a normal control. App. Br. 15. ISSUES AND ANALYSES We are persuaded by, and expressly adopt, the Examiner's findings, reasoning, and conclusions establishing that Appellants' claims are prima facie anticipated by, or obvious over, the cited prior art. We address the arguments raised by Appellants below. A. Rejection of claims 18, 19, 23, 25-27, 29, 32, and 33 under 35 U.S.C. §§ 102(e) and 103(a) over Zhou Issue Appellants argue that the Examiner erred because the structure recited in Zhou is not identical, or substantially identical, to that of the claims and there is therefore no presumption that the claimed properties or functions of the claimed oligonucleotides are inherently found in the prior art teachings. App. Br. 4. 3 Appeal2017-009105 Application 14/629,768 Analysis Appellants argue that Zhou discloses compositions that are substantially different from the claimed oligonucleotides, and that there is no basis to suggest that the probe disclosed in Zhou would specifically hybridize to the NEU4 natural antisense polynucleotide. App. Br. 5. According to Appellants, the claim term "specifically hybridize" requires that the oligonucleotide have sufficient complementarity to the natural antisense polynucleotide so as to upregulate the expression of the NEU4 gene. Id. Appellants point out that, in the composition of Zhou cited by the Examiner, there are two base pair mismatches. Id. Appellants contend that modification of the probes and arrays disclosed in Zhou would not lead to the claimed modified oligonucleotides. App. Br. 5. Appellants assert that there is no requirement for Appellant to provide additional data or results when, in fact, no evidence has been provided by the Examiner that the products disclosed in the prior art reference are identical or similar to the claimed oligonucleotides. Id. Appellants maintain that there is no inherent anticipation nor any presumption of inherency between any products disclosed in Zhou and the claimed oligonucleotides of the instant invention. Id. Appellants argue that Zhou discloses a method of genetic analysis of mouse genes utilizing sequences in such a manner as to make them available for a variety of analyses as probes. App. Br. 6. Appellants note that, in one embodiment, the nucleic acids disclosed therein (well over a million) are provided on an array as probes to detect and measure the expression of at least 30,000 mouse genes. Id. Appellants assert that there is not a single reference to any one of the million probes being used as a therapeutic or as 4 Appeal2017-009105 Application 14/629,768 an individual drug or pharmaceutical composition or as being useful separate and apart from its use in combination with the other probes on an array. Id. Appellants argue that these disclosures are not identical or substantially similar to any of Applicant's claimed compositions. Id. Appellants assert that there is no disclosure of Zhou that any of the probes' described therein were made. Id. Appellants dispute the Examiner's finding that one of the probes utilized in Zhou to test for mouse genes (SEQ ID NO: 68942) was substantially similar to one of oligonucleotides disclosed Appellant's Specification (SEQ ID NO: 9). 3 App. Br. 6. Appellants contend that the Examiner finds that that this alignment demonstrates that Zhou discloses an oligonucleotide that meets the structural limitations of Appellants' claims. Id. However, Appellants argue, Zhou does not disclose any oligonucleotide that is similar to or identical to Appellants' claimed composition. Id. Furthermore, Appellants assert, there is no basis to suggest that the hypothetical probe of Zhou referenced by the Examiner is complementary to, and would specifically hybridize with, Appellants' recited natural antisense polynucleotide. Id. at 7. Appellants further object to the fact that the Examiner used a database to find sequence similarities between potential target sequences of mouse genes and their claimed oligonucleotide. App. Br. 8. According to Appellants, such use "is a long way from finding anticipatory prior art, especially with the facts as provided herein." Id. Appellants argue that 3 SEQ ID NO: 9, without substitutions, is recited as a limitation in claims 31, 34, 35, and 36. However, as we note in fn.2 supra, those claims are not included in the rejections, but are objected to by the Examiner. 5 Appeal2017-009105 Application 14/629,768 using a portion of a sequence used as a potential probe in a mouse gene array and comparing it to a portion of a claimed oligonucleotide does not support a conclusion that Appellants' claimed invention is anticipated or obvious. Id. Appellants next point to SEQ ID NO: 68942, which the Examiner has selected from the disclosures of Zhou as anticipating Appellants' claimed invention. App. Br. 8. Appellants assert that the probe disclosed by Zhou has four different oligonucleotides on the 5' side, two mismatches in the sequence cited by the Examiner, two different oligonucleotides on the 3' end and is therefore a different (i.e., non-identical) molecule. Id. Appellants contend that, absent hindsight, there is no reason that a person of ordinary skill in the art would choose or create an isolated oligonucleotide from the sequences shown in Zhou. Id. at 8-9. Appellants also note that Zhou discloses arrays having many probes on the array to test for mouse genes. App. Br. 9. Appellants point out that Zhou teaches that these probes are selected from almost one million specifically identified target sequences as recited in the sequence listing provided in Zhou. Id. Appellants assert that there is no basis to suggest that any one of the actual probes or probes on an array would specifically hybridize to a natural antisense polynucleotide of a NEU4 gene. Id. Furthermore, argue Appellants, Zhou discloses that the polymers attached to such solid substrates uses include gene expression monitoring, profiling, library screening, genotyping and diagnostics. Id. Appellants assert that there is no basis to suggest that the product disclosed in Zhou and the product claimed in the present application arc identical, or even similar. Id. The Examiner responds that claim 18 is directed to a synthetic oligonucleotide having a modification, wherein the oligonucleotide is 10 to 6 Appeal2017-009105 Application 14/629,768 30 nucleotides in length comprising at least one modification. Ans. 10. The Examiner finds the claims further require the oligonucleotide is an antisense compound which specifically hybridizes to a human natural antisense polynucleotide of the NEU4 gene and upregulates the function and/or expression of the gene. Id. The Examiner finds that the oligonucleotide probe disclosed by Zhou meets the definition of an oligonucleotide as defined by Appellants' Specification and structurally meets the requirements of the claims. Ans. 11. The Examiner finds further that oligonucleotides disclosed by Zhou can be modified, and thus meets the definition of a modified oligonucleotide as defined by the Specification. Id. With respect to Appellants' argument that the Examiner employed "some software" used to find the sequence, a database of publically available prior art sequences is routinely used to search any claimed sequence in a patent application by the Examiners at the USPTO. Ans. 11. As is usually done, the Examiner conducted a search of the claimed sequence in a publically available database of sequences known in the prior art, the Publication Site for Issued and Published Sequences (PSIPS), available at: seqdata.uspto.gov (last visited August 23, 2016). Id. The Examiner observes that the composition of claim 18 is a modified oligonucleotide of 10 to 30 nucleotides in length that is capable of hybridizing to a natural antisense polynucleotide of a NEU4 gene. Ans. 11. Therefore, the Examiner finds, any oligonucleotide sequence that is between 10 and 30 nucleotides in length and is complementary, as defined by the instant specification, to a natural antisense polynucleotide of a NEU4 gene will structurally meet the limitations of the instant claims. The Examiner 7 Appeal2017-009105 Application 14/629,768 notes that the claims on appeal do not require the oligonucleotide to be 100% complementary to the claimed target polynucleotide nor do they require a specific modification of the oligonucleotide. Ans. 11-12. The Examiner selected one of the exemplary oligonucleotides defined in Appellants' Specification as being capable of hybridizing to a natural antisense polynucleotide of a NEU4 Gene (SEQ ID No: 9) and conducted a search against the database of publically available prior art sequences and found a match with SEQ ID No: 68942 of Zhou. The alignment of the two sequences are depicted below: SEQ 9 SEQ 68942 1 GGCAGATTCAGGGCATGGG 1.9 I f I l I I l I I I I f I l I I I 5 GGCAGATTTAGGGCATGAG .23 Alignment of SEO ID NO: 9 of Appellants' Specification and SEO ID NO: 68942 as disclosed by Zhou The Examiner finds that SEQ ID NO: 68942 of Zhou is 25 nucleotides in length, and that 17 of the nucleotides are identical to SEQ ID NO: 9. Ans. 12. The Examiner finds that Zhou discloses that the oligonucleotide can comprise modifications such as peptide nucleic acids, or have modified bases and linkages other than phosphodiester. Id. (citing Zhou col. 6). The Examiner acknowledges that Appellants' argument that Zhou does not disclose SEQ ID NO: 9 because SEQ ID NO: 9 is modified with LNA (as disclosed in Table 1 of the Specification) is correct. Ans. 13. However, the Examiner points out that the rejection does not find that Zhou discloses SEQ ID NO: 9 per se. Rather, the Examiner finds that Appellants' rejected claims do not require that specific modification of the oligonucleotide. Id. Therefore, the Examiner finds, SEQ ID NO: 68942 of 8 Appeal2017-009105 Application 14/629,768 Zhou meets the structural limitations of Appellants' claimed oligonucleotide. Id. The Examiner concludes that because the oligonucleotide disclosed by Zhou meets the structural requirements of the claims, and because Appellants' SEQ ID NO: 9 is substantially identical in structure with Zhou's SEQ ID NO: 68942, a prima facie case of anticipation has been established and the activity of the oligonucleotide of Zhou, i.e., upregulating the function and/or expression of target polynucleotide of a NEU4 gene, is presumed inherent due to the identity of the structures. Ans. 15. We are not persuaded by Appellants' arguments. We understand the gravamen of Appellants' arguments to be that, because SEQ ID. NO: 68942 of Zhou is not identical to SEQ ID NO: 9 of Appellants' Specification, it is therefore unlikely to be capable of performing the required function of claim 18 reciting: "wherein said oligonucleotide is an antisense compound which specifically hybridizes to a human natural antisense polynucleotide of the Sialidase 4 (NEU4) gene and upregulates the function and/or expression of a Sialidase 4 (NEU4) gene in vivo or in vitro as compared to a normal control." We do not find this argument persuasive. As the Examiner has pointed out, the rejected claims4 do not require that the claimed modified oligonucleotide have the sequence of SEQ. ID NO: 9, but, rather, that it consists of "10 to 30 nucleotides in length comprising at least one modification wherein the at least one modification is selected from: at least 4 See fn.3 supra. 9 Appeal2017-009105 Application 14/629,768 one modified sugar moiety; at least one modified intemucleotide linkage; at least one modified nucleotide, and combinations thereof." See claim 18. Zhou discloses: An "oligonucleotide" or "polynucleotide" is a nucleic acid ranging from at least 2, preferably at least 8, 15 or 20 nucleotides in length, but may be up to 50, 100, 1000, or 5000 nucleotides long or a compound that specifically hybridizes to a polynucleotide. Polynucleotides of the present invention include sequences of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) or mimetics thereof which may be isolated from natural sources, recombinantly produced or artificially synthesized. Zhou col. 6, 11. 13-24. 5 Zhou further discloses that the oligonucleotides can be modified as recited in the claims: As used herein, a probe may include natural (i.e. A, G, U, C, or T) or modified bases (7-deazaguanosine, inosine, etc.). In addition, a linkage other than a phosphodiester bond may join the bases in probes. Modifications in probes may be used to improve or alter hybridization properties. Thus, probes may be peptide nucleic acids in which the constituent bases are joined by peptide bonds rather than phosphodiester linkages. Id. at 11. 34--41. We therefore agree with the Examiner that Zhou discloses synthetic, modified oligonucleotides that meet the structural requirements recited in claim 18. The only remaining issue before us, then, is whether Zhou's SEQ ID NO: 68942, which meets the structural requirements of the claims, can "specifically hybridize[ ] to a human natural antisense polynucleotide of the Sialidase 4 (NEU4) gene and upregulate[] the function and/or expression of 5 Zhou also discloses that: "'[p]olynucleotide' and 'oligonucleotide' are used interchangeably in this application." Zhou col. 6, 11. 28-29. 10 Appeal2017-009105 Application 14/629,768 a Sialidase 4 (NEU4) gene in vivo or in vitro as compared to a normal control," as required by the claims. Appellants' Specification does not expressly define the claim term "specifically hybridizes," but relevantly discloses that: It is understood in the art that the sequence of an oligomeric compound need not be 100% complementary to that of its target nucleic acid to be specifically hybridizable. Moreover, an oligonucleotide may hybridize over one or more segments such that intervening or adjacent segments are not involved in the hybridization event ( e.g., a loop structure, mismatch or hairpin structure). The oligomeric compounds of the present invention comprise at least 70%, or at least about 75%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 99% sequence complementarity to a target region within the larger nucleic acid sequence to which they are targeted. For example, an antisense compound in which 18 of 20 nucleotides of the antisense compound are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity. Spec. ,r 49 ( emphasis added). Table 1 of Appellants' Specification further discloses a series of nucleotide sequences capable of hybridizing to, and modulating the expression of, ofNEU4, including SEQ ID NO: 9: fohte 1: As can be observed from Table 1, there is considerable variety of nucleotide sequences that, in addition to that of SEQ ID NO: 9, are capable of modulating expression and/or function ofNEU4. See also Spec. ,r,r 122- 128. Appellants' identify, inter alia, SEQ ID NO: 9 of their Specification as 11 Appeal2017-009105 Application 14/629,768 being capable of specifically hybridizing to, and upregulating the expression and/or function of, NEU4. The portion of Zhou's SEQ ID NO: 68942 identified by the Examiner differs from the nucleotide sequence of Appellants' SEQ ID NO: 9 by two base pairs of 19, as depicted supra, or almost 90% complementarity. Given the Specification's disclosure that the nucleotide sequence of the oligonucleotide need not be 100% complementary to the target sequence of NEU4, and can be as low as 70% (see Spec. ,r 49), and given the variability of sequences capable of specifically hybridizing to, and modulating the expression of, NEU4 (see SEQ ID NO: 8-11), we find that the Examiner has made a prima facie showing that SEQ ID NO: 68942, which is nearly identical to SEQ ID NO: 9, would inherently have the same properties of modulating the expression ofNEU4. Therefore, the burden shifts to Appellants to show that SEQ ID NO: 68924 does not have the same modulatory properties of SEQ ID NO: 9: Where, as here, the claimed and prior art products are identical or substantially identical, or are produced by identical or substantially identical processes, the PTO can require an applicant to prove that the prior art products do not necessarily or inherently possess the characteristics of his claimed product. ... Whether the rejection is based on "inherency" under 35 U.S.C. § 102, or "prima facie obviousness" under 35 U.S.C. § 103, jointly or alternatively, the burden of proof is the same, and its fairness is evidenced by the PTO' s inability to manufacture products or to obtain and compare prior art products. In re Best, 562 F.2d 1252, 1255 (C.C.P.A. 1977). Appellants have not provided any evidence of record to meet their burden of showing that SEQ ID NO: 68942 does not have the same property of being able to modulate 12 Appeal2017-009105 Application 14/629,768 the expression and/or activity ofNEU4 that is exhibited by their claimed compounds. We consequently agree with the Examiner that the claims are anticipated by Zhou, and we affirm the Examiner's rejection of the claims under 35 U.S.C. § 102(e). Furthermore, because the claims are anticipated, they are also obvious under 35 U.S.C. § 103(a). See In re Kalm, 378 F.2d 959, 962 (C.C.P.A. 1967) ( anticipation is the epitome of obviousness). We therefore affirm the Examiner's rejection of the claims on this ground. B. Rejection of claims 18, 19, 23, 25-27, 29, 32, and 33 under 35 U.S.C. § 103(a) over Zhou and Nikiforov Appellants make the same arguments with respect to this rejection that they presented in Section A, contending that the teachings ofNikiforov do not cure the alleged deficiencies of the disclosures of Zhou. We have explained our reasoning why we agree with the Examiner's findings and conclusion that the claims are anticipated and obvious over Zhou, and we incorporate that reasoning with respect to this rejection. We consequently affirm the Examiner's rejection of the claims under 35 U.S.C. § 103(a). DECISION The Examiner's rejection of claims 18, 19, 23, 25-27, 29, 32, and 33 under 35 U.S.C. §§ 102(e) and/or 103(a) is affirmed. The Examiner's rejection of claims 18, 19, 23, 25-27, 29, 32, and 33 under 35 U.S.C. § 103(a) is affirmed. 13 Appeal2017-009105 Application 14/629,768 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 14 Copy with citationCopy as parenthetical citation