90010867 (B.P.A.I. Aug. 2, 2012)

Ex Parte 5670633 et al

Board of Patent Appeals and InterferencesAug 2, 2012

90010867 (B.P.A.I. Aug. 2, 2012)

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. 90/010,867 02/18/2010 5670633 ISIS-0407RE 3548 32650 7590 08/02/2012 WOODCOCK WASHBURN LLP CIRA CENTRE, 12TH FLOOR 2929 ARCH STREET PHILADELPHIA, PA 19104-2891 EXAMINER PONNALURI, PADMASHRI ART UNIT PAPER NUMBER 3991 MAIL DATE DELIVERY MODE 08/02/2012 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 ISIS Pharmaceuticals, Inc. Appellant ____________ Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 Technology Center 3900 ____________ Before RICHARD E. SCHAFER, RICHARD M. LEBOVITZ, and RAE LYNN P. GUEST, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL This is a decision on appeal by the Patent Owner from the Patent Examiner’s rejections of pending claims in an ex parte reexamination of U.S. Patent No. 5,670,633.1 The Board’s jurisdiction for this appeal is under 35 U.S.C. §§ 6 and 134. We affirm. 1 Issued September 23, 1997 to Cook et al. Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 2 STATEMENT OF THE CASE A request for ex parte reexamination of U.S. Patent 5,670,633 (hereinafter, “the ‘633 patent) was made by a Third Party Requester on February 18, 2010 pursuant to 37 C.F.R. § 1.510. A Final Rejection rejecting pending claims 1 and 3-5 was mailed by the Examiner on February 17, 2011. Patent Owner appealed the Examiner’s adverse decision to the Board of Patent Appeals and Interferences. Notice of Appeal, dated June 17, 2011. In the Appeal Brief, Patent Owner stated that claims 4 and 5 were withdrawn from the appeal. App. Br. 2. Pursuant to M.P.E.P. § 1215.03, the Examiner stated that the withdrawal of the appeal as to claims 4 and 5 operated as an authorization to cancel these claims from the reexamination proceeding and canceled the claims. Answer 2. In their subsequent response to the Examiner’s Answer, Patent Owner did not challenge the propriety of the Examiner’s action. See Reply Br. dated November 23, 2011. We therefore treat claims 4 and 5 as canceled. An oral hearing was held June 20, 2012. A written transcript of the hearing will be entered into the record in due course. The Examiner rejected the claims as follows: 1. Claims 1 and 3 under 35 U.S.C. § 103(a) as obvious over either Ohtsuka (1984)2 or Ikehara (1984)3 in combination with Fazakerley,4 2 Eiko Ohtsuka et al., Recognition by Restriction Endonuclease EcoRI of Deoxyoctanucleotides Containing Modified Sugar Moieties, 139 Eur. J. Biochem. 447 (1984). Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 3 Ohtsuka (1980),5 Kakiuchi6 and Uesugi7 as evidence, and further in view of the ‘633 patent specification disclosure (Background of Invention) as an admission; and 2. Claims 1 and 3 under 35 U.S.C. § 103(a) as obvious over the combination of Inoue (1987),8 Ohtsuka (1984), Ikehara (1984), and Ikehara (1977)9 and further in view of Kakiuchi and Uesugi. Claim 1 is representative and reads as follows: 1. An oligonucleotide that hybridizes with RNA or DNA, having 12 to 40 covalently-bound nucleosides that individually include a ribose or deoxyribose sugar portion and a base portion, wherein: said sugar portions of said nucleosides are joined together by 3'-5' internucleoside linkages such that the base portions of said nucleosides form a mixed base sequence that is 3 Morio Ikehara, 2’-Substituted 2’-Deoxypurinenucleotides Their Confirmation And Properties, Vol. 21 No. 1 Heterocycles 75 (1984). 4 G.V. Fazakerley et al., A → Z Transition in the Synthetic Hexanucleotide (dCdGfl)3, Vol 182 No. 2 FEBS Letters (2394) 365 (1985). 5 E. Ohtsuka, et al., Elongation of oligonucleotides in the 3’-direction with activated mononucleotides and their analogs using RNA ligase, Vol. 8 No. 3 Nucleic Acids Res. 601 (1980). 6 Nobuko Kakiuchi et al., Polynucleotide Helix Geometry and Stability, Vol. 257 No. 4, J. Bio. Chem. 1924 (1982). 7 Seiichi Uesugi et al., Synthesis and Characterization of the Dinucleoside Monophosphates Containing 2’-Fluoro-2’-Deoxyadenosine, 20 Biochem. 3056 (1981). 8 Hideo Inoue et al., Synthesis and Hybridization Studies On Two Complementary Nona(2’-O-methyl)Ribonucleotides, Vol. 15 No. 15 Nucleic Acids Res. 6131 (1987). 9 Morio Ikehara et al., Polynucleotides. L. Synthesis and Properties of Poly (2’-Chloro-2’-Deoxyadenylic Acid) and (Poly 2’-Bromo-2’-Deoxyadenylic Acid), Vol. 4 No. 12 Nucleic Acids Res. 4249 (1977). Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 4 complementary to an RNA base sequence or to a DNA base sequence; and at least two of said nucleosides include a 2'-deoxy-2' fluororibofuranosyl moiety; and wherein a duplex formed between said oligonucleotide and its complement exhibits greater thermal stability than does a duplex formed between said complement and an oligonucleotide that does not include 2'-fluoro substituents. REJECTION 1 Claim 1 Claim 1 is the only independent claim on appeal. Claim 1 is drawn to oligonucleotides “having 12 to 40” nucleoside units, where at least two of the units have “2'-deoxy-2'-fluororibofuranosyl moiety.” Nucleosides contain a nitrogen base10 and a deoxyribose or ribose sugar.11 A nucleoside unit having a “2'-deoxy-2'-fluororibofuranosyl moiety” is one where the hydrogen at the 2’ position of the deoxyribose sugar is replaced with a fluorine. For shorthand, we also refer to this fluorine nucleoside derivative as the “fluororibose derivative” or the “2’- fluorine substituted nucleoside.” The claimed oligonucleotide is recited as a “mixed base sequence that is complementary to an RNA base sequence or to a DNA base sequence” which “exhibits greater thermal stability than does a duplex formed between said complement and an oligonucleotide that does not include 2'-fluoro substituents.” 10 The nucleoside bases are: A (adenine), T (thymine), C (cytosine), G (guanine), or U (uracil). 11 The term “nucleotide” is also used herein; a nucleotide additionally comprises a phosphate group. Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 5 The term “mixed” is not defined in the ‘633 patent. We interpret it to mean that the oligonucleotide is not a homopolymer comprising the same nucleoside unit, but rather is a heteropolymer having at least two different nucleosides units (e.g., where the base is A, T, C, or G) combined (“mixed”) together to form a sequence of nucleosides in a single strand. The term “duplex” in the claim has its ordinary and customary to mean that two complementary oligonucleotide strands are hybridized together to form a double-stranded structure. Issues There are two key issues in this appeal. First, whether a person of ordinary skill in the art would have had a reason to make a mixed oligonucleotide having 12-40 nucleosides with two of them containing a fluororibose sugar? Second, whether the disclosure in Ohtsuka (1984) of a duplex comprising a fluororibose derivative with a reduced melting temperature is a teaching away from the claimed invention when the prior art of record is considered as a whole? Findings of Fact (“Findings”) Ohtsuka (1984) 1. Ohtsuka (1984) synthesized mixed oligonucleotides of eight nucleotides in length, each containing one 2'-deoxy-2'-fluororibose unit. Page 447, “Materials and Methods.” Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 6 • Endonuclease cleavage 2. Ohtsuka (1984) described cleavage with the endonuclease EcoRI of deoxyoctanucleotides (“octamers”) containing aA, Afl, Gfl,12 and rA, i.e. d(G-G)-aA-d(A-T-T-C-C), d(G-G-A-Afl-T -T-C-C), d(G-Gfl-A-A-T-T-C- C), and d(G-G)-rA-d(A-T-T-C-C). Each octamer is self-complementary and can therefore hybridize together to form a duplex. The duplexes of each were recognized by the enzyme less efficiently in the order of aA > Afl > rA. Page 447, first column. 3. Another analog, containing 2' -deoxy-2'-fluoroguanosine at the second position d(G-Gfl-A-A-T-T-C-C), was found to be cleaved faster by EcoRI than d(G-G-A-A-T-T-C-C). Page 447, first column. • Thermal stability 4. Thermal stability of the octamer duplexes was measured by melting temperature. The higher the melting temperature, the more stable the octamer. Table 1, reproduced below, shows that the octamer comprising Afl was less stable as a duplex than octamers comprising dA and aA, Page 449, column 1, Table 1. 12 “Afl” is a nucleotide with adenine as the nitrogen base and a fluorine at the 2’ position of the ribose sugar; “Gfl” is a nucleotide with guanine as the nitrogen base and a fluorine at the 2’ position of the ribose sugar. Both are the fluororibose derivatives of the claimed invention. Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 7 Ikehara (1984) • tRNA 5. Ikehara (1984) described synthesizing tRNA of undisclosed length with Afl (“dAf”) for further study (i.e., “[u]sing these fluorine-containing tRNA, several studies for investigating tRNA structure are expected.”). Page 84-85. • Endonuclease cleavage 6. Ikehara (1984) describe preparation of octamers comprising Gfl (“dGfl”) and found it was cleaved twice as fast as corresponding octamer with the naturally occurring dG at the same position. Another octamer containing Afl at the third position was digested at less than half the rate of the parent octamer. Pages 85-86. • mRNA 7. Ikehara (1984) prepared poly(dAfl) and showed that it “was an especially good messenger compared to poly(rA).” Page 87. Ikehara did not appear to disclose the size of the poly(dAfl). Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 8 Kakiuchi 8. Kakiuchi synthesized homopolymers (dIfl)n and (dCfl)n of undisclosed length.13 Page 1925, column 1. 9. Kakiuchi also synthesized copolymers (rI, dIfl)n of undisclosed length. Page 1925, column 1. • Thermal stability 10. Kakiuchi studied the thermal stability of duplexes of oligonucleotides comprising fluororibose. Kakiuchi found: “The substitution of either strand of (rI)n · (rC)n by fluororibose containing one has the same stabilizing effect on Tm (+11 °C) and this effect is even accentuated, if both strands contain the fluorine substitution (+17 °C) (Table II).” Page 1926, column 1, “Thermal Stability.” 11. Kakiuchi concluded: “The results presented here strongly support the original suggestion [reference omitted] that the polarity of the 2’- substituent plays a key role in the stability and structure of double helices.” Page 1928, first column, 2nd ¶. • Interferon induction 12. Interferon Induction—Interferon induction has been studied extensively with various substituted (rI)n · (rC)n duplexes (40). 13 “Ifl” is a nucleotide with inosine as the nitrogen base and a fluorine at the 2’ position of the ribose sugar; “Cfl” is a nucleotide with cytosine as the nitrogen base and a fluorine at the 2’ position of the ribose sugar. Both are the fluororibose derivatives of the claimed invention. Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 9 It has already been established that (dIfl) n · (rC) n is an excellent interferon inducer in a variety of systems, including in rabbits (39). This observation is confirmed by the present results (Table III), but, in addition, we have also found (rI) n · (dCfl) n to be an effective inducer of interferon in primary rabbit kidney cells. On the other hand, the duplex with both strands fluorinated, i.e. (dIfl)n · (dCfl) n failed to induce interferon. Page 1927, first column. Fazakerley • DNA conformation 13. Fazakerley studied the DNA conformation of synthetic hexanucleotide (dCdGfl)3, an oligonucleotide mixed base copolymer which comprised three nucleotides that each contain a fluororibose sugar. Page 365, second column; page 368, second column. Ohtsuka, 1980 • RNA ligase 14. Ohtsuka studied the addition of adenosine analogs, including Afl, to the 3’ end of an oligonucleotide using RNA ligase. Page 606-607. Uesugi 15. Uesugi prepared three A-A dimer analogues containing dAfl and A residues: dAfl-dAfl, dAfl-A, and A-dAfl. Abstract. Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 10 • Thermal stability 16. Uesugi taught that dimers containing Afl significantly increased the stability of duplexes as compared to the same duplex with the naturally occurring A: Interaction with Poly(uridylic acid). All three dimers containing 2’-fluoro group form complexes with poly(U) at 0.8°C. The mixing curves for dAfl-dAfl, dAfl-A, and A-dAfl with poly(U) (Figure 7) show that complex formation occurs with a stoichiometry of 2U·1A. As shown in Figure 8, the complexes of poly(U) with dimers with the 2’-fluoro group exhibit a thermal transition with a sufficiently defined melting temperature (Tm). The Tm values of dAfl-dAfl·2poly(U), dAfl- A·2poly(U), and A-dAfl·2poly(U) are 13, 9, and 7°C, respectively. A significant increase in thermal stability of dAfl- dAfl-2poly(U) complex is observed as compared to A- A·2poly(U) (Tm was 7 °C under the same conditions). At present, it is not clear whether the 3’-endo preference or the presence of fluorine atom itself has anything to do with the increased thermal stability of the dAfl-dAfl-poly(U) complex. Uesugi, page 3060, col. 2. Discussion The difference between the claimed invention and the cited prior art is that the cited prior art does not expressly disclose a mixed oligonucleotide having 12-40 nucleosides that contains at least two nucleosides having a fluororibose sugar. Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 11 Reason to make an oligonucleotide having 12-40 nucleosides and comprising at least two fluororibose sugars The evidence provided by the Examiner shows that the prior art was replete with nucleic acids14 comprising fluororibose sugars, including nucleic acids comprising at least two fluororibose sugars as claimed: • Mixed base oligonucleotides of eight bases in length containing one fluororibose derivative (Findings 1-3 & 6; Ohtsuka, 1984; Ikehara, 1984); • Mixed base oligonucleotides of six bases in length containing three fluororibose derivative (Finding 13; Fazakerley); • Homopolymers of fluororibose derivatives of undisclosed length (Findings 7 & 8; Ikehara, 1984; Kakiuchi); • Copolymers of mixed fluororibose derivatives of undisclosed length (Finding 9; Kakiuchi); and • tRNAs of undisclosed length comprising at least one fluororibose derivatives (Finding 5; Ikehara, 1984). • Dimers comprising two fluororibose derivatives (Finding 15; Uesugi). At least five different properties of the fluororibose containing nucleic acids were studied: 1) sensitivity to endonuclease cleavage (Findings 2, 3, 6); 2) thermal stability (Findings 4, 10, 16); 3) ability to induce interferon (Finding 12); 4) DNA conformation (Finding 13); and 5) RNA ligase activity (Finding 14). Thus, the evidence establishes that oligonucleotides comprising 2’-fluorine substituted nucleosides were recognized as useful 14 We use the term “nucleic acids” to encompass oligonucleotides, copolymers, homopolymers, and tRNA in either single-stranded or double- stranded form. Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 12 research tools to study the properties of nucleic acids, providing a person of ordinary skill in the art reason to have made them for such purposes. While the prior art might not have explicitly taught mixed base oligonucleotides having 12 to 40 base units as claimed, size does not appear to be a critical factor since homopolymers, copolymers, and tRNA’s of undisclosed size had been produced and studied. Findings 5, 7, 8, & 9. Persons of ordinary skill in the art clearly recognized that fluororibose containing nucleic acids of varying lengths were useful for any of the purposes described in the prior art, irrespective of size. Thus, the choice of an oligonucleotide having 12 to 40 base units would have been a routine matter of selecting a desired length as taught in the prior art. Patent Owner complained that the Examiner did not provide a reason for selecting the claimed oligonucleotide size range with two or more fluororibose substitutions. App. Br. 11; Reply Br. 2. This argument is unpersuasive. The evidence cited by the Examiner established nucleic acids of 6 and 8 nucleotides in length, and homopolymers, copolymers, and tRNA of undisclosed length comprising 2’-deoxy-fluorine substituted oligonucleotides had been described in the cited prior art. A broad genus of nucleic acids comprising fluororibose nucleotides was thus taught in the cited prior art, a teaching broad enough to include the claimed narrower class of oligonucleotides. Patent Owner did not invent oligonucleotides comprising at least two fluororibose derivatives (see Findings 7, 8, 9, 13, & 15), yet is attempting to withdraw from the public domain the narrower class of oligonucleotides Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 13 having 12-40 nucleotides when it has not been shown that this class has any properties or advantages over the broader class. The law is replete with cases in which the difference between the claimed invention and the prior art is some range or other variable within the claims. These cases have consistently held that in such a situation, the applicant must show that the particular range is critical, generally by showing that the claimed range achieves unexpected results relative to the prior art range. In re Woodruff, 919 F.2d 1575, 1578 (Fed. Cir. 1990). (Internal citations omitted.) Patent Owner is not justified in bringing the Examiner to task for not identifying a specific reason for choosing an oligonucleotide 12-40 nucleotides in length. Reply Br. 2. As discussed already, a broad genus of oligonucleotides with 2’-fluorine substituted nucleosides was taught in the prior art, making any size within it obvious. Patent Owner has not even distinguished in the Appeal Brief the claimed oligonucleotides from the copolymers and tRNA disclosed in the prior art (Findings 5, 9, & 12). Patent Owner provided a written declaration by Dr. Brian Stephen Sproat in support of the patentability of the claims. Dr. Sproat has a D. Phil. degree and states that he is experienced in the synthesis and biochemistry of oligonucleotides, the pertinent field of the claimed invention. Sproat Decl. ¶ 1. Dr. Sproat is therefore qualified as expert in this proceeding. Dr. Sproat testified in his declaration that it would not have been obvious to combine the cited prior art because the purposes disclosed in the publications are so disparate and different synthetic techniques were utilized. Sproat Decl. ¶¶ 8 & 9; App. Br. 10. Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 14 This argument is not persuasive. The Examiner cited six different publications which describe fluororibose substituted nucleic acids (Ohtsuka, 1984; Ikehara, 1984; Kakiuchi; Fazakerley; Ohtsuka, 1980; Uesugi), indicating that such compounds were well-established research tools. The substituted nucleic acids had been used in various experiments, all aimed at determining their properties. All six publications involve fluororibose substituted nucleic acids, and therefore person of ordinary skill in the art would have reasonably considered them all relevant to the claimed oligonucleotides of the same type. Teaching away Patent Owner contends that Ohtsuka (1984) teaches away from the claimed invention. App. Br. 9 & 13. “Under the proper legal standard, a reference will teach away when it suggests that the developments flowing from its disclosures are unlikely to produce the objective of applicant’s invention. A statement that a particular combination is not a preferred embodiment does not teach away absent clear discouragement of that combination.” Syntex (USA) LLC v. Apotex, Inc., 407 F.3d 1371, 1380 (Fed. Cir. 2005) (internal citations omitted). In support, Patent Owner relied upon Dr. Sproat’s testimony in his written declaration: Although the Office Action contends that it would have been obvious to introduce additional 2'-F groups into the oligonucleotides that the Ohtsuka 1984 reference and the Ikehara reference disclose, the actual teaching of the Ohtsuka 1984 reference is directly to the contrary, and indicates that adding such 2'-F groups is something that those of ordinary Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 15 skill in the art would have wanted to avoid. The Ohtsuka 1984 reference, for example, teaches that introduction of a 2'-F group into d(G-G-A-A-T-T-C-C) actually reduced the extent to which the resulting compound (i.e., d(G-G-Af-A-T-T-C-C)) was able to hybridize with a complementary oligomer. In fact, the authors reported that the melting temperature of the mono-2'-F oligomer was as much as 3.8 °C lower than the corresponding 2'-H molecule (see, e.g., Table 1 on page 449). Given this disclosure, I believe that a person of ordinary skill seeking to develop “[a]n oligonucleotide that hybridizes with. RNA or DNA” (as claimed in the 633 Patent) would have concluded that 2'-F groups are something to be avoided, and that even the single 2'-F group found in the disclosed oligomers was one too many due to the adverse effect it appeared to have on hybridization. Sproat Decl. ¶ 7. Dr. Sproat is correct that Ohtsuka (1984) showed that an octamer comprising Afl was less stable as a duplex than octamers comprising dA and aA. Finding 4. However, Dr. Sproat did not acknowledge in his declaration the additional teachings in the cited prior art on the thermal stability of duplexes comprising oligonucleotides with fluororibose derivatives. Kakiuchi taught that “substitution of either strand of (rI)n · (rC)n by fluororibose containing one has the same stabilizing effect on Tm (+11 °C) and this effect is even accentuated, if both strands contain the fluorine substitution (+17 °C) (Table II).” Finding 10. The fluororibose containing strand referred to by Kakiuchi is a homopolymer of fluororibose derivatives. Finding 8. Uesugi taught that dimers containing Afl significantly increased the stability of duplexes as compared to the same duplex with the naturally occurring A. Finding 16. Thus, Dr. Sproat’s opinion that a person of ordinary skill in the art “would have concluded that 2’-F groups are Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 16 something to be avoided” (Sproat Decl. ¶ 7) is not consistent with the evidence as a whole, since each of Kakiuchi and Uesugi teach thermal stability of duplexes can be enhanced with fluororibose derivatives. Moreover, the inventors appear to have admitted in the ‘633 patent that fluororibose derivatives significantly stabilized duplex DNA: M. Ikehara et al., Nucleic Acids Res. 5:3315 (1978) show that a 2'-fluorine substituent in poly A, poly I, and poly C duplexed to their U, C, or I complement are significantly more stable than the ribo or deoxy poly duplexes as determined by standard melting assays. ‘633 patent, col. 3, ll. 47-52. Dr. Sproat did not address this statement in the ‘633 patent nor the cited Ikehara (1978) publication. We therefore do not find Patent Owner’s argument about a teaching away persuasive since, when the prior art of record is considered as a whole, the evidence does not establish that fluororibose derivatives would be “unlikely to produce the objective of applicant’s invention.” Syntex, 407 F.3d at 1380. In sum, it is not evident that Dr. Sproat, in rendering his opinion, considered all the evidence in the record of thermal stability of duplexes comprising 2’-fluorine substituted nucleosides. Rather, Dr. Sproat seemed focused on only one publication. Patent Owner contends that teachings with a homopolymer would not be relevant to a mixed based oligonucleotide as claimed.15 However, Kakiuchi generalized its teachings about the stabilizing effect of its fluororibose derivatives to “double helices” (Finding 11) and thus did not restrict its teaching as narrowly as argued by Patent Owner’s representative. 15 Oral Hearing Transcript, pp. 20-21. Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 17 In sum, there is sufficient evidence to establish that one of ordinary skill in the art would have reasonably expected that an oligonucleotide of the claimed size, with two or more fluororibose substituents, could be produced with greater thermal stability in duplex form than the same oligonucleotide lacking such substituents. Each of Ohtsuka (1984), Kakiuchi, and Uesugi teach that oligonucleotides could be routinely screen for greater thermal stability when complexed in a duplex as claimed. While Ohtsuka (1984) would indicate that not all substituted oligonucleotides would have enhanced stability, “[o]bviousness does not require absolute predictability of success.” In re O'Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988). Kakiuchi and Uesugi expressly establish that oligonucleotides with such properties could be made. Thus, when the evidence is considered as a whole, Ohtsuka’s teachings would not have deterred a person of ordinary skill in the art from making the claimed oligonucleotides. REJECTION 2 Rejection 2 is based on prior art which overlaps with Rejection 1. In this rejection, the Examiner cited Inoue for teaching that 2'-O-methyl- ribonucleotides have higher thermal stability compared to oligonucleotides which do not have the modified nucleotides. Answer 7. The Examiner recognized that Inoue does not teach oligonucleotides comprising 2'- fluororibose derivatives as claimed, but determined that it would have been obvious to one of ordinary skill in the art to have substituted them for the 2'- O-methyl-ribonucleotides of Inoue to impart thermal stability. Answer 8. We shall affirm the rejection for the reasons given by the Examiner. Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 18 Patent Owner contends that it would not have been obvious to have replaced the 2'-O-methyl-ribonucleotides of Inoue for a nucleoside with a fluororibose derivative because of Ohtsuka (1984)’s teaching that the latter have “negative consequence.” App. Br. 13. We addressed this argument in Rejection 1, concluding that in further view of Kakiuchi, Uesugi, and the admissions in the ‘633 patent, persons of ordinary skill in the art would have had reason to utilize 2'-fluororibose derivatives as claimed. SUMMARY We affirm the Rejections 1 and 2 of claim 1. Claim 3 was not argued separately and therefore falls with claim 1. 37 C.F.R. § 41(c)(1)(vii). TIME PERIOD FOR RESPONSE Requests for extensions of time in this ex parte reexamination proceeding are governed by 37 C.F.R. § 1.550(c). See 37 C.F.R. § 41.50(f). AFFIRMED ack Appeal 2012-005595 Reexamination Control 90/010,867 Patent 5,670,633 19 cc: Patent Owner: WOODCOCK WASHBURN LLP CIRA CENTRE, 12TH FLOOR 2929 ARCH STREET PHILADELPHIA, PA 19104-2891 Third Party Requester DANN, DORFMAN, HERRELL & SKILLMAN 1601 MARKET STREET SUITE 2400 PHILADELPHIA, PA 19103-2307