UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD

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2 UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte CHARLES ALLERSON, BALKRISHEN BHAT, ANNE B. ELDRUP, MUTHIAH MANOHARAN, RICHARD H. GRIFFEY, BRENDA F. BAKER, and ERIC E. SWAYZE Appeal Technology Center 1600 Before DEMETRA J. MILLS, RICHARD M. LEBOVITZ, and MELANIE L. McCOLLUM, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL This appeal involves claims to a composition for use in gene modulation comprising a double-stranded oligonucleotide having alternating 2 -modified nucleosides. The Examiner has rejected the claims as obvious and on the ground of obviousness-type double patenting. We have jurisdiction under 35 U.S.C We affirm.

3 I. STATEMENT OF THE CASE Claim 36, the only independent claim on appeal, is directed to a double-stranded oligonucleotide in which at least one strand comprises two different 2 -substituted nucleosides which are alternated with one another. Claims 36, 44, 46-49, 52-64, 74-80, 93, , and 106 are pending and stand rejected by the Examiner as follows: 1. Under 35 U.S.C. 103(a) as obvious over Elbashir, 1 Giese, 2 Fosnaugh, 3 and Morrissey 4 in view of the combined teachings of Arnold, 5 Damha, 6 and McKay On the ground of nonstatutory obviousness-type double patenting as obvious over claims 4, 5, 34, 37, 38,46,49-51, 53-63, 72, 74-78, 94-96, 104, and 105 of copending Application No. 10/701,007 ( the 007 application ). This is a provisional rejection as the 007 application claims have not been patented. 3. On the ground of nonstatutory obviousness-type double patenting as obvious over claims of copending Application No. 11/054,848 ( the Elbashir et al., Functional anatomy of sirnas for mediating efficient RNAi in Drosophila melanogaster embryo lysate, 20 (23) The EMBO Journal (2001). 2 Giese et al., US 2004/ A1, published Sep. 16, Fosnaugh et al., US 2003/ A1, published Jul. 31, Morrissey et al., US 2003/ A1, published Nov. 6, Arnold, Jr. et al., US 6,262,036 B1, issued Jul. 17, Damha et al., US 2005/ A1, published Jun. 30, McKay et al., US 6,133,246, issued Oct. 17,

4 application ). This is a provisional rejection as the 848 application claims have not been patented. Appellants did not provide arguments as to Grounds 2 and 3. Consequently, we summarily affirm these rejections. The 007 application, upon which Ground 2 is based, is subject to Appeal which has concurrently been decided with this appeal. The 848 application upon which Ground 3 is based, is subject to Appeal which has concurrently been decided with this appeal. An oral hearing was held December 12, A transcript will be entered into the record in due course. Claim 36 is the only independent claim on appeal which is pending and reads as follows: 36. A composition comprising first and second chemically synthesized oligomeric compounds, wherein: the first oligomeric compound is fully complementary to and capable of hybridizing to the second oligomeric compound and to a selected nucleic acid target; each of the first and second oligomeric compounds independently comprises from 17 to 23 nucleosides; the first oligomeric compound comprises a contiguous sequence of linked nucleosides that define an alternating motif of the formula: 5'-Q(-L-Z-L-Q) n (-L-Z) nn -3' wherein: each L is an internucleoside linking group; each Q is a 2'-substituted nucleoside wherein each of the 2'-substituent groups are the same and are other than H or OH; each Z is a 2'-substituted nucleoside wherein each of the 2'-substituent groups are the same and are other than H or OH and are also other than the 2'-substituent groups of each Q; and n is from 8 to 14 and nn is 0 or 1. II. OBVIOUSNESS REJECTION 1 3

5 The Examiner rejected the claims over a combination of prior art publications: Elbashir, Giese, Fosnaugh, and Morrissey in view of Arnold, Damha, and McKay. The first group of publications (Elbashir, Giese, Fosnaugh, and Morrissey) describe sirna duplexes. SiRNA (silencing RNA) is a doublestranded RNA (a duplex ) that had been found in the prior art to specifically and potently disrupt the activity of genes which contain sequences homologous to the sequences in the sirna. Spec. 3: 0008 & 4: Claim 36 encompasses sirna double-stranded molecules. The second group of publications (Arnold, Damha, and McKay) describe single-stranded antisense RNA. Single stranded antisense oligonucleotides are also known to disrupt gene activity, but by a different mechanism than double stranded sirna. Answer 18. The Examiner determined that the sirna prior art described various 2 modifications of the ribose sugar of the constituent nucleotides, but not an alternating motif as recited in claim 36 in which two different 2 -substituted nucleosides are alternated with one another. Answer 8: However, the Examiner found that the antisense oligonucleotide prior art described oligonucleotides comprising alternating 2'-modified nucleosides and the advantages of such modifications with respect to enhanced target binding stability, target binding, and uptake. Id. at 8-9. The Examiner determined it would have been it would have been obvious to one of ordinary skill in the art to have modified the prior art sirna with the teaching of the singlestranded antisense oligonucleotide prior art in order to enhance their binding and stability. Id. at 9: 14 to 10:7 4

6 App. Br. 7. III. APPELLANTS ARGUMENTS One skilled in the art could not determine from the description provided in Elbashir whether, for example, incorporation of one or more 2' - substituents anywhere in an sirna duplex would result in active molecules, because the only 2' -substituentcontaining duplex tested in the experiments described in Elbashir was inactive in RNAi. The full 2 'O-methyl compounds described in Elbashir, for example, likely have improved stability and affinity for a target RNA, but they are reported to have no activity, thus making them unsuitable for use as sirnas. App. Br. 12. App Br. 8. App. Br. 9. The Giese application, however, does not describe with particularity sirna molecules having alternating 2' modifications, and, accordingly, provides no information regarding the stability and inhibitory activity of such sirna molecules. Fosnaugh and Morrissey describe vast genuses of chemical modifications and broadly discuss oligonucleotides comprising any number of such modifications [but]... do not describe with any particularity the effect that different motifs of modifications have on sirna activity, nor do they teach ways of designing and optimizing chemically modified sirnas. Single stranded antisense RNA reduces gene activity through a pathway that requires RNase H activity. App. Br. 12. The RNAi [sirna] and RNAse H-dependent pathways [used for anti-sense RNA] for reducing target RNA are sufficiently different that there would have been no reason for those skilled in the art to have believed at the time of the invention that the types and patterns of chemical modifications beneficial for the 5

7 substrates utilized in one pathway would be also be beneficial for the substrates utilized in the other. App. Br. 13. The claimed invention was not obvious to try because the number of possible modifications is not finite, but rather there was a vast number of choices and the efficacy of sirna was not reasonably predictable at the time of invention. App. Br. 18. IV. FINDINGS OF FACT The findings of fact ( FF ) are numbered below. The first time a finding appears, the corresponding numeral is in bold and bracketed. V. DISCUSSION Claim 36 is directed to a composition comprising first and second oligomeric compounds. The first oligomeric compound is fully complementary and capable of hybridizing to the second oligomeric compound. The first oligomeric compound comprises a contiguous sequence of linked nucleosides that define an alternating motif of specifically recited formula. The formula specifically defines a sequence of alternating nucleosides Q and Z, where each nucleoside is substituted at the 2 position of the ribose sugar and the 2 -substituents are different for Q and Z. Appellants arguments focus on the alleged large number of choices in the cited prior art necessary to have made the claimed sirna molecule and the lack of predictability and direction from the cited sirna or singlestranded antisense prior art. 6

8 The fact is that Giese teaches sirna which comprise an alternating motif, including two different alternating 2 -modified nucleosides. We reproduce the relevant passages from Giese below which establish this fact (emphasis added). [FF1] ( 0065) FIG. 2 illustrates some embodiments of the ribonucleic acid molecules of the present invention with patterns of modified and unmodified groups of nucleotides which are also referred to herein as a pattern of modification. The modified groups of nucleotides are also referred to herein as a group of modified nucleotides. The unmodified nucleotides or unmodified groups of nucleotides referred to as flanking group(s) of nucleotides herein, as used herein may also have one or several of the modification(s) as disclosed herein which, however, is/are different from the modification of the nucleotides forming the group(s) of modified nucleotides. [FF2] ( 0116)... The term unmodified nucleotide as used herein means either not having any of the aforementioned modifications at the nucleotide forming the respective nucleotide or group of nucleotides, or having a modification which is different from the one of the modified nucleotide and group of nucleotides, respectively. [FF3] ( 0124) In a particular embodiment of this aspect of the present invention the interfering ribonucleic acid subject comprises two strands, whereby a 2'-O-methyl modified nucleotide and a non-modified nucleotide, preferably a nucleotide which is not 2'-O-methyl modified, are incorporated on both strands in an alternating fashion, resulting in a strand having a pattern MOMOMOMOM etc where M is a 2'-Omethyl nucleotide and O is a non-modified nucleotide. In paragraph 124 (FF3), Giese describes an alternating pattern of modified and unmodified nucleotides. In paragraphs 65 (FF1) and 116 (FF2), Giese teaches that an unmodified nucleotide may have a 7

9 modification which is different from the modification of the modified nucleotide. Thus, Giese clearly describes sirna with a motif of alternating modified nucleotides [FF4]. Modifications are described in paragraph 24 at the 2 -position of the nucleotide [FF5] so the alternating pattern described by Giese clearly includes alternating different 2 -modified nucleotides as claimed [FF6]. For this reason, we do not agree with Appellants that the Giese application... does not describe with particularity sirna molecules having alternating 2' modifications. App. Br. 8. It is true that Elbashir teaches that complete substitution of one or both strands of sirna with 2 -O-methyl substituted nucleotides (a 2 modification) abolished its gene silencing activity and that this is the only teaching in Elbashir of the effect of 2 -O-methyl substitution on sirna activity. Elbashir, Figure 3 at p. 6882; p. 6886, col. 2, ll. 6-10; App. Br. 7. However, Elbashir is not the only prior art teaching of sirna with 2 - modifications. First, as already discussed, Giese teaches 2 -modified nucleotides incorporated into sirna. Figures and 15 of Giese show various sirnas with internal 2 -O-methyl substituted nucleotides which had gene silencing activity (Answer 7): [FF7] ( 0076) FIG. 12 shows that alternating 2'-O-methyl modification result in activity of the modified RNAi molecules compared to unmodified forms.... As may be taken therefrom RNAi molecules with alternating modifications are stabilized against endonuclease degradation and active in mediating a PTEN protein knock down. [FF8] ( 0079) FIG. 15 shows that sirna molecules with distinct 2'-O-methyl ribonucleotides modifications show increased stability in serum and mediate protein knock-down in HeLa cells. 8

10 Second, Fosnaugh also describes sirna comprising nucleotides with 2 -modified nucleotides: [FF9] ( 0018]) The sense region of a sirna molecule can comprise one or more (e.g., about 1, 2, 3, 4, 5, or more) 2'-Omethyl modified pyrimidine nucleotides. [FF10] ( 0019) The antisense region of a sirna molecule can comprise one or more (e.g., about 1, 2, 3, 4, 5, or more) 2'- deoxy-2'-fluoro modified pyrimidine nucleotides. [FF11] As shown in Figure 4 reproduced below, Fosnaugh also discloses examples of sirna with all pyrimidine nucleotides that may be present [as] 2'-O-methyl modified nucleotides except for (N N) nucleotides and all pyrimidine nucleotides that may be present [as] 2'-deoxy-2'-fluoro modified nucleotides except for (N N) nucleotides. Fosnaugh, p. 16, 145. {Figure 4 shows examples of sirnas with 2 modified nucleotides}. Thus, while it may be true that the prior art did not explicitly teach with any particularity the effect that different motifs of modifications have on sirna activity (App. Br. 9), the doubt that 2 modifications could be 9

11 incorporated into biologically active sirna would have been dispelled by the explicit teachings of Giese and Fosnaugh of sirna comprising a variety of different 2 -modifications, including 2'-O-methyl modifications (FF7 & FF8) and an alternating motif (FF1-FF7). And contrary to Appellants contention that the prior art did not teach ways of designing and optimizing chemically modified sirnas (App. Br. 9), both Giese and Fosnaugh teach how to design sirnas and test them for activity. Fosnaugh, Examples 3, 5, and 6; Giese, Examples 1, 7, 8 and 9 [FF12]. Appellants contend that well-established differences in the mechanisms between sirna and single-stranded antisense activity would have deterred one of ordinary skill in the art from applying antisense teachings to sirna. However, the Examiner noted that the types of linkages and modifications described in the sirna art originated in the antisense prior art (Answer 18: 4-6), providing clear evidence that one of ordinary skill in the art looked to the antisense art for sirna modifications that could be routinely tested using sirna assays, e.g., as taught by Fosnaugh and Giese. Obviousness is not determined by a rigid test, but rather is predicated upon the totality of the evidence. In this case, where there are teachings of biologically active sirna comprising 2 -modifications (FF7; FF8; Answer 7), including alternating motifs (FF1-FF6; FF7), a person of ordinary skill in the art would have had reason to have made the claimed sirna and a reasonable expectation that such sirna would be active. The only information that could be seen to militate against such conclusion is Elbashir s teaching that a strand wholly made of one type of 2 -modified nucleosides is inactive. But this teaching is countered by the express 10

12 disclosure in Giese of 2 -modified sirna with gene silencing activity (FF7 & FF8) and the routineness of testing for active sirna constructs as evidenced by both Giese and Fosnaugh. As far as arguments as to the number of possible choices, the claims are not limited to particular 2 -modified nucleosides; the claims only require the nucleosides are different from each other. Giese clearly teaches different alternating nucleosides (F1F1-FF6). For the foregoing reasons, we affirm the obviousness rejection 1 of claims 36, 44, 46-49, 52-64, 74-80, 93, , and 106. Since the claims were not argued separately, they fall together. We also summarily affirm obviousness rejections 2 and 3 of claims 36, 44, 46-49, 52-64, 74-80, 93, , and 106. 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 (a). AFFIRMED alw 11