Ex Parte Sampson et alDownload PDFBoard of Patent Appeals and InterferencesDec 18, 200910324409 (B.P.A.I. Dec. 18, 2009) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES ____________ Ex parte JEFFREY R. SAMPSON, ROBERT A. ACH, and PAUL WOLBER ____________ Appeal 2009-015422 Application 10/324,409 Technology Center 1600 ____________ Decided: December 18, 2009 ____________ Before ERIC GRIMES, LORA M. GREEN, and RICHARD M. LEBOVITZ, Administrative Patent Judges. LEBOVITZ, Administrative Patent Judge. DECISION ON APPEAL This is a decision on the appeal by the patent applicants from the rejection of claims 1-50. The Board’s jurisdiction for this appeal is under 35 U.S.C. §§ 6(b) and 134. We affirm. Appeal 2009-015422 Application 10/324,409 STATEMENT OF THE CASE “Naturally occurring ribonucleic acid (RNA) and deoxyribonucleic (DNA) acid molecules contain nucleotides which are capable of forming base pairs through hydrogen bond interactions with complementary nucleotides” (Spec. 1). Intramolecular base pairing between complementary nucleotides in a single molecule of DNA or RNA results in the formation of secondary structures, such as loops, duplexes, hairpin structures, three-way junctions, and four-way junctions (Spec. 2). Secondary structure in a nucleic acid molecule can interfere with hybridization of complementary nucleic acid molecules, limiting “the sensitivity, specificity and utility of applications that rely upon hybridization of probes used to analyze nucleic acid molecules” (id.). These applications include in situ hybridization, DNA array technology, and gene expression assays (id.). To address the aforementioned problems, the instant application is said to provide nucleic acid molecules which contain modified nucleotide bases which do not form stable hydrogen bonds with each other, but which base pair with their natural complements (id. at 4-5; see Fig. 1). Examples include 2-aminoadenosine for adenine and 2-thiothymidine for thymine (id. at 8). The nucleic acids which contain the modified nucleotides have reduced secondary structure because of the absence of intramolecular base pairing and are referred to by the inventors as “unstructured nucleic acids” or “UNAs.” The modified nucleotides are called “UNA nucleotides” because they impart reduced secondary structure when incorporated into a nucleic acid. This is the second time this application has been before us. A previous Appeal (2007-2963) was decided October 31, 2007 (“Decision” or 2 Appeal 2009-015422 Application 10/324,409 “Dec.”) in which we affirmed the rejections of claims 1-3, 5-7, and 9-50, reversed the rejection of claims 4 and 8, and set forth a new ground of rejection over claims 4 and 8. Appellants amended the claims (Feb. 1, 2008) following the Decision. Subsequently, Appellants filed a Request for Continued Examination (“RCE”; filed Jul. 18, 2008) in response to a Final Rejection in which the Examiner had rejected the amended claims as obvious over the Kutyavin and Vivekananda references and over copending application No. 10/423,199 (Mar. 20, 2008). This appeal is from the Examiner’s rejections in the RCE. Claims 1-50, which are all the pending claims, stand rejected. Appellants seek review of the following rejections: Claims 1-50 under 35 U.S.C. § 103(a) as obvious in view of Kutyavin et al. (U.S. Pat. No. 5,912,340, issued Jun. 15, 1999) and Vivekananda et al. (U.S. Pat No. 6,569,630 B1, issued May 27, 2003) (Ans. 4); and Claims 1-18 on the ground of nonstatutory obviousness-type double patenting as unpatentable over claims 1 and 3-9 of copending Application Serial No. 10/423,199 (Ans. 4-5). Claim 1, which is representative, is reproduced below: 1. A first single-stranded unstructured nucleic acid molecule with reduced secondary structure relative to a nucleic acid molecule of substantially identical nucleotide sequence having naturally occurring nucleotides, wherein said molecule possesses at least two sequence elements each of at least three contiguous nucleotides that are complementary to one another, wherein said complementary sequence elements have reduced levels of base- pairing stability relative to a nucleic acid molecule of substantially identical nucleotide sequence having naturally occurring nucleotides and said sequence elements in said substantially identical nucleotide sequence having naturally occurring nucleotides hybridize to each other to produce intramolecular base pairs resulting in a secondary structure, wherein said complementary sequence elements of the first unstructured nucleic acid 3 Appeal 2009-015422 Application 10/324,409 molecule can form stable base-pairs with complementary sequence elements present in a second nucleic acid molecule. REJECTION OVER KUTYAVIN AND VIVEKANANDA Statement of the issue The claims are directed to a “single stranded unstructured nucleic acid molecule” (“UNA”) as were the claims in the first appeal before us. The claimed UNA: possesses at least two sequence elements . . . that are complementary to one another, wherein said complementary sequence elements have reduced levels of base-pairing stability relative to a nucleic acid molecule of substantially identical nucleotide sequence having naturally occurring nucleotides. In the previous Decision, we interpreted the aforementioned claim limitation to mean that the sequence elements comprise modified complementary nucleotides which are unable to base pair with one another, but retain the ability to base pair with their naturally occurring complements (Decision 4- 5). For example, where one sequence element comprises an adenine (A) nucleotide and the other sequence element comprises a thymine (T) nucleotide, the modified nucleotides 2-aminoadenosine and 2-thiothymidine, respectively, would be substituted. 2-aminoadenosine and 2-thiothymidine are unable to base pair with each other, but form base pairs with their naturally occurring complements, thymine and adenine, respectively (Spec. 8). In the earlier Decision, we had affirmed the rejection of claim 1 over Kutyavin alone because Kutyavin described a nucleic acid molecule incorporating modified base pairs with a reduced ability to bind to each other and therefore would have inherently been “unstructured” with “reduced secondary structure relative to a nucleic acid molecule of 4 Appeal 2009-015422 Application 10/324,409 substantially identical nucleotide sequence having naturally occurring nucleotides” as required by claim 1 as it read then (Decision 7-8). During subsequent prosecution, claim 1 was amended, inter alia, to require that the recited two sequence elements each have “at least three contiguous nucleotides” that are complementary to each other. Because the claim requires that the “complementary sequence elements have reduced levels of base-pairing stability,” the Examiner interpreted this to mean that modified UNA nucleotides were incorporated at each of these positions. The Examiner found that it would have been obvious to persons of ordinary skill in the art to have designed a nucleic acid with two sequence elements, each having at least three contiguous modified nucleotides that are complementary to one another because “such minimal regions of complementarity have been taught by both Vivekananda and Kutyavin (see e.g. col. 6-7 of Vivekananda).” (Ans. 11.) The Examiner also reasoned that the skilled worker “would have been motivated to design and synthesize such nucleic acid molecules” with modified nucleotides for their advantages as taught by Kutyavin and Vivekananda to control self-annealing so they would be available to hybridize to target RNA or DNA (id. at 11-12). Appellants state that “the appealed claims are different from those present in the last appeal because they require a nucleic acid that has a pair of complementary triplets [three contiguous nucleotides] that would cause secondary structure if they weren’t substituted with UNA nucleotides.” (App. Br. 8-9.) Appellants acknowledge that Kutyavin describes nucleic acid molecules with UNA nucleotides and methods of making UNA nucleotide-containing nucleic acids by synthetic and enzymatic methods (id. at 9). However, Appellants contend that Kutyavin does not disclose or 5 Appeal 2009-015422 Application 10/324,409 suggest “a nucleic acid that has a pair of complementary triplets that would otherwise cause secondary structure if they weren’t substituted by UNA nucleotides” (id.). Appellants argue that Kutyavin did not recognize UNA nucleotides could be used to disrupt secondary structure, did not use them for this purpose, and that its oligonucleotides did not have reduced secondary structure (id. at 9 & 11). Because of these deficiencies, Appellants contend while one of skill in the art might find modified nucleotides in Kutyavin’s disclosure, Kutyavin provides nothing that would point one of skill in the art towards making an oligonucleotide containing those modified nucleotides to reduce the secondary structure of the oligonucleotide. (Id. at 14.) The issues in this appeal are: 1) whether the Examiner erred in concluding that it would have been obvious to have made the claimed UNA molecule in view of Kutyavin’s failure to recognize that UNA nucleotides could be used to disrupt the secondary structure of a nucleic acid; and 2) whether the Examiner erred in finding that Kutyavin’s nucleic acid molecules had reduced secondary structure as compared to a molecule with unmodified nucleotides. Principles of Law The question is not whether the combination was obvious to the patentee but whether the combination was obvious to a person with ordinary skill in the art. Under the correct analysis, any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 420 (2007). 6 Appeal 2009-015422 Application 10/324,409 Findings of Fact (FF) 1. Kutyavin describes a matched pair of oligonucleotides (ODNs) which are termed “Selective Binding Complementary (SBC) ODNs” (Kutyavin, at col. 1, ll. 64-65). 2. Each ODN includes modified nucleotide bases that form stable hydrogen bonds with their natural complementary base partner, but which do not form stable hydrogen bonds with their modified complementary base partner (Kutyavin, at col. 1, ll. 40-47). 3. “[T]he matched pair of oligonucleotides . . . do not form substantially stable hydrogen bonded hybrids with one another” (Kutyavin, at col. 1, ll. 51-53), but are able to form stable duplex hybrids with a complementary target nucleotide sequence comprising only natural, unmodified bases (id. at col. 2, ll. 14-23). 4. Kutyavin states that a “sufficient number of the modified . . . nucleotides are incorporated such that complementary positions in both SBC ODNS are modified into a matched pair of SBC ODNs of the present invention so that the pair of the matched set does not form a stable hybrid” (Kutyavin, at col. 4, ll. 39-43). 5. However, both members of the matched pair are complementary to a target sequence and able to form a stable hybrid with it (Kutyavin, at col. 4, ll. 47-55; at col. 1, ll. 39-43). 6. Kutyavin states: Due to the increased (approximately double) number of hydrogen bonds in such hybrids (when compared to hybrids that would be formed between a single ODN and duplex nucleic acid) the hybrids formed with the ODN pairs of the present invention are more stable, and lend themselves for gene mapping, diagnostic and therapeutic use. 7 Appeal 2009-015422 Application 10/324,409 (Kutyavin, at col. 1, ll. 58-64.) 7. Secondary structure occurs in a single molecule of DNA or RNA when there are regions of sequence complementarity that permit the sequences to hybridize together to form intramolecular loop, hairpin, duplex, and junction structures (Spec. 1-2 & 6). Analysis It is undisputed that Kutyavin describes nucleic acid molecules which contain modified UNA nucleotides (App. Br. 9). Based on this fact, the Examiner found that Kutyavin’s nucleic acid would be unstructured and have reduced secondary structure as compared to a nucleic acid with naturally occurring bases as required by claim 1, because the former incorporates modified nucleotides which do not base pair with one another and therefore would not form the intramolecular bonds present in secondary structure (FF2, 3, & 7; Ans. 14). This finding is supported by the facts and consistent with our Decisions in related cases having similar claims also rejected over the Kutyavin patent (Appeal No. 2008-5551 in Application Serial No. 10/423,199, decided Feb. 4, 2009; Appeal No. 2007-2963 in Application Serial No. 10/324,409, decided Oct. 31, 2007). Appellants contend that the Examiner erred because Kutyavin did not recognize that its modified nucleotides would serve to reduce secondary structure and did not use them for this purpose (App. Br. 9 & 11). This argument does not persuade us that the Examiner erred. It is true that Kutyavin utilized its modified nucleotides to prevent two complementary oligonucleotides from hybridizing together, a different purpose than stated in the present application. It is also correct that Kutyavin makes no explicit mention in its disclosure that its modified 8 Appeal 2009-015422 Application 10/324,409 oligonucleotides would have reduced secondary structure as compared to the same oligonucleotide prepared with naturally occurring nucleotides. However, Kutyavin’s failure to recognize an inherent property of its nucleic acid molecules does not defeat the rejection. The Examiner did not rely on inherency as a basis for concluding that it would have been obvious to have made the claimed unstructured nucleic acid molecules, but rather found reason to make the modification in the reasons put forth by Kutyavin (Ans. 10-12). Appellants’ argument fails to take sufficient account of the Supreme Court’s ruling in KSR that “any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed.” 550 U.S. at 420. Therefore, it is not fatal to the rejection that the Examiner had a different reason for modifying the Kutyavin patent than the reason given by Appellants in making the claimed unstructured molecule. The proper question is whether the Examiner gave a sufficient basis for combining Kutyavin with Vivekananda to have made the claimed UNA molecule. As the reason for combining the prior art teachings, the Examiner cited Kutyavin’s teaching of the desirability of making oligonucleotides with modified nucleotide bases which do not form stable base pairs with one another, but which are able to form stable duplex hybrids with a complementary target nucleotide sequence comprising only natural, unmodified bases (FF2-4 & 6; Ans. 6-7 & 11-12). These modified nucleic acids are explicitly described by Kutyavin as useful in number of applications, providing the reason to have made any desired nucleic acid with any number of modified nucleotides according to Kutyavin’s directions 9 Appeal 2009-015422 Application 10/324,409 (FF4; Ans. 11). Appellants do not identify a defect in the Examiner’s reasoning other than to argue that Kutyavin’s purpose is different from their own (App. Br. 13-14). However, as discussed above, this argument is misplaced. The Examiner had a sufficient reason to combine the prior art teachings and therefore established that the claimed invention was prima facie obvious. Appellants also argue that Kutyavin’s “oligonucleotides . . . do not inherently contain reduced secondary structure as compared to otherwise identical oligonucleotides made up of natural nucleotides.” (App. Br. 11.) This argument is not convincing. As long as some complementary bases were present in the oligonucleotides and substituted by modified UNA nucleotides, they would have reduced structure in comparison to the same oligonucleotide without them. These facts were established in the previous Decision (Dec. 10, FF2) and have not been specifically disputed by Appellants. DOUBLE-PATENTING REJECTION Claims 1-18 stand provisionally rejected on the ground of nonstatutory obviousness-type double patenting as unpatentable over claims 1 and 3-9 of copending Application Serial No. 10/423,199. Application Serial No. 10/423,199 is abandoned and is thus no longer pending (see Notice of Abandonment, Apr. 27, 2009). Accordingly, we dismiss the rejection as moot. 10 Appeal 2009-015422 Application 10/324,409 CONCLUSION OF LAW AND SUMMARY The Examiner did not err in concluding that it would have been obvious to persons of ordinary skill in the art to have made the claimed unstructured nucleic acid in view of the teachings of Kutyavin and Vivekananda. The rejection of claim 1 is affirmed. Claims 2-50 fall with claim 1 because separate reasons for their patentability were not provided. 37 C.F.R. 41.37(c)(1)(vii). The obviousness-type double patenting rejection of claims 1-18 over Application Serial No. 10/423,199 is dismissed as moot because the application was abandoned. TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED cdc AGILENT TECHNOLOGIES INC. INTELLECTUAL PROPERTY ADMINISTRATION,LEGAL DEPT. MS BLDG. E P.O. BOX 7599 LOVELAND CO 80537 11 Copy with citationCopy as parenthetical citation