Ex Parte HsiehDownload PDFBoard of Patent Appeals and InterferencesNov 24, 200811173635 (B.P.A.I. Nov. 24, 2008) Copy Citation UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE BOARD OF PATENT APPEALS AND INTERFERENCES __________ Ex parte HUANGPIN BEN HSIEH __________ Appeal 2008-5237 Application 11/173,635 Technology Center 1600 __________ Decided: November 24, 2008 __________ Before TONI R. SCHEINER, RICHARD M. LEBOVITZ, and FRANCISCO C. PRATS, Administrative Patent Judges. PRATS, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to an oligonucleotide-protein conjugate. The Examiner has entered two rejections for anticipation. We have jurisdiction under 35 U.S.C. § 6(b). We affirm one of the Examiner’s anticipation rejections and reverse the other. Appeal 2008-5237 Application 11/173,635 STATEMENT OF THE CASE Claims 1-15 are pending and on appeal (App. Br. 1). Claims 1, 2, 4, 7, 8, 10, and 13 are illustrative and read as follows: 1. An oligonucleotide-protein conjugate produced by coupling an albumin protein to an oligonucleotide while the oligonucleotide is attached to a support media. 2. The oligonucleotide-protein conjugate of claim 1 wherein the albumin protein is bovine serum albumin (BSA). 4. The oligonucleotide-protein conjugate of claim 2 wherein the ratio of oligonucleotide to BSA ranges from about 1 to about 50. 7. A protein conjugated oligonucleotide produced by passing a first solution including an oligonucleotide through a support media thereby coupling said nucleotide to said support media, passing a second solution including an albumin protein adapted to form a conjugate with said oligonucleotide through said support media, thereby conjugating said protein with said oligonucleotide while said oligonucleotide is coupled to said support media. 8. The protein conjugated oligonucleotide of claim 7 wherein the albumin protein is bovine serum albumin (BSA)[.] 10. The protein conjugated oligonucleotide of claim 8 wherein the ratio of oligonucleotide to BSA ranges from about 1 to about 50. 13. A conjugate of an oligonucleotide and bovine serum albumin (BSA) wherein the ratio of oligonucleotide to BSA ranges from about 1 to about 50. 2 Appeal 2008-5237 Application 11/173,635 The Examiner relies on the following documents to show unpatentability: Manoharan US 6,656,730 B1 Dec. 2, 2003 A. Bidaine et al., THE PHOTOTRITYL GROUP. PHOTOCROSSLINKING OF OLIGONUCLEOTIDES TO BSA, 6 Bioorganic & Medicinal Chemistry Letters 1167-1170 (1996). The following rejections are before us for review: Claims 1, 2, 4-8, and 10-15 stand rejected under 35 U.S.C. § 102(b) as being anticipated by Bidaine (Ans. 4-8). Claims 1, 3, 7, and 9 stand rejected under 35 U.S.C. § 102(b) as being anticipated by Manoharan (Ans. 8-11). ANTICIPATION -- BIDAINE ISSUE The Examiner cites Bidaine as disclosing “an oligonucleotide-BSA complex that is formed on a membrane of cutoff 30,000 from Millipore and photocrosslinking of oligonucleotides to BSA” (Ans. 4). The Examiner reasons that, “[a]lthough independent claim 1 requires coupling an albumin protein to an oligonucleotide while the oligonucleotide is attached to a support media, claim 1 does not require that an oligonucleotide-protein conjugate recited in claim 1 must contain support media” (id. at 5). Rather, the Examiner contends, claim 1 is a product-by-process claim (id.). Thus, the Examiner argues, “[i]f the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process” (id.) (citing In re Thorpe, 777 F.2d 695, 697 (Fed. Cir. 1985). 3 Appeal 2008-5237 Application 11/173,635 Appellant argues that the Examiner erred in finding that Bidaine anticipates claims 1, 7, and 13 because Bidaine does not disclose that its oligonucleotide-protein conjugate is linked by covalent bonds (App. Br. 5- 7). Appellant further argues that Bidaine does not disclose preparing the oligonucleotide-protein conjugate using support media attached to the oligonucleotide (id. at 7-10). Moreover, Appellant argues, language directed to the method of making a product can be used to characterize the claimed product, and, as shown in the Specification, the claimed conjugates are distinguishable from Bidaine’s (id. at 10-11). Appellant further argues that the oligonucleotide to conjugation ratios recited in claims 4-6 and 10-15, are not disclosed by Bidaine (id. at 12-13). The issue with respect to this rejection, then, is whether the Examiner erred in finding that Bidaine describes an oligonucleotide-protein conjugate that meets the structural requirements of the claims. FINDINGS OF FACT (“FF”) 1. Bidaine discloses that “a photoactivatable trityl cap was used to immobilize an oligonucleotide on BSA (bovine serum albumin)” (Bidaine 1167). 2. Specifically, Bidaine discloses synthesizing an oligonucleotide linked to a trityl functional group through 1,2-dideoxy-D-ribofuranose (see Bidaine 1167-68). The tritylated oligonucleotide had the following structure: 4 Appeal 2008-5237 Application 11/173,635 The tritylated oligosaccharide (compound 7), as shown above, “was acylated by N-hydroxysuccinimidyl p-benzoylbenzoate, to give 8” (id. at 1167). Thus, compound 8 differs from compound 7 in that compound 8 has the hydrophobic crosslinking group “X” hooked to the trityl group at the primary amine moiety (id.) 3. Bidaine discloses that “[a]lbumin is well known for its capacity to bind hydrophobic drugs” (Bidaine 1167). Bovine serum albumin has a molecular weight of about 66,000 Daltons (see Spec. 2). Bidaine also discloses that when a mixture of the tritylated oligonucleotide compound 8 and excess BSA (“2 molar equivalents, or more”) were ultrafiltered against a membrane having a 30,000 Dalton cutoff, “the oligonucleotide was more than 90% retained by BSA. Without BSA, it passed through the membrane” (Bidaine 1167). Thus, Bidaine showed that BSA was capable of adsorbing tritylated oligonucleotide compound 8. 4. Bidaine discloses that a complementary filtration experiment was run, showing that compound 7 was also adsorbed onto BSA (Bidaine 1170 n. 17). The experiment used oligonucleotide:BSA ratios of 1:0.5, 1:1, 1:2, 1:5, 1:20, and 1:50 (id.). 5. Bidaine also discloses covalently binding tritylated oligonucleotide compound 8 to BSA (Bidaine 1169). Specifically, Bidaine discloses that tritylated oligonucleotide compound 8 was dissolved along with “a large excess of BSA (25:1 molar ratio), [and] was irradiated in a small glass tube by a slide projector for 7 hours (i.e. the time necessary for its complete disappearance). A conjugate 5 Appeal 2008-5237 Application 11/173,635 BSA-oligonucleotide was isolated by preparative anion exchange FPLC and dialyzed against water (membrane cutoff 12000)” (id. (citation omitted)). Bidaine calculated that 1 mole of compound 8 yielded “0.4 μmole of conjugate” (id.). 6. Bidaine discloses that the BSA-oligonucleotide conjugate was able to capture an oligonucleotide having the complementary sequence, thus showing that the sequence of compound 8 “was accessible and not extensively degraded by photolysis” (Bidaine 1169). PRINCIPLES OF LAW It is well settled that “[t]o anticipate a claim, a prior art reference must disclose every limitation of the claimed invention, either explicitly or inherently.” In re Schreiber, 128 F.3d 1473, 1477 (Fed. Cir. 1997). It is also “well settled that the presence of process limitations in product claims, which product does not otherwise patentably distinguish over the prior art, cannot impart patentability to that product.” SmithKline Beecham Corp. v. Apotex Corp., 439 F.3d 1312, 1318 (Fed. Cir. 2006) (quoting In re Stephens, 345 F.2d 1020, 1023 (CCPA 1965). As stated in In re Thorpe, 777 F.2d at 697 (citations omitted): [E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process. Also, once the Examiner establishes that a product recited in terms of its process of making is prima facie unpatentable due to anticipation, Appellant bears the burden of proving “that the prior art products do not 6 Appeal 2008-5237 Application 11/173,635 necessarily or inherently possess the characteristics of his claimed product.” Id. at 698 (quoting In re Fitzgerald, 619 F.2d 67, 70 (CCPA 1980); In re Best, 562 F.2d 1252, 1255 (CCPA 1977)). ANALYSIS Appellant’s arguments do not persuade us that the Examiner erred in finding that Bidaine describes an oligonucleotide-protein conjugate that meets the structural requirements of the claims. Claims 1 and 7 require the recited compound to be either an “oligonucleotide protein conjugate” (claim 1), or a “protein conjugated oligonucleotide” (claim 7), the protein in both cases being an albumin. Contrary to Appellant’s argument, Bidaine discloses that the tritylated oligonucleotide compound 8 was in fact covalently linked to BSA by photocrosslinking, to form a “conjugate” (see FF 5). Because Bidaine’s oligonucleotide-BSA conjugate meets all of the structural limitations in claims 1 and 7, we agree with the Examiner that it was reasonable to conclude that Bidaine’s conjugate is encompassed by those claims. Given this reasonable finding that claims 1 and 7 are prima facie anticipated by Bidaine, the burden shifted to Appellant to show non- anticipation. In re Thorpe, 777 F.2d at 698. We find that Appellant has not met the burden of adequately rebutting the Examiner’s prima facie case of anticipation. Specifically, Appellant argues that claims 1 and 7 require the use of “support media” to prepare the claimed compound, and that the filter membrane used by Bidaine in the filtration experiments is not the same medium disclosed in the Specification as being used to prepare the claimed conjugates (App. Br. 7-8). Moreover, Appellant urges, claims 1 and 7 7 Appeal 2008-5237 Application 11/173,635 require linkage of the oligonucleotide to the support, which is not disclosed in Bidaine (id. at 8-10). Appellant further urges that the claimed process limitations impart a structural difference to the claimed product because the process limitations result in higher conjugation ratios as compared to other methods of producing oligonucleotide-BSA conjugates (id. at 11-12). We are not persuaded by these arguments. Appellant does not point to, nor explain, any structural difference between a conjugate produced using the asserted media and the conjugate of Bidaine. Moreover, neither claim 1 nor claim 7 requires any specific conjugation ratio. Therefore, because Appellant has not met the burden of showing that Bidaine’s conjugate is structurally different from the conjugates recited in claims 1 and 7, we affirm the Examiner’s anticipation rejection of those claims. Because they were not argued separately, claims 2 and 8 fall with claims 1 and 7. See 37 C.F.R. § 41.37(c)(1)(vii). Appellant argues that the Examiner erred in finding that Bidaine meets the limitations in claims 4-6 and 10-15 requiring the conjugates to have specific oligonucleotide to BSA ratios. Specifically, Appellant notes that the Examiner relied on note 17 in Bidaine to meet this limitation (see FF 4), but argue: A close review of note 17 in the paper to Bidaine et al. reveals that the ratios of oligonucleotide to BSA are merely the relative amounts of oligonucleotide that is adsorbed on BSA. These amounts of oligonucleotide and BSA are not amounts of each in a conjugated product as called for in the claims at issue. This is yet another significant distinction between the pending claims and the limited disclosure by Bidaine et al. (App. Br. 13.) 8 Appeal 2008-5237 Application 11/173,635 We select claim 4 as representative of the argued claims. See 37 C.F.R. § 41.37(c)(1)(vii). Claim 4 recites “[t]he oligonucleotide-protein conjugate of claim 2 wherein the ratio of oligonucleotide to BSA ranges from about 1 to about 50.” Claim 2, in turn, recites “[t]he oligonucleotide-protein conjugate of claim 1 wherein the albumin protein is bovine serum albumin (BSA).” Thus, claim 4 recites an oligonucleotide-BSA conjugate in which the oligonucleotide:BSA ratio ranges from about 1:1 to about 50:1. Bidaine’s tritylated oligonucleotide compound 8 contains a single hydrophobic crosslinking moiety “X” that allows conjugation of the oligonucleotide to the BSA (see FF 2). Thus, when Bidaine reacted the oligonucleotide compound 8 with an excess of BSA to produce conjugated molecules (FF 5), each oligonucleotide moiety could, at most, carry only a single BSA molecule. Given the excess of BSA used in Bidaine’s conjugation reaction, and the oligonucleotide contruct’s capacity to bind at most a single BSA molecule to the hydrophobic crosslinking moiety “X”, we agree with the Examiner that it was reasonable to conclude that the conjugates produced by Bidaine’s conjugation reaction had at least a 1:1 oligonucleotide:BSA ratio, which is encompassed by claim 4’s ratio of from about 1:1 to 50:1. Appellant’s argument therefore does not persuade us that the Examiner erred in concluding that Bidaine meets the oligonucleotide:BSA ratio recited in claim 4. We therefore affirm the Examiner’s rejection of claim 4 as anticipated by Bidaine. Because they were not argued separately, claims 5, 6, and 10-15 fall with claim 4. See 37 C.F.R. § 41.37(c)(1)(vii). 9 Appeal 2008-5237 Application 11/173,635 ANTICIPATION -- MANOHARAN ISSUE Claims 1, 3, 7, and 9 stand rejected under 35 U.S.C. § 102(b) as being anticipated by Manoharan (Ans. 8-11). The Examiner cites Manoharan as disclosing “an oligonucleotide- albumin complex on membranes” in which “the synthesized oligonucleotide is attached to 3'-amino modified controlled pore glass . . . and the conjugation reaction is performed with the oligonu[cle]otide still bound to the solid support” (id. at 8 (citations omitted)). The Examiner reasons that claim 1 encompasses Manoharan’s oligonucleotide-albumin complex because Appellant’s Specification does not define the claim term “conjugate” and therefore “the claims do not require a protein conjugated oligonucleotide formed by covalent bonds” (id. at 9). Appellant contends the Examiner erred in finding that Manoharan anticipates the cited claims because Manoharan merely discloses a test of the efficiency of the oligonucleotides’ binding to human serum albumin (App. Br. 15-16). Appellant argues that the disclosed easily reversible binding is not a covalent bond, and that Manoharan therefore “fails to disclose a procedure to make a ‘conjugated’ oligonucleotide-protein product” (id. at 16; see also Reply Br.16). The issue with respect to this rejection, then, is whether the Examiner erred in interpreting the claims as encompassing Manoharan’s membrane- bound oligonucleotide-albumin complex. FINDINGS OF FACT 7. Manoharan discloses methods for increasing the concentration of therapeutic or diagnostic oligonucleotides, such as antisense 10 Appeal 2008-5237 Application 11/173,635 oligonucleotides, in serum (Manoharan, col. 10, l. 60, through col. 12, l. 1). To accomplish this, “a drug moiety that is known to bind to a serum protein is selected and conjugated to an oligonucleotide” (id. at col. 10, ll. 62-64). 8. Manoharan discloses examples in which oligonucleotides were covalently bound to a variety of drugs, including ibuprofen (Manoharan, col. 38, l. 50 through col. 42, l. 8), penicillin (id. at col. 44, l. 20 through col. 45, l. 9), and aspirin (id. at col. 45, l. 54 through col. 46, l. 3). The covalently bound drug-oligonucleotide constructs are referred to as being “[c]onjugated” (id. at col. 44, ll. 24 and 52; col. 45, l. 55). 9. Manoharan discloses a test of the capacity of its drug-oligonucleotide conjugates to bind to human serum albumin (Manoharan, col. 46, l. 4 through col. 47, l. 45). Specifically, mixtures of human serum albumin and radioactively labeled oligonucleotide-drug conjugates, or unconjugated oligonucleotides, were placed on ultrafiltration membranes having a 30,000 Dalton cutoff, and gently spun until about 20% of the sample had passed through the filter, after which the binding efficiencies were determined based on the amounts of bound and free label present (id. at col. 46, ll. 21-40). Manoharan discloses that binding of the “unconjugated” oligonucleotide controls was “very weak,” whereas “[a]ddition of the ibuprofen conjugate increased the affinity substantially” (id. at col. 46, ll. 58-60). 10. Manoharan does not refer to the binding of the drug-oligonucleotide constructs to the albumin as “conjugation,” nor does Manoharan disclose that the drug-oligonucleotide conjugates became covalently bound to the albumin. Rather, Manoharan discloses that “[b]inding of drugs to albumin is usually rapidly reversible” (Manoharan, col. 4, ll. 35-36). 11 Appeal 2008-5237 Application 11/173,635 11. Appellant’s Specification uses the term “conjugation” to refer to a covalent linkage between the oligonucleotide and albumin. For example, the Specification discloses that “[c]onjugation between BSA and an oligonucleotide generally occurs by introducing an amino linker to the oligonucleotide and then conjugating the BSA to the linker. One example of an amino linker is a C-12 amino linker” (Spec. 8). 12. The Specification discloses an example of “conjugation” of an oligonucleotide to BSA through a C-12 amino linker (id. at 14), and designates the product as having the structure “oligo-NH-BSA” (id. at 15). The Specification discloses determining the molecular weight of the C-12 amino-linked oligonucleotide-BSA construct (id.) The Specification designates the conjugate’s structure as “Oligo-C12-NH-BSA,” and refers to the construct as “conjugated oligonucleotide-BSA” (id.). PRINCIPLES OF LAW During examination, the PTO must interpret terms in a claim using “the broadest reasonable meaning of the words in their ordinary usage as they would be understood by one of ordinary skill in the art, taking into account whatever enlightenment by way of definitions or otherwise that may be afforded by the written description contained in the applicant’s specification.” In re Morris, 127 F.3d 1048, 1054 (Fed. Cir. 1997). Thus, while “the PTO must give claims their broadest reasonable interpretation, this interpretation must be consistent with the one that those skilled in the art would reach.” In re Cortright, 165 F.3d 1353, 1358 (Fed. Cir. 1999). 12 Appeal 2008-5237 Application 11/173,635 ANALYSIS We agree with Appellant that the Examiner erred in interpreting the claims as encompassing Manoharan’s membrane-bound oligonucleotide- albumin complex. The independent claims subject to this ground of rejection, 1 and 7, recite that the claimed compound is an “oligonucleotide protein conjugate” (claim 1), or a “protein conjugated oligonucleotide” (claim 7). We note, as the Examiner argues,1 that a generic dictionary defines “conjugate” as merely meaning “to rejoin together” (Ans. 12). We do not agree, however, that the generic definition advanced by the Examiner governs the claim interpretation in this case. Rather, we agree with Appellant that the claims require some type of covalent linkage between the oligonucleotide and the protein. While it is true that claims must be given their broadest reasonable interpretation consistent with the Specification, Morris, 127 F.3d at 1054, claim terms must also be interpreted as they would by one of ordinary skill in the pertinent art. See Cortright, 165 F.3d at 1358. In the instant case, the prior art cited by the Examiner consistently uses the term “conjugate” to refer only to covalently linked moieties, and 1 The Examiner also presents a significant amount of argument in the Response to Reply Brief mailed July 24, 2007. This document, in essence, is a Supplemental Examiner’s Answer. The Examiner may furnish a Supplemental Examiner’s Answer in response to new issues raised in a Reply Brief. MPEP § 1207.05. However, “[e]very supplemental examiner’s answer must be approved by a Technology Center (TC) Director or designee.” Id. Because the document mailed July 24, 2007, does not evidence the required approval, we do not consider the arguments presented therein. 13 Appeal 2008-5237 Application 11/173,635 does not use that term to refer to non-covalently associated species. For example, Manoharan only uses “conjugate” to refer to the covalently linked drug-oligonucleotide construct (FF 7, 8), but does not use that term to refer to the oligonucleotide construct when it is reversibly bound to the albumin (FF 9, 10). Similarly, Bidaine only uses “conjugate” to refer to the covalently bound oligonucleotide-BSA construct, but does not use that term to refer to the oligonucleotide when it is merely adsorbed to BSA in filtration experiments (see FF 3-5). Moreover, consistent with the cited prior art’s usage of the term, Appellant’s Specification uses “conjugate” to refer only to covalently linked species (FF 11, 12). Thus, there is no evidence that Appellant sought to diverge from the art-accepted meaning of the term evidenced by Manoharan and Bidaine. We therefore agree with Appellant that, when given their broadest reasonable interpretation consistent with the Specification and the prior art, the claims require some type of covalent linkage between the oligonucleotide and the protein moieties. Manoharan discloses binding experiments between drug-oligonucleotide conjugates and human serum albumin (FF 9). Manoharan does not refer to the albumin-oligonucleotide association as being a “conjugate” nor does Manoharan state that the oligonucleotide construct is covalently bound to the albumin (FF 10). Rather, Manoharan states that drugs usually bind reversibly to albumin (FF 10). Because the Examiner does not point to, nor do we see, any evidence that Manoharan’s oligonucleotide construct is covalently bound to albumin, as required by claims 1 and 7, we reverse the Examiner’s rejection of those claims, and their dependent claims 3 and 9, as anticipated by Manoharan. 14 Appeal 2008-5237 Application 11/173,635 SUMMARY We affirm the Examiner’s rejection of claims 1, 2, 4-8, and 10-15 under 35 U.S.C. § 102(b) as anticipated by Bidaine. We reverse the Examiner’s rejection of claims 1, 3, 7, and 9 under 35 U.S.C. § 102(b) as anticipated by Manoharan. AFFIRMED-IN-PART lp MARK S. SVAT, ESQ. FAY, SHARPE, FAGAN, MINNICH & McKEE, LLP 1100 SUPERIOR AVENUE, SEVENTH FLOOR CLEVELAND OH 44114-2579 15 Copy with citationCopy as parenthetical citation