SOMALOGIC, INC.

Patent Trials and Appeals Board

Mar 23, 2022

2020004886 (P.T.A.B. Mar. 23, 2022)

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. 15/311,714 11/16/2016 Daniel W. DROLET 01137-0007-00US 9837 110041 7590 03/23/2022 McNeill Baur PLLC 125 Cambridge Park Drive Suite 301 Cambridge, MA 02140 EXAMINER SHIN, DANA H ART UNIT PAPER NUMBER 1635 NOTIFICATION DATE DELIVERY MODE 03/23/2022 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): amelia.baur@mcneillbaur.com docketing@mcneillbaur.com eofficeaction@appcoll.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte DANIEL W. DROLET, CHI ZHANG, DANIEL J. O’CONNELL, and SHASHI GUPTA1 Appeal 2020-004886 Application 15/311,714 Technology Center 1600 Before DONALD E. ADAMS, ERIC B. GRIMES, and JEFFREY N. FREDMAN, Administrative Patent Judges. GRIMES, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134(a) involving claims to an aptamer that binds C3 protein, which have been rejected for lack of adequate written description. We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. STATEMENT OF THE CASE “The present disclosure relates generally to the field of nucleic acids, and more specifically, to aptamers capable of binding to human complement 1 Appellant identifies the real party in interest as SomaLogic, Inc. Appeal Br. 3. “Appellant” refers to “applicant” as defined in 37 C.F.R. § 1.42. Appeal 2020-004886 Application 15/311,714 2 component 3 (C3 or C3-Protein).” Spec. 1:7-9. “The term aptamer . . . refers to a non-naturally occurring nucleic acid that has a desirable action on a target molecule.” Id. at 13:33-34. C3 protein is a member of the complement system, which “plays a major role in innate immunity.” See id. at 1:13-20. However, “[t]he over- activation of complement can . . . attack the host’s own cells.” Id. at 2:12- 13. “Inhibitors of C3 . . . are desirable as they may prevent . . . the activation of the terminal complement pathway.” Id. at 2:2-4. “The present disclosure . . . provid[es] aptamers that can inhibit the bioactivity of human C3- Protein.” Id. at 2:17-18. Claims 2, 10, 11, 14, 15, 21-27, and 55-65 are on appeal.2 Claim 11, reproduced below, is illustrative: 11. An aptamer that binds C3 protein, wherein the aptamer comprises a first region and a second region, wherein: the first region comprises the sequence 5'-PAGPC-3' (SEQ ID NO: 132) and the second region comprises the sequence 5'-GPAYRPP-3' (SEQ ID NO: 157), wherein each P is independently, and for each occurrence, a C-5 modified pyrimidine nucleoside; Y is C, U, or T; and R is G or A, wherein each C-5 modified pyrimidine nucleoside is independently selected from: 5-(N-1-naphthylmethylcarboxyamide)-2'- deoxyuridine (NapdU), 5-(N-1-naphthylmethylcarboxyamide)- 2'-O-methyluridine, 5-(N-1-naphthylmethylcarboxyamide)-2'- fluorouridine, 5-(N-2-naphthylmethylcarboxyamide)-2'- deoxyuridine (2NapdU), 5-(N-2-naphthylmethylcarboxyamide)- 2'-O-methyluridine, 5-(N-2-naphthylmethylcarboxyamide)-2'- fluorouridine, 5-(N-1-naphthylethylcarboxyamide)-2'- deoxyuridine (NEdU), 5-(N-1-naphthylethylcarboxyamide)-2'- O-methyluridine, 5-(N-1-naphthylethylcarboxyamide)-2'- fluorouridine, 5-(N-2-naphthylethylcarboxyamide)-2'- 2 Claim 5 is also pending but is not rejected. See Ans. 3. Appeal 2020-004886 Application 15/311,714 3 deoxyuridine (2NEdU), 5-(N-2-naphthylethylcarboxyamide)-2'- O-methyluridine, 5-(N-2-naphthylethylcarboxyamide)-2'- fluorouridine, 5-(N-3-benzofuranylethylcarboxyamide)-2'- deoxyuridine (BFdU), 5-(N-3-benzofuranylethylcarboxyamide)- 2'-O-methyluridine, 5-(N-3-benzofuranylethylcarboxyamide)-2'- fluorouridine, 5-(N-3-benzothiophenylethylcarboxyamide)-2'- deoxyuridine (BTdU), 5-(N-3-benzothiophenylethyl- carboxyamide)-2'-O-methyluridine, and 5-(N-3- benzothiophenylethylcarboxyamide)-2'-fluorouridine, and wherein the 3'-end of the first region is covalently linked to the 5'-end of the second region by at least one linker. OPINION Claims 2, 10, 11, 14, 15, 21-27, and 55-65 stand rejected under 35 U.S.C. § 112(a) on the basis that they “contain[] subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor . . . had possession of the claimed invention.” Non-Final Action3 4-5. The Examiner finds that the claims are directed to “a C3 protein- binding aptamer comprising a 5-mer of SEQ ID NO:132 as the ‘first region’ and a 7-mer of SEQ ID NO:[1574] as the ‘second region,’” but the Specification “fails to describe that the combination of SEQ ID Nos:132 and [157] is sufficient to provide the required C3 protein-binding function.” Id. at 5. The Examiner finds, instead, that “it is prima facie apparent from 3 Office Action mailed Nov. 14, 2018. The Final Action mailed June 7, 2019) refers to the earlier Office Action for an explanation of the rejection. 4 The Non-Final Action refers to SEQ ID NO: 156 but Appellant later amended the Specification and claims to refer to the relevant sequence as SEQ ID NO: 157. See Response filed April 10, 2019. Appeal 2020-004886 Application 15/311,714 4 Figures 1A-1B that at least a 23-mer contiguous sequence or a highly homologous sequence thereof is commonly found in some of the clones.” Id. The Examiner also finds that the only aptamers described in the Specification with C3 protein-binding function have NapdU as the C-5 modified pyrimidine. Id. at 7. The Examiner cites Ochsner5 as evidence that “the aptamer sequences are not identical when different C-5 modified pyrimidine libraries are used.” Id. Specifically, the Examiner points to Ochsner’s Table 4 as showing that “target-binding aptamer sequences differ depending on the specific C-5 modified pyrimidines used” and “particular pools containing TyrdU, NapdU, TrpdU, or 2NapdU . . . generated unique nucleotide sequences that are not found in other C-5 modified pools.” Id. The Examiner also cites Gupta6 and Davies7 as further evidence of “nucleotide sequence variability depending on the specific type of C-5 modification.” Id. at 8. Appellant argues that Figure 1A of the present application describes the sequences of 25 independently derived aptamers that bind C3 protein. . . . Figure 1B shows a consensus sequence based on the sequences shown in Figure 1A. The motifs 5'-PAGPC-3' and 5'-GPAYRPP-3' recited in claim 11 are derived from the consensus sequence, and are shared by the 25 independently derived aptamers that bind C3 protein. 5 Ochsner et al., US 2012/0231467 A1, published Sept. 13, 2012. 6 Gupta et al., “Chemically Modified DNA Aptamers Bind Interleukin-6 with High Affinity and Inhibit Signaling by Blocking Its Interaction with Interleukin-6 Receptor,” J. Biol. Chem. 289:8706-8719 (2014). 7 Davies et al., “Unique motifs and hydrophobic interactions shape the binding of modified DNA ligands to protein targets,” Proc. Natl. Acad. Sci. USA 109:19971-19976 (2012). Appeal 2020-004886 Application 15/311,714 5 Appeal Br. 8. In addition, Appellant argues, “the application provides more than 100 additional representative species within the claimed genus that share the common structure and function recited in claim 11.” Id. at 9. “Appellant asserts that the specification clearly teaches a representative number of species within the genus of claim 11.” Id. Appellant argues that “[t]he 5'-PAGPC-3' and 5'-GPAYRPP-3' motifs comprise very little sequence variability,” and the exemplified species include C3-binding aptamers with either G or A at position “R” and C3- binding aptamers with either C or T at position “Y” of the 5'-GPAYRPP-3' motif. Id. at 9-10.8 Appellant also argues that “aptamers comprising 2'-deoxy and 2'-O-methyl nucleosides are exemplified throughout the specification, e.g., in Tables 2 through 8; and 2'-fluoro modified nucleosides are a well known substitute for 2'-deoxy nucleosides.” Id. at 10. Appellant argues, “[f]urthermore, the data in the specification demonstrate that the combination of the common structural features of SEQ ID NOs: 132 and 157 correlates with C3 binding, and variations within the aptamer sequence that are outside of those sequences are well tolerated.” Id. at 11. Appellant points to the consensus sequence of Figure 1B, showing “sequence variability within positions 1 through 9, 15, and 23, the portions of the sequence outside of the common structure recited in claim 11.” Id. Appellant also points out that “[t]he aptamer represented by SEQ ID NO: 5 binds C3 with a Kd of 0.0313 nM . . . and the aptamer represented by SEQ ID NO: 151 binds C3 with a Kd of 26.7 nM.” Id. Appellant argues that, 8 Position “Y” can also be U but Appellant argues that “U and T are generally considered to be interchangeable in the art.” Appeal Br. 10. Appeal 2020-004886 Application 15/311,714 6 “while those aptamers differ in length, sequence, and nucleoside modifications, they both bind C3. Those aptamers therefore support the claimed genus by demonstrating that aptamers that share the common structure recited in claim 11, but that differ elsewhere, retain C3 binding.” Id. With regard to the teachings of Ochsner that were cited by the Examiner, Appellant argues that “Oschner’s Table 4 shows sequences of aptamers that bind C. difficile binary toxin A chain selected from different aptamer libraries,” but “the fact that aptamers that do not share common structural elements may bind the same target protein has no bearing on whether aptamers that do share common structural elements but differ in that they comprise similar, but not identical, C-5 modifications, will bind the same target.” Id. at 12. We conclude that the Examiner has not persuasively shown that the Specification’s written description does not demonstrate that Appellant was in possession of the claimed aptamers at the time the application was filed. “[T]he test for [the written description requirement] is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date.” Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010). A “sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Id. at 1350. Appeal 2020-004886 Application 15/311,714 7 However, “[i]t is not necessary that every permutation within a generally operable invention be effective in order for an inventor to obtain a generic claim, provided that the effect is sufficiently demonstrated to characterize a generic invention.” Capon v. Eshhar, 418 F.3d 1349, 1359 (Fed. Cir. 2005). [W]hat is needed to support generic claims to biological subject matter depends on a variety of factors, such as the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, the predictability of the aspect at issue, and other considerations appropriate to the subject matter. Id. Here, Appellant’s Specification describes the structure of aptamers comprising SEQ ID NO: 132 and SEQ ID NO: 157, connected by a linker, in which “P,” “Y,” and “R” have the meanings recited in claim 11. See, e.g., Spec. 5:1-15, 6:21 to 7:1. The issue of concern to the Examiner, however, is whether the Specification adequately describes aptamers meeting the structural limitations of claim 11 that also bind C3 protein, as recited in the preamble of the claim. In this regard, the Examiner finds that Appellant’s Figures 1A and 1B show that “at least a 23-mer contiguous sequence or a highly homologous sequence thereof is commonly found in some of the clones.” Non-Final Action 5. Appellant’s Figure 1A shows the nucleotide sequences of “twenty- five independently derived and active . . . aptamer sequences” (SEQ ID NO: 4 through SEQ ID NO: 28), with shading to indicate “nucleotides Appeal 2020-004886 Application 15/311,714 8 identical to the most frequently sequenced aptamer of pattern 1, 8491-3_3.” Spec. 10:27-31. Appellant’s Figure 1B is reproduced below: Figure 1B shows the 23-nucleotide consensus sequence for the aptamers in Figure 1A. Id. at 10:31-32. The consensus sequence includes SEQ ID NO: 132 (positions 10-14) and SEQ ID NO: 157 (positions 16-22, with Y = C and R = G). The consensus sequence also shows a high degree of similarity at other positions: 100% P at positions 2 and 6, 100% G at position 3, 96% C at position 5, 92% C at position 7, and 92% A at position 9. The twenty-five aptamers shown in Figure 1A are recited in Appellant’s claim 5, along with ninety-nine other specific aptamers (SEQ ID NOs: 32, 33, 39 to 69, 72, 73, 78 to 118, 121 to 130, and 139 to 151). The Examiner has withdrawn the rejection of claim 5. See Ans. 3. Claim 5 depends from claim 11, and therefore all of the aptamers recited in claim 5 include the SEQ ID NO: 132-linker-SEQ ID NO: 157 structure of claim 11. Thus, it is undisputed that the Specification fully describes, by structure and binding affinity, 124 aptamers having both the structure and the function recited in claim 11. See Spec. 52-66, Tables 2-8. While the exemplified aptamers bind C3 with different affinities, see id., Appellant’s claims recite only “[a]n aptamer that binds C3 protein,” and thus do not require any specific degree of binding affinity. In our view, these 124 representative species are sufficient to demonstrate that Appellant was in possession of an “aptamer that binds C3 Appeal 2020-004886 Application 15/311,714 9 protein, wherein the aptamer comprises . . . the sequence 5'-PAGPC-3' (SEQ ID NO: 132) and . . . the sequence 5'-GPAYRPP-3' (SEQ ID NO: 157),” as recited in claim 11. The Examiner, however, raises a second concern with the scope of claim 11, finding that “the specification fails to describe that any given C-5 modified pyrimidine at ‘P’ positions in the recited SEQ ID NOs confers C3 protein-binding function. The instant specification at best describes only a single species: NapdU.” Non-Final Action 7. Appellant responds that “‘P’ is selected from only six specific pyrimidine nucleobases in the context of a 2'-deoxy, 2'-O-methyl, or 2'- fluoro nucleoside. The six nucleobase options for ‘P’ are uridines modified at the 5-position with one of six very similar bicyclic aromatic groups.” Appeal Br. 9. Appellant reproduces part of the Specification’s Figure 9 in a table, as shown below: Appeal 2020-004886 Application 15/311,714 10 The table shows the structures of 1-naphthylmethyl, 2- naphthylmethyl, 1-naphthylethyl, 2-naphthyl-2-ethyl, 3-benzofuranylethyl, and 3-benzothiophenylethyl groups. All of these groups include a (carboxamide) moiety, connected via one or two methylenes to a bicyclic group consisting of two phenyl rings or a five-membered heterocyclic ring and a phenyl ring. We agree with Appellant that the C-5 modifications encompassed by claim 11 are very similar bicyclic aromatic groups. The Examiner, however, cites Ochsner as evidence that libraries with different C-5 modified pyrimidines generate different aptamers that bind to the same target. Non-Final Action 7. The Examiner finds that Ochsner discloses that “different nucleotide sequences [were] isolated for C. difficile binary toxin A chain using particular pools containing TyrdU, NapdU, TrpdU, or 2NapdU, wherein each pool generated unique nucleotide sequences that are not found in other C-5 modified pools.” Id. 9 Appellant responds that Ochsner “shows sequences of aptamers that bind C. difficile binary toxin A chain selected from different aptamer libraries,” but “the present claims . . . are directed to aptamers comprising common structural elements.” Appeal Br. 12. Appellant argues that “the fact that aptamers that do not share common structural elements may bind the same target protein has no bearing on whether aptamers that do share common structural elements but differ in that they comprise similar, but not identical, C-5 modifications, will bind the same target.” Id. at 12. 9 The Examiner also cites Gupta and Davies showing “[t]he nucleotide sequence variability depending on the specific type of C-5 modification” but does not point to any specific evidence in either of these references. Non- Final Action 8. Appeal 2020-004886 Application 15/311,714 11 Ochsner discloses “aptamers capable of binding to toxins produced by Clostridium difficile.” Ochsner, abstract. The disclosure at issue relates to “SELEX with C. difficile Toxins A/B.” Id. ¶ 108. “‘SELEX’ . . . refer[s] generally to a combination of (1) the selection of nucleic acids that interact with a target molecule in a desirable manner, for example binding with high affinity to a protein, with (2) the amplification of those selected nucleic acids.” Id. ¶ 62. “The SELEX process can be used to identify aptamers with high affinity to a specific target molecule.” Id. Ochsner states that “[l]ibraries of 40mer random sequences were used that contained one of the six modified nucleotides,” including (as most relevant here) NapdU and 2NapdU. Id. ¶ 108. “Seven or eight rounds of selection were carried out.” Id. “The aptamer pools obtained after the last round of SELEX were tested for affinity to their targets.” Id. ¶ 109.10 “For toxin A, the aptamer pool . . . 4939 (NapdU) [was] active. . . . Pools 5564 (2NapdU) and 5577 (2NapdU) were also active.” Id. Representative clones from SELEX pools . . . 4939 (NapdU), . . . 5564 (2NapdU), 5577 (2NapdU) . . . were evaluated for affinity to toxin A in filter binding assays. Nearly all clones had good affinity to the recombinant 57.1 kDa toxin A fragment that had been used for selection, however, only some of the clones demonstrated affinity for the native, 308 kDa toxin A. Id. ¶ 113. Ochsner states that for pool 4939 (NapdU), “[t]hree unrelated sequences were found five times each in this pool.” Id. ¶ 116. For pool 5564 10 “Targets suitable for SELEX were prepared by PCR amplification of desired gene fragments from C. difficile genomic DNA. . . . For toxin A, a recombinant polypeptide was obtained that consisted of the carboxy- terminal β-hairpin repeats 17-32.” Id. ¶ 106. Appeal 2020-004886 Application 15/311,714 12 (2NapdU), in addition to the most active clone, “[s]everal other clones were also present . . . , sharing one of the three sequence patterns NAAAGNAGGN, GNNRNCMKNCNGA . . . , or CGGGNCGNGACAGANCGCA, respectively (N=2NapdU; R=A or G; M=A or C; K=G or N).” Id. ¶ 118. For “[p]ool 5577 (2NapdU): The active clones shared all or part of the pattern NACCGAACGNNnNCAGNCNGA (N=2NapdU; n=A, G, C or 2NapdU). These sequences had been selected in a special SELEX, where a competing toxin A aptamer (4943-51) was present in twofold excess over the target protein concentration.” Id. ¶ 120. Thus, the Examiner is correct in stating that Ochsner’s pools containing NapdU or 2NapdU each “generated unique nucleotide sequences that are not found in other C-5 modified pools.” Non-Final Action 7. However, Ochsner also shows that the SELEX process can result in different aptamers binding to the same target, even when those aptamers have the same modified base. For example, three “unrelated” sequences were each found five times in pool 4939, having the modified base NapdU. Ochsner ¶ 116. See also id. ¶¶ 118-119 (pools 5564 and 5577 both contained 2NapdU, but the sequence patterns for the two pools are different). As Appellant points out, Ochsner does not provide evidence on the issue relevant to the Examiner’s rejection: “[W]hether aptamers that do share common structural elements but differ in that they comprise similar, but not identical, C-5 modifications, will bind the same target.” Appeal Br. 12. That is, given an aptamer that includes one modified base (e.g., NapdU) and is known to bind to a specific target (e.g., C3 protein), is the same Appeal 2020-004886 Application 15/311,714 13 aptamer with a different modified base (e.g., 2NapdU) likely to also bind to that target? The Examiner has not provided evidence that bears directly on this question. We therefore cannot conclude that the rejection of the claims for lack of adequate written description is supported by a preponderance of the evidence. The rejection of claims 2, 10, 11, 14, 15, 21-27, and 55-65 under 35 U.S.C. § 112(a) is reversed. DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 2, 10, 11, 14, 15, 21- 27, 55-65 112(a) Written Description 2, 10, 11, 14, 15, 21- 27, 55-65 REVERSED