Carsten Rudolph et al.

Patent Trials and Appeals BoardNov 29, 2019

14839886 - (D) (P.T.A.B. Nov. 29, 2019)

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. 14/839,886 08/28/2015 Carsten Rudolph ETIS-009-105 7267 75436 7590 11/29/2019 MORSE, BARNES-BROWN & PENDLETON, P.C. ATTN: Patent Group Director CityPoint 480 Totten Pond Road, 4th Floor WALTHAM, MA 02451 EXAMINER NGUYEN, QUANG ART UNIT PAPER NUMBER 1633 NOTIFICATION DATE DELIVERY MODE 11/29/2019 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): patentmail@morse.law PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte CARSTEN RUDOLPH and MICHAEL KORMANN ____________ Appeal 2019-000025 Application 14/839,886 Technology Center 1600 ____________ Before DONALD E. ADAMS, TAWEN CHANG, AND RYAN H. FLAX, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims 53–60.2 We have jurisdiction under 35 U.S.C. § 6(b). We REVERSE. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies the real party in interest as ethris GmbH (Appellant’s July 27, 2018 Appeal Brief (Appeal Br.) 2). 2 Pending claims 40–52 stand withdrawn from consideration (Examiner’s Final Office Action (Final Act.) 2). Appeal 2019-000025 Application 14/839,886 2 STATEMENT OF THE CASE Appellant’s disclosure “relates to a polyribonucleotide, in particular messenger RNA, which contains a combination of unmodified and modified nucleotides, for protein expression and the use of such RNAs for the therapy of diseases and for diagnostic procedures” (Spec.3 1). Appellant’s claim 53 is representative and reproduced below: 53. A method of decreasing binding of a polyribonucleotide to retinoic acid-inducible gene I (RIG-1), comprising producing a polyribonucleotide that encodes a protein or protein fragment by in vitro transcription using a reaction mixture comprising ATP, CTP, GTP and UTP, wherein at least 5%; and not more than 50% of the UTP in the reaction mixture comprises the analog 5-iodouridine (I5U), and wherein at least 5% and not more than 50% of the CTP in the reaction mixture comprises an analog selected from the group consisting of 2’- amino-2’-deoxycytidine (C2’NH2), 2’-fluoro-2’-deoxycytidine (C2’F), or 5-iodocytidine (I5C), wherein the analog of UTP and the analogs of CTP are selected to minimize binding of the polyribonucleotide to RIG-1, and wherein the remainder of the ATP, CTP, GTP and UTP does not include a modified nucleoside; providing the polyribonucleotide so produced; and administering the polyribonucleotide to a subject or cell, wherein the protein or protein fragment encoded by the polyribonucleotide is expressed in the subject or cell, and wherein the polyribonucleotide has decreased binding to RIG-1 relative to a control polyribonucleotide that does not comprise the analogs. (Appeal Br.4 13.) 3 Appellant’s August 28, 2015 Specification. 4 Appellant’s May 16, 2018 Appeal Brief. Appeal 2019-000025 Application 14/839,886 3 Grounds of rejection before this Panel for review: I. Claims 53, 56, 59, and 60 stand rejected under 35 U.S.C. § 102(e) as anticipated by Hoerr.5 II. Claims 53–60 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Hoerr, Naldini,6 and Kariko.7 Anticipation: ISSUE Does the preponderance of evidence on this record support Examiner’s finding that Hoerr teaches Appellant’s claimed invention? FACTUAL FINDINGS (FF) FF 1. Hoerr discloses “based-modified RNA and the use thereof for increasing the expression of a protein and for the preparation of a pharmaceutical composition” and “further describes an in vitro transcription method, in vitro methods for increasing the expression of a protein using a base-modified RNA, and an ex vivo and in vivo method” (Hoerr ¶ 1; see generally Final Act.8 3). FF 2. Hoerr discloses that its “base-modified RNA . . . comprises any RNA that codes for at least one protein/peptide” (Hoerr ¶ 19; see Final Act. 3–4). FF 3. Hoerr discloses, as a preferred embodiment of its disclosure, that the base-modified RNA of the present invention may e.g. contain at least 10% of all RNA cytidine-5’-triphosphate 5 Hoerr et al., US 2010/0047261 A1, published Feb. 25, 2010. 6 Naldini et al., US 2010/0041737 A1, published Feb. 18, 2010. 7 Kariko et al., WO 2007/024708 A2, published Mar. 1, 2007. 8 Examiner’s July 3, 2017 Final Office Action. Appeal 2019-000025 Application 14/839,886 4 nucleotides (or all cytidine-5’-triphosphate nucleotides of the coding region) modified to base-modified cytidine nucleotides, . . . and/or at least 10% of all guanosine-5’- triphosphate nucleotides (or all guanosine-5’-triphosphate nucleotides of the coding region) modified to base-modified guanosine nucleotides, . . . and/or at least 10% of all uridine-5’- triphosphate nucleotides (or all uridine-5’-triphosphate nucleotides of the coding region) modified to base-modified uridine nucleotides. (Hoerr ¶ 54; see Final Act. 3–4.) FF 4. Hoerr discloses that a nucleotide having a base modification of the base-modified RNA used according to the invention is preferably selected from the group of the base-modified nucleotides consisting of: 2-amino-6-chloropurineriboside-5’-triphosphate 2-aminoadenosine-5’-triphosphate 2-thiocytidine-5’-triphosphate 2-thiouridine-5’-triphosphate 4-thiouridine-5’-triphosphate 5-aminoallylcytidine-5’-triphosphate 5-aminoallyluridine-5’-triphosphate 5-bromocytidine-5’-triphosphate 5-bromouridine-5’-triphosphate 5-iodocytidine-5’-triphosphate 5-iodouridine-5’-triphosphate 5-methylcytidine-5’-triphosphate 5-methyluridine-5’-triphosphate 6-azacytidine-5’-triphosphate 6-azauridine-5’-triphosphate 6-chloropurineriboside-5’-triphosphate 7-deazaadenosine-5’-triphosphate Appeal 2019-000025 Application 14/839,886 5 7-deazaguanosine-5’-triphosphate 8-azaadenosine-5’-triphosphate 8-azidoadenosine-5’-triphosphate benzimidazole-riboside-5’-triphosphate N1-methyladenosine-5’-triphosphate N1-methylguanosine-5’-triphosphate N 6-methyladenosine-5’-triphosphate O6-methylguanosine-5’-triphosphate pseudouridine-5’-triphosphate puromycin-5’-triphosphate xanthosine-5’-triphosphate Particular preference is given to nucleotides for base modifications selected from the group of base-modified nucleotides consisting of 5-methylcytidine-5’-triphosphate, 7- deazaguanosine-5’-triphosphate, 5-bromocytidine-5’- triphosphate, and pseudouridine-5’-triphosphate. (Hoerr ¶¶ 20–49 (emphasis added); see Final Act. 3–4.) FF 5. Hoerr discloses that its [b]ase-modified RNA sequences used according to the invention can likewise also contain sugar modifications. A sugar modification in connection with the present invention is a chemical modification of the sugar of the nucleotides present and typically includes, without implying any limitation, sugar modifications selected from the group consisting of 2’-deoxy- 2’-fluoro-oligoribonucleotide (2’-fluoro-2’-deoxycytidine-5’- triphosphate, 2’-fluoro-2’-deoxyuridine-5’-triphosphate), 2’- deoxy-2’-deamine oligoribonucleotide (2’-amino-2’- deoxycytidine-5’-triphosphate, 2’-amino-2’-deoxyuridine-5’- triphosphate ), 2’-O-alkyl oligoribonucleotide, 2’-deoxy-2’-C- alkyl oligoribonucleotide (2’-O-methylcytidine-5’-triphosphate, 2’-methyluridine-5’-triphosphate), 2’-C-alkyl oligoribonucleotide, and isomers thereof (2’-aracytidine-5’- triphosphate, 2’-arauridine-5’-triphosphate), or Appeal 2019-000025 Application 14/839,886 6 azidotriphosphate (2’-azido-2’-deoxycytidine-5’-triphosphate, 2’-azido-2’-deoxyuridine-5’-triphosphate). The base-modified RNA sequence used according to [Hoerr’s] invention preferably does not contain any sugar modifications or backbone modification, however. (Hoerr ¶¶ 56–57 (emphasis added); see Final Act. 3–4.) FF 6. Hoerr discloses: an in vitro transcription method for the preparation of base- modified RNA, comprising the following steps: a) preparation/provision of a nucleic acid coding for a protein of interest, in particular as described above; b) addition of the (desoxy)ribonucleic acid to an in vitro transcription medium comprising a RNA polymerase, a suitable buffer, a nucleic acid mix, comprising one or more base- modified nucleotides as described above as replacement for one or more of the naturally occurring nucleotides A, G, C and/or U, and optionally one or more naturally occurring nucleotides A, G, C or U if not all of the naturally occurring nucleotides A, G, C or U are to be replaced, and optionally a RNase inhibitor; c) incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid; d) optional purification and removal of the unincorporated nucleotides from the in vitro transcription medium. A nucleic acid as described in step a) of the in vitro transcription method according to the invention can be any nucleic acid as described above that codes for a protein of interest, in particular as mentioned herein, preferably a diagnostically relevant protein, a therapeutically active protein, or any other protein used or usable for laboratory or research purposes. (Hoerr ¶¶ 119–124; see Final Act. 3–5.) Appeal 2019-000025 Application 14/839,886 7 FF 7. Hoerr discloses that its “base-modified RNA . . . can be used for the preparation of a pharmaceutical composition for the treatment of tumours and cancer diseases, heart and circulatory diseases, infectious diseases or autoimmune diseases, as well as for the treatment of monogenetic diseases, for example in gene therapy” (Hoerr ¶ 105; see also id. ¶ 106; see Final Act. 3–5). FF 8. Hoerr discloses: The choice of a pharmaceutically acceptable carrier is determined in principle by the manner in which the pharmaceutical composition used according to the invention is administered. The pharmaceutical composition used according to the invention can be administered, for example, systemically. Routes for administration include, for example, transdermal, oral, parenteral, including subcutaneous or intravenous injections, topical and/or intranasal routes. (Hoerr ¶ 110; see Final Act. 4.) ANALYSIS Examiner finds that Hoerr discloses the entirety of Appellant’s claimed invention (Final Act. 3–5). We are not persuaded. “A claim is anticipated only if each and every element as set forth in the claim is found, either expressly or inherently described, in a single prior art reference.” Verdegaal Bros., Inc. v. Union Oil Co., 814 F.2d 628, 631 (Fed. Cir. 1987). In this regard, we note that “[u]nder the principles of inherency, if the prior art necessarily functions in accordance with, or includes, the claimed limitations, it anticipates.” In re Cruciferous Sprout Litig., 301 F.3d 1343, 1349 (Fed. Cir. 2002) (citations and internal quotation marks omitted). “Inherency, however, may not be established by probabilities or possibilities. The mere fact that a certain thing may result from a given set of circumstances is not sufficient.” In re Robertson, 169 Appeal 2019-000025 Application 14/839,886 8 F.3d 743, 745 (Fed. Cir. 1999) (citations and internal quotation marks omitted). The method of Appellant’s independent claim 53 requires, inter alia, the selection of an UTP and a CTP analog that minimizes binding of the polyribonucleotide to RIG-1 (see Appeal Br. 13). According to Examiner, when a person of ordinary skill in this art selects, from Hoerr’s lists of modified bases, the modified uridine and cytidine residues, 5-iodouridine (I5U) and 2’-amino-2’-deoxycytidine (C2’NH2), 2’-fluoro-2’-deoxycytidine (C2’F), or 5-iodocytidine (I5C), respectively, the resulting “mRNA molecules would inherently possess decreased binding to RIG-1” (Final Act. 4; see also id. at 7 and 8; cf. FF 4–5 (Hoerr discloses the use of a number of modified residues, including I5U and I5C)). However, Appellant’s declarant states, “I, as one of skill in the art with significant experience in this field, do not and would not have envisioned or otherwise found the presently claimed invention, with its specific combination of features, readily or immediately apparent based on the teachings of Hoerr” (Krieg Decl.9 ¶ 14; see id. ¶ 15 (Krieg declares that “the potential number of possible polyribonucleotides theoretically taught [in Hoerr] is extremely large and provides only a general disclosure from which [Appellant’s] claimed invention, with its specific combination of features, is not immediately apparent to me”); see also Reply Br. 3–4). As Examiner recognizes, Appellant “argue[s] that one of skill in the art would not select particular combinations in order to minimize binding to 9 Declaration of Arthur M. Krieg, M.D., signed November 19, 2015. Appeal 2019-000025 Application 14/839,886 9 RIG-1 when reading the Hoerr reference” (Final Act. 7). As Appellant explains: Hoerr provides no explicit disclosure for obtaining a base- modified RNA that includes only modified UTP and CTP, where the specific base-modified nucleotides are 5-iodouridine and 5-iodocytidine. Rather, as previously indicated, the disclosure of Hoerr is simply too extensive, and the possible combinations and permutations too numerous, to allow the skilled person to “at once envisage” the very specific invention now claimed. (Reply Br. 4; see id. (Appellant contends that Hoerr provides “simply no suggestion . . . that would have guided one of skill in the art to make[, inter alia,] the necessary selections of which nucleotides are to be modified . . . to obtain the claimed invention from among the vast possibilities.”).) Thus, here, as in Arkley, for the instant rejection under 35 U.S.C. § 102(e) to have been proper, the . . . reference must clearly and unequivocally disclose the claimed compound or direct those skilled in the art to the compound without any need for picking, choosing, and combining various disclosures not directly related to each other by the teachings of the cited reference. Such picking and choosing may be entirely proper in the making of a § 103, obviousness rejection . . . but it has no place in the making of a § 102, anticipation rejection. In re Arkley, 455 F.2d 586, 587–88 (CCPA 1972). On this record, Examiner failed to explain how Hoerr directs those skilled in this art to select the specific modified bases necessary to achieve Appellant’s claimed invention. CONCLUSION The preponderance of evidence on this record fails to support Examiner’s finding that Hoerr teaches Appellant’s claimed invention. The Appeal 2019-000025 Application 14/839,886 10 rejection of claims 53, 56, 59, and 60 under 35 U.S.C. § 102(e) as being anticipated by Hoerr is reversed. Obviousness: ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? FACTUAL FINDINGS (FF) FF 9. Examiner relies on Hoerr as discussed above (see Final Act. 10–12; see also FF 1–8). FF 10. Examiner finds that Hoerr does “not teach . . . a method comprising the step of producing a modified polyribonucleotide encoding a protein or protein fragment that further contain[s] a micro-RNA [(miRNA)] binding site and/or further encapsulating the modified polyribonucleotide in a nanoparticle or in a cationic lipid” (Final Act. 12–13 (emphasis omitted)). FF 11. Examiner relies on Naldini to disclose “vectors . . . for transgene expression for gene transfer and therapy . . . engineered [to contain] miRNA[] target sequence in order to be recognized by endogenous miRNAs cell type specific, thus regulating transgene expression in a subset of cells” (Final Act. 13 (emphasis omitted); see generally id. at 12–14). FF 12. Examiner relies on Kariko to disclose “an in vitro transcribed RNA molecule (e.g., mRNA) comprising . . . a modified nucleoside,” wherein “the modified RNA molecule is encapsulated in a nanoparticle” or “mixed with a cationic lipid transfection reagent” (Final Act. 14). Appeal 2019-000025 Application 14/839,886 11 ANALYSIS Based on the combination of Hoerr, Naldini, and Kariko, Examiner concludes that, at the time Appellant’s invention was made, it would have been prima facie obvious to modify Hoerr’s polyribonucleotide to “further compris[e] a micro-RNA binding site in the 3’UTR and/or the modified polyribonucleotide further encapsulated in a nanoparticle or a cationic lipid” (Final Act. 14–15). We are not persuaded. As discussed above, Examiner failed to establish an evidentiary basis on this record to support a finding, or conclusion, that a person of ordinary skill in this art would have selected only those base analogs from Hoerr that would have resulted in a polyribonucleotide having decreased binding to RIG-1 relative to a control polyribonucleotide that does not comprise the analogs, as is required by Appellant’s claimed invention (see Appeal Br. 13). In this regard, we note that an invention composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art. . . . [I]t can be important to identify a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418 (2007). On this record, Examiner further failed to explain how Naldini and Karido alone, or in combination, make up for the foregoing deficiency in Hoerr. As Appellant explains, “Naldini and Karido, whether considered alone or in combination, fail to cure these deficiencies of Hoerr” (Appeal Br. 8). Appeal 2019-000025 Application 14/839,886 12 CONCLUSION The preponderance of evidence relied upon by Examiner fails to support a conclusion of obviousness. The rejection of claims 53–60 under 35 U.S.C. § 103(a) as unpatentable over the combination of Hoerr, Naldini, and Kariko is reversed. DECISION SUMMARY In summary: Claims Rejected Basis Affirmed Reversed 53, 56, 59, 60 § 102(e) Hoerr 53, 56, 59, 60 53–60 § 103 Hoerr, Naldini, Kariko 53–60 Overall Outcome 53–60 REVERSED