Ex Parte Zabetakis et al

Patent Trials and Appeals BoardMar 13, 2019

14158208 - (D) (P.T.A.B. Mar. 13, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 14/158,208 01/17/2014 26384 7590 03/13/2019 NAVAL RESEARCH LABORATORY AS SOCIA TE COUNSEL (PA TENTS) CODE 1008.2 4555 OVERLOOK A VENUE, S.W. WASHINGTON, DC 20375-5320 FIRST NAMED INVENTOR Daniel Zabetakis 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 ATTORNEY DOCKET NO. CONFIRMATION NO. 102468-USl 6953 EXAMINER SHAHNANSHAH,KHATOLS ART UNIT PAPER NUMBER 1645 MAIL DATE DELIVERY MODE 03/13/2019 PAPER 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. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte DANIEL ZABETAKIS, GEORGE P. ANDERSON, ELLEN R. GOLDMAN, KENDRICK TURNER, and P. AUDREY BROZOZOG LEE Appeal2017-008909 Application 14/158,208 Technology Center 1600 Before ULRIKE W. JENKS, TIMOTHY G. MAJORS, and MICHAEL A. VALEK, Administrative Patent Judges. MAJORS, Administrative Patent Judge. DECISION ON APPEAL Appellants 1 submit this appeal under 35 U.S.C. Â§ 134 involving claims to a method of producing a single-domain antibody expressed as a fusion protein with the acid tail of a-synuclein. The Examiner rejected the claims as obvious. We have jurisdiction under 35 U.S.C. Â§ 6(b ). We REVERSE. 1 Appellants identify the Real Party in Interest as the United States of America. App. Br. 2. Appeal2017-008909 Application 14/158,208 STATEMENT OF THE CASE Appellants' invention relates to "a method of producing a single- domain antibody ( sdAb) [that] includes causing a bacteria to express the sdAb into cytoplasm of the bacteria, wherein the sdAb is expressed as a fusion protein with the acid tail of a-synuclein." Spec. ,r 2. "Single-domain antibodies ... are recombinant derivatives of heavy- chain-only antibodies found in camelids and sharks." Id. ,r 13. As further explained in the Specification, "[b ]acterial expression is a favorable means of producing recombinant proteins in large quantities," and "[t]ypically, sdAbs are produced with a periplasmic localization tag ... [that] directs the bacterial cell to export the protein from the cytoplasm into the periplasmic space." Id. ,r 15. Exportation to the periplasm is favorable compared to the cytoplasm because, for sdAbs that contain disulfide bonds, the reducing environment of the cytoplasm tends to cleave those bonds, and render the proteins less stable. Id. ,r 16. "When sdAbs lack the disulfide bond, they do not refold on cooling after thermal denaturation." Id. ,r 17 ("loss of refolding imposes a severe limitation on the utility of sdAb"). Although exportation of proteins to the periplasm carries benefits ( e.g., "a more favorable environment for the formation of disulfide bonds"), there are downsides. Id. ,r 15. Indeed, the Specification explains, "periplasmic expression introduces a significant bottleneck in protein production ... and usually results in significantly lower yield compared to expression in the cytoplasm." Id. ,r 16. Accordingly, the Specification explains, "[i]t would be beneficial to ameliorate the effects of cytoplasmic expression in order to benefit from increased protein production." Id. 2 Appeal2017-008909 Application 14/158,208 The Specification describes "a solution to the problem of refolding of cytoplasmically expressed sdAb using the acid tail of a-synuclein (ATS)." Id. ,r 18. And, the Specification reports, "the results described herein, with the ATS tail significantly assisting refolding sdAbs, was surprising and unexpected." Id. ,r 20. Claims 1-8 are on appeal. Claim 1, the only independent claim, is illustrative, and reads: 1. A method of producing a single-domain antibody ( sdAb ), the method comprising: causing a bacteria to express the sdAb into cytoplasm of the bacteria, wherein the sdAb is expressed as a fusion protein with the acid tail of a-synuclein; and then purifying the sdAb, wherein the fusion protein is expressed free of a periplasmic location tag. App. Br. 5 (Claims App'x.). The claims are rejected under 35 U.S.C. Â§ I03(a) as obvious over Colby2 and De Genst. 3 Final Act. 2-3; Ans. 3-5. DISCUSSION The issue on appeal is whether a preponderance of the evidence cited by the Examiner supports the Examiner's conclusion of obviousness. The Examiner finds that Colby discloses methods of producing a single-domain antibody, which methods express the antibody into the 2 Colby et al., US 2005/0226863 Al, publ. Oct. 13, 2005. 3 Erwin J. De Genst et al., Structure and Properties of a Complex of a- Synuclein and a Single-Domain Camelid Antibody, 402 J. MOL. BIOL. 326-- 343 (2010). 3 Appeal2017-008909 Application 14/158,208 cytoplasm of a bacteria. Ans. 3. The Examiner further finds that Colby describes expression of the sdAb as a fusion protein, and that, via mutation, disulfide bonds are removed from the antibody. Id. at 3--4 ( citing Colby Figs. 3 and 20, ,r,r 18, 45, and 62). Because the Examiner finds that Colby does not teach the acid tail of a-synuclein, the Examiner turns to De Genst. Id. at 4. According to the Examiner, De Genst teaches the use of a single-domain antibody (NbSyn2), which binds to a-synuclein, and more specifically that NbSyn2 binds to the C-terminal residues of a-synuclein. Id.; De Genst 326 ( describing "a crystal structure ofNbSyn2 bound to a peptide encompassing the nine C-terminal residues of a-synuclein"). The Examiner finds that De Genst's disclosure of a full-length a-synuclein would inherently include the acid-tail, amino acid sequence SEQ ID No: 1 for a-synuclein. Id. (see claim 7 (reciting amino acid, SEQ ID No: 1 for the acid tail). Appellants argue that the Examiner has provided no sufficient reason to combine the references to arrive at the invention claimed. App. Br. 3--4. According to Appellants, Colby relates to cytoplasmic expression of an antibody fusion with yellow fluorescent protein, which was expressed in yeast, not bacteria. Id. at 3. De Genst, Appellants argue, "has nothing to do with bacterial expression of proteins" and "is silent regarding fusion proteins with a-synuclein." Id. Appellants contend, the Examiner's rationale "fails to explain" how Colby's teachings of disulfide-free sdAbs produced in the cytoplasm "relates to De Genst, much less explain why anyone would construct the same type of fusion protein" as claimed. Id. at 4. 4 Appeal2017-008909 Application 14/158,208 Appellants also argue that the claimed invention provides unexpected results-namely "the ability of the acid tail of a-synuclein to significantly assist in refolding." Id. at 4 (citing Spec. ,r 20). As to those alleged unexpected results, Appellants contend the Examiner has provided no coherent response or contravening evidence. Reply 2. 4 Appellants' argument, on the record before us, is persuasive. It is the Examiner's burden to make a prima facie showing of obviousness. In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992) (The Examiner "bears the initial burden ... of presenting aprimafacie case ofunpatentability."). Here, however, the Examiner has not done so. The Examiner fails to provide any legally-sufficient, and evidence- backed, reason to explain why Colby and De Genst would be combined to arrive at the subject matter of claim 1. As Appellants contend, "the Examiner has not provided any reason why a person of ordinary skill in the art would modify the references by isolating the acid tail of a-synuclein to express as part of a fusion protein with a single-domain antibody in the cytoplasm of a bacteria." Reply 1. That De Genst may disclose a-synuclein and its sequence, and describe a single-domain antibody (NbSyn2) designed to target and bind to a-synuclein, does not establish a motivation to express an sdAb as a fusion protein having the acid tail of a-synuclein as claimed. Colby describes methods to express single-domain antibodies, including as 4 Appellants' June 1, 2017 Reply Brief does not include page numbers, but we treat the filing as though the pages were consecutively numbered. 5 Appeal2017-008909 Application 14/158,208 fusions with yellow fluorescent protein (YFP), in the cytoplasm. 5 But Colby is unrelated a-synuclein, and no portion of Colby or other persuasive reasoning is cited to explain why the ordinarily skilled person would design sdAb fusions with the a-synuclein tail. This is not, as the Examiner responds, a matter of arguing the references individually. Ans. 6-7. Rather, this goes to a threshold legal and factual matter for which the Examiner bears the burden of proof. That is, assuming all the limitations of claim 1 may be found within a combination of Colby and De Genst, the Examiner is still required to establish some "apparent reason to combine the known elements in the fashion claimed." KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,418 (2007). 6 Having decided that the Examiner has not provided a persuasive reason to combine the teachings of Colby and De Genst to arrive at the method of claim 1, prima facie obviousness is not shown. We need not reach Appellants' evidence of alleged unexpected results. For the reasons above, the preponderance of the evidence does not support the Examiner's conclusion of obviousness. Accordingly, we reverse the rejection of claim 1 and dependent claims 2-8. In re Fritch, 972 F.2d 5 Colby's teachings are not limited to expression in yeast, as Appellants' contentions suggest. App. Br. 3. To the contrary, Colby broadly describes eukaryote and prokaryote recombinant host systems, and suggests expression in bacteria (e.g., E. coli). Colby~~ 117-118. 6 "[A] patent composed of several elements is not proved obvious merely by demonstrating that each of its elements was, independently, known in the prior art." KSR, 550 U.S. at 418. "[I]t can be important to identify a reason that would have prompted a person of ordinary skill in the relevant field to combine elements in the way the claimed new invention does." Id. 6 Appeal2017-008909 Application 14/158,208 1260, 1266 (Fed. Cir. 1992) ("[D]ependent claims are nonobvious if the independent claims from which they depend are nonobvious."). SUMMARY We reverse the rejection for obviousness on appeal. REVERSED 7