Ex Parte Fox et al

Patent Trial and Appeal BoardFeb 25, 2019

13811568 (P.T.A.B. Feb. 25, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 13/811,568 06/24/2013 66469 7590 02/27/2019 RATNERPRESTIA 2200 RENAISSANCE BL VD SUITE 350 KING OF PRUSSIA, PA 19406 FIRST NAMED INVENTOR Joseph M. Fox 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. U0D-338US 4859 EXAMINER DONOHUE, SEAN R ART UNIT PAPER NUMBER 1618 NOTIFICATION DATE DELIVERY MODE 02/27/2019 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): PCorrespondence@ratnerprestia.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte NICHOLAS LOEBEL and CALE STREET Appeal2017-004485 Application 13/811,568 Technology Center 1600 Before JEFFREY N. FREDMAN, JOHN G. NEW, and RICHARD J. SMITH, Administrative Patent Judges. FREDMAN, Administrative Patent Judge. DECISION ON APPEAL This is an appeal 1,2 under 35 U.S.C. Â§ 134(a) involving claims to a radiolabeled Diels-Alder adduct of a trans-cyclooctene with a tetrazine. 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 Parties in Interest as the University of Delaware and the University of Southern California (see App. Br. 1 ). 2 We have considered and herein refer to the Specification of Jan. 22, 2013 ("Spec."); Final Office Action of Dec. 22, 2015 ("Final Act."); Appeal Brief of Aug. 22, 2016 ("App. Br."); and Examiner's Answer of Nov. 3, 2016 ("Ans."). Appeal2017-004485 Application 13/811,568 Statement of the Case Background "Positron emission tomography (PET) is a non-invasive imaging modality that utilizes positron-emitting radionuclides .... For example, F- 18 PET has a number of attributes that make it clinically attractive, including 100% positron efficiency, a very high specific radioactivity, and a short half- life of -110 min" (Spec. 1 :4--7). "The invention provides an extremely fast and reactive method for generating radionuclide labeled probes based on TTCO [tetrazine-trans-cyclooctene]-ligation, employing a Diels-Alder reaction between 3,6-diaryl-s-tetrazines and trans-cyclooctenes, one of which is labeled with a radionuclide, for example 18F" (Spec. 4:9-12). The Claims3 Claims 1, 4, 13, 14, and 20 are on appeal. Claims 1 and 20 are representative and read as follows: 1. A Diels-Alder adduct of a trans-cyclooctene with a tetrazine, wherein the adduct bears a substituent labeled with a radionuclide, wherein the substituent is a substituent on the trans-cyclooctene residue of the Diels-Alder adduct. 20. The compound according to structure 9 1~ Oh~.~ H. ~~"" 3 We limit our consideration of the merits of the appealed rejection to the elected species. See Ex parte Ohs aka, 2 USPQ2d 1460, 1461 (BP AI 1987). Thus, we read the claims as limited to compound 9 shown in claim 20 (see Response to Election/Restriction filed on June 29, 2015). 2 Appeal2017-004485 Application 13/811,568 The Issue4 The Examiner rejected claims 1, 4, 13, 14, and 20 under 35 U.S.C. Â§ 103(a) as obvious over Blackman, 5 Royzen, 6 Arstad, 7 and Zhang8 (Ans. 2- 6). The Examiner finds Blackman teaches "strained click reactions that take advantage of intrinsic reactivity of cylcooctyne towards organic azides" that "could form the basis of powerful bioorthogonal reaction" (Ans. 2). The Examiner finds that Royzen teaches "synthesis of trans-cyclooctene derivative" and functionalization of that derivative with a hydroxy substituent (see Ans. 3--4). The Examiner finds Arstad teaches "a need for labelling agents such as 18F-labelled prosthetic groups and methodologies, which allow rapid, chemoselective introduction of a label such as a radionuclide" (Ans. 4). The Examiner finds Zhang teaches a "labeling strategy has been developed for introducing 18F onto a target molecule by first attaching 18F to a prosthetic groups" (Ans. 5). 4 We note that claim 10, identified as rejected in the Examiner's Answer, was cancelled in an Amendment filed Nov. 16, 2015. 5 Blackman et al., Tetrazine Ligation: Fast Bioconjugation Based on Inverse-Electron-Demand Diels-Alder Reactivity, 130 J. Am. Chem. Soc. 13518-9 (2008). 6 Royzen et al., A Photochemical Synthesis of Functionalized trans- Cyclooctenes Driven by Metal Complexation, 130 J. Am. Chem. Soc. 3760- 1 (2008). 7 Arstad et al., WO 2006/067376 A2, published June 29, 2006. 8 Zhang et al., {1 8F]Fluoroalkyl Agents: Synthesis, Reactivity and Application for Development of PET Ligands in Molecular Imaging, 7 Current Topics in Medicinal Chem. 1817-28 (2007). 3 Appeal2017-004485 Application 13/811,568 The Examiner finds: It would have been obvious to one of ordinary skill in the art at the time of invention to modify the compounds taught by Blackman et al. (i.e., compounds transcyclooctene discussed above) by simply incorporating a [18F]fluoroethyl radical as taught by Royzen et al., because it would advantageously enable inverse-electron-demand diels- alder reactivity with appropriate tetrazine bearing biomolecule in the absence of catalysis and in tum PET imaging. (Ans. 6). The issue with respect to this rejection is: Does the evidence of record support the Examiner's conclusion that Blackman, Royzen, Arstad, and Zhang suggest the compound 9 of claim 20? Findings of Fact 1. Blackman teaches "a bioorthogonal reaction that proceeds with unusually fast reaction rates without need for catalysis: the cycloaddition of s-tetrazine and trans-cyclooctene derivatives" (Blackman 13518, col. 1). 2. Blackman teaches "[b ]ioorthogonal reactions, unnatural transformations that are unaffected by biological functionality, are broadly useful tools with applications that span synthesis, chemical biology, and materials science . . . and the enhanced reactivity enables applications for dynamic in vivo imaging" (Blackman 13 518, col. 1 ). 3. Scheme 3a of Blackman is reproduced below: an.Â· I; HOÂ· Â·. / ,_,.. 4 Blackman teaches "trans-Cyclooctene derivative 5 is readily accessible from 4 Appeal2017-004485 Application 13/811,568 cis-cyclooctene 4 by a photochemical protocol" (Blackman 13 518, col. 2). 4. Royzen teaches the "unusual reactivity and well-defined chiral structure of trans-cyclooctene make it an attractive framework for stereocontrolled synthesis" (Royzen 3760, col. 1). 5. Royzen teaches compound 2b as reproduced below: (Royzen 3761, col. 1). 6. Royzen teaches functionalizing compound 2B in Figure 2a as reproduced below: a 2b (mlnor diastereomar) NaH j l,............_,CO ... fi THF L ..,..---CQ..,H H O " ~ H s "Figure 2. (a) Preparation and X-ray structure of a trans-cyclooctene with an axial substituent. 1,3-Diaxial interactions are highlighted" (Royzen 3761, col. 1 ). 7. Arstad teaches "a need for labelling agents such as 18F-labelled prosthetic groups and methodologies, which allow rapid, chemoselective introduction of a label such as a radionuclide, for example 18F, particularly into peptides" (Arstad 1 :32 to 2:2). 8. Zhang teaches "fluorine-18 ... is an important positron emitter for theimaging study using PET due to its optimal decay characteristics ... So far, a number of methods for introducing 18F into a taqrget molecule have 5 Appeal2017-004485 Application 13/811,568 been developed" (Zhang 1817, col. 1 ). Principles of Law A prima facie case for obviousness requires "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'! Co. v. Teleflex Inc., 550 U.S. 398,418 (2007). Analysis Appellants contend that "Arstad does not discuss trans-cyclooctenes" and "provides no motivation to instead use an 18F-containing transcyclooctene, and particularly Appellants' Compound 9" (App. Br. 4--5). Appellants contend "Zhang does not disclose or suggest making compounds where the 18F fluoroalkyl group is attached to oxygen, such as Appellants' claimed compound 9" (id. at 5, emphasis omitted). Appellants contend "nothing in Zhang suggests substituting a trans-cyclooctene with an [ 18F]fluoroethyl radical" and "motivation cannot come from Zhang, who does not discuss labeling biomolecules and provides no suggestion to do so. More particularly, Zhang provides no motivation to label a biomolecule indirectly via an 18F-containing trans-cyclooctene" (id.). The Examiner responds that because "Arstad teaches click reactions that enable applications for in vivo dynamic imaging" and " 18F-labelled bioactive peptides have great clinical potential because of their utility in PET to quantitatively detect and characterize a wide range of diseases", it would have been obvious to a person of ordinary skill to incorporate 18F-label onto the diels-alder substrates of Blackman because it would advantageously enable applications for quantitative dynamic in vivo imaging and high yield conjugation without the need for a catalysis in organic solvents, 6 Appeal2017-004485 Application 13/811,568 water, cell media, or cell lysate. (Ans. 8). We find that Appellants have the better position because the Examiner has not established a persuasive "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, 550 U.S. at 418. While Blackman mentions in vivo imaging (FF 2) and Arstad and Zhang discuss the use of 18F in labeling agents (FF 78), the Examiner does not persuasively demonstrate why the ordinary artisan would have found it obvious to incorporate an 18F into the trans-cyclooctene compound 2b of Royzen. Royzen does not teach that compound 2b or compound 3 may be used in medical imaging. Royzen does not even teach that these compounds are used as biological linkers. Moreover, while Blackman generally discusses bioconjugation and medical imaging (FF 1-3), Blackman does not discuss labeling any compound, much less compound 5, with any type of label. Even the single mention of imaging in Blackman (FF 2) does not identify how the imaging occurs or provide any suggestion or reason to image using any type of label, much less a radioactive label such as 18F. Thus, the Examiner's prima facie case of obviousness is not persuasive because there is no persuasive evidence linking the 18F labeling teachings of Arstad and Zhang with the trans-cyclooctene compounds of Royzen and Blackman, sufficient to provide a reason to label a trans- cyclooctene compound with 18F. Conclusion of Law The evidence of record does not support the Examiner's conclusion that Blackman, Royzen, Arstad, and Zhang suggest the compound 9 of claim 7 Appeal2017-004485 Application 13/811,568 20. SUMMARY In summary, we reverse the rejection of claims 1, 4, 13, 14, and 20 under 35 U.S.C. Â§ 103(a) as obvious over Blackman, Royzen, Arstad, and Zhang. REVERSED 8