Ex Parte Chang et alDownload PDFPatent Trial and Appeal BoardNov 20, 201713642082 (P.T.A.B. Nov. 20, 2017) Copy Citation 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. 13/642,082 07/17/2013 Christopher J. Chang BERK-134 6916 84220 7590 11/22/2017 UC Berkeley - OTL Bozicevic, Field & Francis LLP 201 REDWOOD SHORES PARKWAY SUITE 200 REDWOOD CITY, CA 94065 EXAMINER DONOHUE, SEAN R ART UNIT PAPER NUMBER 1618 NOTIFICATION DATE DELIVERY MODE 11/22/2017 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): docket@bozpat.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte CHRISTOPHER J. CHANG, GENEVIEVE C. vande BITTNER, ELENA A. DUBIKOVSKAYA, and CAROLYN R. BERTOZZI1 Appeal 2016-007504 Application 13/642,082 Technology Center 1600 Before JEFFREY N. FREDMAN, TAWEN CHANG, and RYAN H. FLAX, Administrative Patent Judges. FLAX, Administrative Patent Judge. DECISION ON APPEAL This is a decision on appeal under 35 U.S.C. § 134(a) involving claims directed to a compound. Claims 1—13 are on appeal as rejected under 35 U.S.C. § 103(a) and for obviousness-type double patenting. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 Appellants identify the Real Party in Interest as “The Regents of the University of California.” App. Br. 3. Appeal 2016-007504 Application 13/642,082 STATEMENT OF THE CASE The Specification states: Reactive oxygen species (ROS) are involved in various cell signaling pathways that are necessary for cell growth and survival. Correlations have been shown between misregulation of ROS and various diseases, including cancer, diabetes, heart disease, and neurodegenerative diseases. Hydrogen peroxide has been a focus of research geared toward understanding ROS in health and disease because it is a relatively long-lived ROS; thus, it is able to travel through a cell or even across cell membranes before it reacts with a target biomolecule. Various efforts have been made to detect hydrogen peroxide. For example, fluorescent scaffolds with boronate detection groups have been synthesized for the examination of hydrogen peroxide in cellular systems. Chemiluminescent probes based on peroxalate nanoparticles or on luminol, have been developed. There remains a need in the field for compounds and methods of detecting ROS, including hydrogen peroxide. Spec. H3—5. Claims 1 and 12 are independent claims. We find Claim 1 to be representative and it is reproduced below: 1. A compound of the formula L>Y (Formula I) wherein R1 and R2 are selected from hydrogen and alkyl; or R1 and R2 together form a boronic ester ring or substituted boronic ester ring; 2 Appeal 2016-007504 Application 13/642,082 wherein A ring is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; wherein L1 is cleavable linker group that provides for release of Y upon reaction of the-B(OR1)(OR2) group with a reactive oxygen species; and wherein Y is a detectable moiety selected from luciferin, an aminoluciferin, a coelenterazine, a modified coelenterazine, a coelenterazine analog, dihydroluciferin, luciferin 6' methylether and luciferin 6' chloroethylether that is released upon reaction of the compound with a reactive oxygen species to generate a detectable signal. App. Br. 23 (Claims App’x). The following rejections are on appeal: Claims 1—8 and 13 stand rejected under 35 U.S.C. § 103(a) over Chang,2 Jones,3 Srikun,4 Patani,5 and/or Rao.6 Final Action 4; Answer 3. Claims 1—4 and 9-13 stand rejected under 35 U.S.C. § 103(a) over Chang, Jones, Srikun, Patani, Adamczyk,7 and/or Rao. Final Action 4; Answer 7. 2 US 2007/0141658 A1 (published June 21, 2007) (“Chang”). 3 Lisa R. Jones et al., Releasable Luciferin-Transporter Conjugates: Tools for the Real-Time Analysis of Cellular Uptake and Release, 128 J. Am. Chem. Soc. 6526-27 (2006) (“Jones”). 4 Duangkhae Srikun et al., An ICT-Based Approach to Ratiometric Fluorescence Imaging of Hydrogen Peroxide Produced in Living Cells, 130 J. Am. Chem. Soc. 4596-97 (2008) (“Srikun”). 5 George A. Patani & Edmond J. LaVoie, Bioisosterism: A Rational Approach in Drug Design, 96 Chem. Rev. 3147—76 (1996) (“Patani”). 6 US 2009/0246862 Al (published Oct. 1, 2009) (“Rao”). 7 Maciej Adamczyk et al., Synthesis of 3,7-dihydroimidazo[l,2a]pyrazine-3- ones and Their Chemiluminescent Properties, 59 Tetrahedron 8129-42 (2003) (“Adamczyk”). 3 Appeal 2016-007504 Application 13/642,082 Claims 1—13 stand rejected under the ground of non-statutory double patenting over claims 1, 2, and 14—18 of Chang 823s in view of Jones, Srikun, Patani, Adamczyk, and/or Rao. Final Action 8; Answer 9. Claims 1—13 stand rejected under the ground of non-statutory double patenting over claims 1, 2, and 14—18 of Chang 2588 9 in view of Jones, Srikun, Patani, Adamczyk, and/or Rao. Final Action 8; Answer 11. DISCUSSION Only those arguments made by Appellants in the Briefs have been considered in this Decision. Arguments not presented in the Briefs are waived. See 37 C.F.R. § 41.37(c)(l)(iv). I. Obviousness In analyzing patentability and determining obviousness “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007). “[Wjhen the question is whether a patent claiming the combination of elements of prior art is obvious,” the answer depends on “whether the improvement is more than the predictable use of prior art elements according to their established functions.” Id. at 417. “If a person of ordinary skill can implement a predictable variation [of a known work], § 103 likely bars its patentability.” Id. “For the same reason, if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar 8 US 7,842,823 B2 (issued Nov. 30, 2010) (“Chang 823”). 9 US 8,791,258 B2 (issued July 29, 2014) (“Chang 258”). 4 Appeal 2016-007504 Application 13/642,082 devices in the same way, using the technique is obvious unless its actual application is beyond his or her skill.” Id. The obviousness analysis “can take account of the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. at 418. “A person of ordinary skill is also a person of ordinary creativity, not an automaton.” Id. at 421. Obviousness over Chang, Jones, Srikun, Patani, and/or Rao We find, in view of the above-cited precedent, the Examiner has established a prima facie case that claim 1 would have been obvious over the cited prior art combination and we agree with and adopt the Examiner’s reasoning and findings of fact. Answer 3—8, 12—16. For example, as determined by the Examiner, Chang is directed, most generally, to detecting H2O2 with a cell-permeable, light-emitting probe, attached to a carrier via a linker, and, more specifically, to “fluorogenic probes for reactive oxygen species” that “utilize a boronate deprotection mechanism to provide high selectivity and optical dynamic range for detecting EfCE.” Chang Abstr., 1140,71; see also Answer 4—5 (discussing Chang). Chang teaches “an array of pro-fluorescent compounds that include at least one boronate moiety,” like appealed claim 1 and as specifically recited by appealed claim 2, bound to an aryl group, and also potentially bound to an “electron withdrawing, electron donating group and/or linker group, optionally attaching the compound to a carrier species” and/or “a fluorophore.” Chang 1171, 78, 81; see also Answer 4—5 (discussing Chang). Chang states, “[a]n array of other strategies for attaching linkers to a useful probe and forming conjugates between the probe and a carrier species are known to those of skill in the art.” Chang | 82. Such “a linker . . . can be located at any 5 Appeal 2016-007504 Application 13/642,082 position on any aryl nucleus or on a chain.” Id. 198. The Examiner states that Chang does not disclose the identical compound claimed, where a boronic ester is tethered to an aryl group, which is connected with a cleavable linker, and that Chang does not teach luciferin derivatives of the formulas II, III, and IV claimed. Answer 5. Further, like Chang, Jones is directed to using light-emitting, molecular probes with associated releasable linkers for the real-time analysis of cellular uptake (and, necessarily, cellular composition). Jones 6526. Jones is cited for teaching that luciferin is a well-known fluorescing compound to serve as a releasable-reporter-cellular-assay. Jones 6526—27; see also Answer 5 (discussing Jones). Jones teaches that luciferin emits light upon the uptake of the conjugate, of which it is a part, into cells and the luciferin’s subsequent release from the conjugate via the cleaving of a linker. Jones 6527 (left col.); see also Answer 5 (discussing Jones). Thus, Jones teaches that a cell-permeable conjugate that can release luciferin would be an effective agent to visually identify such release in real-time. Jones indicates that avoiding the use of protecting groups (e.g., like those used in Chang) by using its transporter-linker-conjugate provides the advantage of flexibility and economical processing for a transporter-probe-conjugate system. Jones 6526 (right col.). Therefore, Jones provides motivation for its combination with Chang to achieve this stated advantage. Moreover, Srikun is cited as disclosing an TECE-detecting, fluorescing compound, Peroxy Lucifer 1 (PL1), which is taught to be “capable of visualizing highly localized changes in H2O2 concentrations generated by live cells.” Srikun 4596 (left col.); see also Answer 6 (discussing Srikun). 6 Appeal 2016-007504 Application 13/642,082 As a logical intermediary between Chang and Jones, Srikun discloses that a “[rjeaction of PL1 with H2O2 triggers chemoselective cleavage of a boronate-based carbamate protecting group to deliver the green fluorescent aminonaphthalimide dye 3.” Srikun 4596 (right col.). This cleavage is based on FLCF-mediated boronate cleavage deprotection and is highly selective. Id. 4596, 4597. Like Chang, Srikun teaches using the same boronate-based groups as recited in the appealed claims. Appellants’ arguments over this (and every other) rejection are based on the contention that the references are too different from one another to reasonably be combined and that doing so would circumvent the goals of the respective references. Appellants also frame the Examiner’s rejection(s) as focusing on Chang as a primary reference, only to be tweaked by modifications based on the other references; overlooking that “where a rejection is predicated on [multiple] references each containing pertinent disclosure ... we deem it to be of no significance, but merely a matter of exposition, that the rejection is stated to be on A in view of B instead of on B in view of A, or to term one reference primary and the other secondary.” In re Bush, 296 F.2d 491, 496 (CCPA 1961). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” KSR, 550 U.S. at 420. Further, “[n]on-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references. . . . [The references] must be read, not in isolation, but for what [they] fairly teach[] in combination with the prior art as a whole.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). 7 Appeal 2016-007504 Application 13/642,082 Appellants argue that Chang does not disclose imaging in vivo in a live subject or a detectable moiety Y as claimed. App. Br. 9; see also id. at 11 (similar argument regarding Srikun). This argument is not persuasive. Claim 1 does not recite imaging in vivo in a live subject; claim 1 is a compound claim, not a method claim. Also, the Examiner acknowledged that Chang does not disclose the specific fluorescing compounds of the appealed claims, but cites other prior art that is reasonably combined with Chang for such disclosure; the various references disclose the component parts claimed and suggest their combination. Appellants also argue: The proposed incorporation of Jones’ luciferin and Srikun’s cleavable linking group into Chang’s pro-fluorescent compounds would produce a compound that retains none of the characteristics of Chang’s fluorogenic probe and no longer follows a reaction pathway that involves oxidative addition of a -OH group to a profluorophore to produce a fluorophore. Rather, the proposed modification to Chang would require an external activating enzyme, e.g., luciferase, to generate a signal. As such, the proposed modification would destroy the principle of operation of Chang’s fluorogenic probe that does not require an external activating enzyme. App. Br. 10. In support, Appellants cite Chang at paragraph 3,10 which identifies one of several drawbacks of the prior art to be “the need for [an] external activating enzyme.” Id. We are not persuaded by this argument. While it is accurate that Chang identifies this aspect of the prior art as undesirable, it is an overextended interpretation of Chang by Appellants to 10 Appellants cite to the patented, issued version of the publication Chang, but we refer herein to the published version cited by the Examiner. 8 Appeal 2016-007504 Application 13/642,082 suggest that Chang teaches omitting “an external activating enzyme” to be a “principle of operation” of its disclosed invention. While not needing an enzyme for fluorescence might be an advantage offered by Chang’s disclosed invention, it is not described as a critical, essential, or even particularly important, feature. Appellants also argue that there would have been no reason to modify Chang in view of Jones because Chang’s contended core advantage of not requiring an external enzyme (or a bioluminescent substrate), such as would be used in a luciferin-based probe, would be destroyed by such a modification. App. Br. 10—12 (citing Eisai Co. Ltd. v. Dr. Reddy’s Labs., Ltd., 533 F.3d 1353 (Fed. Cir. 2008)). This argument is not persuasive. “[A] given course of action often has simultaneous advantages and disadvantages, and this does not necessarily obviate motivation to combine.” Medichem, S.A. v. Rolabo S.L., 437 F.3d 1157, 1165 (Fed. Cir. 2006). Jones specifically states that “[t]he avoidance of protecting groups [like those used in Chang] in this sequence provides a flexible and step economical route to these densely functionalized transporter conjugates, which bodes well for the use of this system for the synthesis and study of other transporter-linker conjugates.” Jones 6526 (right col.). Thus, Jones explicitly provides a reason to modify a system as disclosed in Chang to omit protecting groups in favor of a luciferin-based probe for quantifying in vitro and in vivo cell activities in real time. Id. at 6526—27. As determined by the Examiner, the claimed compound is no more than the predictable use of prior art elements according to their established 9 Appeal 2016-007504 Application 13/642,082 functions. For the reasons above, we are unpersuaded that the Examiner erred in the determination of obviousness and we affirm this rejection. Obviousness over Chang, Jones, Srikun, Patani, Adamczyk, and/or Rao We find the Examiner has established a prima facie case that claim 1 would have been obvious over this cited prior art combination and we agree with and adopt the Examiner’s reasoning and findings of fact. Answer 3—9, 12—16. In addition to the teachings of the other cited prior art, as discussed above, the Examiner also cited Adamczyk as disclosing “a concise and versatile synthesis of several 3,7-dihydroimidazo[l,2a]pyrazine-3-ones, including those with functionality for conjugation” and the “relative chemiluminescence signal” provided thereby. Id. at 8 (citing Adamczyk 8129,8130,8132,8134). Appellants make only the same arguments over this rejection that they made for the first obviousness rejection, which were discussed above as not being persuasive. App. Br. 13—18. As indicated above, we conclude that the balance of evidence supports that the Examiner did not err in making this obviousness rejection and, therefore, we affirm the rejection. II. Double Patenting Double Patenting over Chang 823 and the previously cited prior art combination The Examiner determined that the appealed claims would have been obvious over the claims of the Chang 823 patent in view of the prior art combination cited in the obviousness rejections discussed above. Answer 9. The Examiner determined that the Chang 823 claims are directed to the 10 Appeal 2016-007504 Application 13/642,082 chemical conjugate formula disclosed by Chang at paragraph 71, which is discussed above. As we concluded, supra, this chemical compound, combined with Jones, Srikun, Patani, Rao, and/or Adamczyk would have rendered the appealed claims obvious. Appellants only argue this rejection as follows: Appellants note that U.S. Patent No. 7,842,823 is the issued patent corresponding to Chang et al. (US 2007/0141658), discussed above. As such, the arguments applied in the Grounds of Rejection II under 35 U.S.C. § 103(a) over Chang, in view of Jones, Srikun, Patani, Adamczyk and/or Rao, discussed in detail above, may also be applied here to this rejection. App. Br. 18. We remain unpersuaded by these arguments. Therefore, for the same reasons as set forth above concerning the obviousness rejections, we affirm this double patenting rejection. Double Patenting over Chang 258 The Examiner determined that the appealed claims would have been obvious over the claims of the Chang 258 patent in view of the prior art combination cited in the obviousness rejections discussed above. Answer 9. The Examiner determined that the Chang 258 claims are directed to a chemical conjugate formula similar to that disclosed by Chang at paragraph 72. As we concluded, supra, such a chemical compound, combined with Jones, Srikun, Patani, Rao, and Adamczyk would have rendered the appealed claims obvious. Appellants present essentially the same arguments over the claims of Chang 258 as made over the Chang reference in relation to the obviousness rejections, i.e., that Chang 258 fails to disclose the detectable moiety Y, cleavable linker and aryl group of the appealed claims, and present the same 11 Appeal 2016-007504 Application 13/642,082 arguments over the other cited references. App. Br. 18—21. We remain unpersuaded by these arguments for the reasons discussed above. Therefore, for the same reasons as set forth above concerning the obviousness rejections, we affirm this double patenting rejection. SUMMARY The obviousness rejection over Chang, Jones, Srikun, Patani, and/or Rao is affirmed. The obviousness rejection over Chang, Jones, Srikun, Patani, Adamczyk, and/or Rao is affirmed. The double patenting rejection over Chang 823, in view of Jones, Srikun, Patani, Adamczyk, and/or Rao, is affirmed. The double patenting rejection over Chang 258, in view of Jones, Srikun, Patani, Adamczyk, and/or Rao, is affirmed. TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § 1.136(a). AFFIRMED 12 Copy with citationCopy as parenthetical citation