GE HEALTHCARE LIMITED

Patent Trials and Appeals BoardMar 16, 2021

2020004379 (P.T.A.B. Mar. 16, 2021)

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. 15/102,511 06/07/2016 Torgrim Engell 037380.00044-272151- US-6 8512 170688 7590 03/16/2021 Culhane Meadows PLLC Jeff B. Vockrodt 130 7th Avenue #308 New York, NY 10011 EXAMINER DONOHUE, SEAN R ART UNIT PAPER NUMBER 1618 NOTIFICATION DATE DELIVERY MODE 03/16/2021 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): eOfficeAction@AppColl.com jvockrodt@cm.law patentdocket@cm.law PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte TORGRIM ENGELL, ANDREAS RICHARD MEIJER, IMTIAZ AHMED KHAN, ROBERT JAMES NAIRNE, and GRAEME MCROBBIE __________ Appeal 2020-004379 Application 15/102,511 Technology Center 1600 __________ Before ERIC B. GRIMES, RICHARD M. LEBOVITZ, and FRANCISCO C. PRATS, Administrative Patent Judges. PRATS, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims 1–5, 8–12, 14–16, and 20–26. Appellant presented oral argument on March 2, 2021. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 We use the word “Appellant” to refer to “applicant” as defined in 37 C.F.R. § 1.42. Appellant identifies GE Healthcare Limited as the real party in interest. Appeal Br. 1. Appeal 2020-004379 Application 15/102,511 2 STATEMENT OF THE CASE Rejections The following rejections are before us for review: (1) Claims 1–5, 8, 9, 11, 12, 14–16, 20–22, and 24–26, under 35 U.S.C. § 103 as being unpatentable over Engell,2 Barnett,3 and Lemaire.4 Final Act. 4–6 (entered September 4, 2019); and (2) Claims 1–5, 8–12, 14–16, and 20–26, under 35 U.S.C. § 103 as being unpatentable over Engell, Barnett, Lemaire, and Hiscock.5 Final Act. 6–7. The Invention Appellant’s invention “relates to the field of radiopharmaceuticals for in vivo imaging, in particular to a method of purifying a radiotracer which comprises [an] 18F-labelled aminoxy-functionalised biological targeting moiety.” Spec. 1. The Specification discloses that a number of 18F-labelled radiotracer compounds were known in the prior art to be susceptible to radiolytic decomposition, and that radioprotectant compounds such as ascorbic acid and 4-aminobenzoic acid (also known as pABA or para-aminobenzoic acid) 2 WO 2013/174909 A1 (published Nov. 28, 2013). 3 US 2013/0209358 A1 (published Aug. 15, 2013). 4 C. Lemaire et al., Solid Phase Extraction – An Alternative to the Use of Rotary Evaporators for Solvent Removal in the Rapid Formulation of PET Radiopharmaceuticals, 42 J. LABELLED CPD. RADIOPHARM. 63–75 (1999). 5 WO 2012/087912 A1 (published June 28, 2012). Appeal 2020-004379 Application 15/102,511 3 were used to address the radiolysis problem. See Spec. 5–6 (citing Engell, Barnett, and Lemaire). Investigating the radiolysis problem, the inventors of the present application ascertained “the radiochemical impurities present in 18F-labelled aminoxy-functionalised biological targeting moieties, and how the levels of such impurities vary over time.” Spec. 6. “That investigation led to the understanding that in-process radiolysis during attempted purification was the root cause of the RCP (radiochemical purity) problems.” Id. Appellant’s claim 1 is representative and reads as follows: 1. A method of purification of a radiotracer which comprises the following steps: (a) provision of a crude radiotracer composition which comprises an 18F-labelled aminoxy functionalized biological targeting moiety (BTM); (b) adding a formulation buffer that comprises a radioprotectant at a first concentration to said crude radiotracer composition to give a radiotracer solution which comprises said radiotracer in one or more aqueous water-miscible organic solvent(s) of 5 to 25% v/v organic solvent content; (c) passing the radiotracer solution from step (b) through a reverse phase SPE cartridge, wherein the radiotracer is retained on said SPE cartridge; (d) washing the SPE cartridge from step (c) one or more times with a wash solution which comprises a radioprotectant at a second concentration in an aqueous water-miscible organic solvent(s) solution of 15 to 25% v/v organic solvent content; (e) washing the SPE cartridge from step (d) one or more times with water or aqueous buffer solution; and (f) eluting the washed SPE cartridge of step (d) or (e) with an elution solution which comprises a radioprotectant in a third concentration in an aqueous ethanol solution having an ethanol Appeal 2020-004379 Application 15/102,511 4 content of 35 to 80 % v/v, wherein the eluent comprises purified radiotracer in said elution solution; wherein each radioprotectant independently comprises one or more of: ascorbic acid; para-aminobenzoic acid; and gentisic acid, and salts thereof with a biocompatible cation, and wherein the first, the second, and the third concentrations of the radioprotectant can be the same or different. Appeal Br. (Claims Appendix 1).6 DISCUSSION The Examiner’s Rejection The Examiner cited Engell as teaching a process of purifying the radiotracer compound [18F]fluciclatide, a biological targeting moiety encompassed by claim 1, using a solid phase extraction (SPE) procedure having steps corresponding substantially to the steps recited in Appellant’s claim 1. Final Act. 4. Specifically, the Examiner found that Engell’s process includes the steps of applying a formulation buffer containing [18F]fluciclatide to an SPE cartridge, washing the cartridge having the [18F]fluciclatide retained thereon with a wash solution, and then eluting the [18F]fluciclatide from the SPE cartridge with an elution solution. Id. The Examiner noted in particular Engell’s teaching that, after elution from the SPE cartridge, the [18F]fluciclatide was diluted in a buffer that contained the radioprotectant compound pABA. Id. The Examiner found that Engell’s process differs from the process of Appellant’s claim 1 in that Engell does not teach “adding a formulation 6 The Claims Appendix does not include page numbers. In citing to the Claims Appendix we cite to the first page as page 1, and the remaining pages as if numbered consecutively. Appeal 2020-004379 Application 15/102,511 5 buffer that [contains] a radioprotectant such as pABA; washing the SPE cartridge one or more times with solution which comprises a radioprotectant at a second concentration, and eluting the washed SPE [cartridge] with an elution solution which comprises a radioprotectant in a third concentration.” Final Act. 4. The Examiner cited Barnett and Lemaire as evidence that it would have been obvious to include a radioprotectant in the radiotracer formulation buffer, SPE cartridge wash solution, and SPE elution solution used in Engell’s process, as recited in Appellant’s claim 1. See Final Act. 4–6. In particular, the Examiner cited Barnett as disclosing that, because [18F]fluciclatide suffers from the problems of radioactive instability at higher radioactive concentrations, and insufficient radiochemical purity at longer times after synthesis, it is desirable to include the radioprotectant compound pABA in [18F]fluciclatide formulations. See id. at 4–5. The Examiner cited Lemaire as disclosing that, because the radiotracer compound [18F]altanserin is very sensitive to radiolytic composition, when using SPE to purify [18F]altanserin it is desirable to include the radioprotectant compound ascorbic acid in the formulation buffer, as well as the solution used for washing the SPE cartridge including the affixed [18F]altanserin, as recited in Appellant’s claim 1. Final Act. 5. Based on the cited references’ combined teachings, the Examiner concluded that it would have been obvious to modify Engell’s process of using SPE to purify [18F]fluciclatide by including a radioprotectant such as pABA in Engell’s formulation buffer, SPE wash solution, and SPE elution solution, “because it would advantageously enable preventing radiolytic decomposition during SPE purification and wherein the radioprotectant, Appeal 2020-004379 Application 15/102,511 6 pABA, is advantageously suitable for stabilizing [18F]fluciclatide.” Final Act. 5–6. Analysis [T]he examiner bears the initial burden . . . of presenting a prima facie case of unpatentability. . . . After evidence or argument is submitted by the applicant in response, patentability is determined on the totality of the record, by a preponderance of evidence with due consideration to persuasiveness of argument. In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir. 1992); see also In re Jung, 637 F.3d 1356, 1365 (Fed. Cir. 2011) (holding that requiring an applicant to identify “reversible error” in an examiner’s rejection is consistent with long standing Board practice). In the present case, having carefully considered all of the evidence and argument presented by Appellant and the Examiner, we are not persuaded that Appellant has shown reversible error in the Examiner’s conclusion of obviousness as to the process recited in Appellant’s representative claim 1. Appellant contends that the issue of obviousness in this appeal involves the following four questions: 1. Whether there was a reason to add radioprotectant to the crude radiotracer before loading on the SPE cartridge in step (b) of Example 5 in Engell to meet the requirement step (b) of independent claims 1 and 20 based on what was known to a person having ordinary skill in the art at the time of the invention; 2. Whether there was a reason to add radioprotectant to the ethanol phosphoric acid wash of step (c) of Example 5 in Engell to meet the requirement of step (d) of independent claims 1 and 20 based on what was known to a person Appeal 2020-004379 Application 15/102,511 7 having ordinary skill in the art at the time of the invention; 3. Whether there was reasonable expectation of success (e.g., expectation of improved radiochemical purity) for adding radioprotectant when those of skill in the art had no knowledge that radiolysis was happening during the purification of a crude radiotracer on the SPE cartridge; and 4. Whether an unexpected increase in radiochemical purity from 79% to 92% based on adding radioprotectant during steps (b) and (d) demonstrates nonobviousness. Appeal Br. 3–4. As to the first issue, Appellant does not persuade us that the Examiner made reversible error in determining that a skilled artisan had a sufficient reason for adding a radioprotectant to Engell’s radiotracer-containing formulation buffer, before loading the buffer onto the SPE cartridge, as recited in step (b) of Appellant’s claim 1. Specifically, Engell discloses that before being loaded onto the SPE cartridge, the radiotracer used in its experiments, [18F]fluciclatide, was prepared by conjugating [18F]-Fluorobenzaldehyde to a precursor compound. See Engell 26 (Example 4 of Engell disclosing preparation of [18F]fluciclatide via the “conjugation of [18F]-FBA with Precursor 1”); see also id. (Example 5 of Engell disclosing that “the [18F]-fluciclatide solution to be purified (from Example 4) was . . . transferred to the conditioned SPE cartridge”). Engell discloses that acidifying the [18F]-fluciclatide solution before application to the SPE cartridge removes impurities generated by the conjugation reaction. See Engell 4 (“The present method includes an acidification step, which is crucial in ensuring the removal of the DMAB- Appeal 2020-004379 Application 15/102,511 8 peptide conjugate impurity.”); id. at 26 (Example 5 of Engell disclosing addition of H3PO4 to solution for conditioning SPE cartridge as well as [18F]- fluciclatide solution). Barnett discloses preparing [18F]fluciclatide by the same process as Engell—conjugation of [18F]-Fluorobenzaldehyde to Precursor 1. See Barnett ¶ 132 (Example 4 of Barnett). Barnett discloses that preparing [18F]fluciclatide by prior art methods, including conjugating [18F]-Fluorobenzaldehyde to Precursor 1, suffers from certain problems, including: “(i) radioactive instability at higher radioactive concentration (RAC)—meaning that the number of patient doses available from a given radioactive synthesis is limited[, which] means that the radioactive synthesis must be carried out repeatedly when multiple doses are required;” and “(ii) insufficient radiochemical purity (RCP) at longer times after synthesis—thus limiting the usable clinical imaging shelf-life post synthesis.” Barnett ¶¶ 32–33. Barnett discloses that these problems can be addressed “by using the radioprotectant para-aminobenzoic acid (i.e. 4-aminobenzoic acid; pABA) or biocompatible salts thereof.” Barnett ¶ 36. Barnett discloses that its pABA radioprotectant can be added either to the [18F]fluoride precursors used in the conjugation reaction, or to the [18F]fluciclatide following conjugation. Barnett ¶¶ 66–69. Barnett discloses that combining [18F]fluciclatide with pABA, and then subjecting the [18F]fluciclatide to HPLC, results in a significantly higher RCP (radiochemical purity) than when [18F]fluciclatide is not combined with pABA. Barnett ¶ 133 (Barnett’s Example 5). Appeal 2020-004379 Application 15/102,511 9 Barnett thus teaches that adding its pABA radioprotectant to an [18F]fluciclatide-containing solution after synthesis by via conjugation of [18F]-Fluorobenzaldehyde to Precursor 1, but before subsequent purification steps, as recited in Appellant’s claim 1, is desirable because it significantly inhibits the loss of RCP after the [18F]fluciclatide is prepared. Lemaire, similar to Barnett, teaches the desirability of adding a radioprotectant to an [18F]radiotracer compound before subsequent purification steps. Lemaire describes an evaluation of SPE, the same purification technique recited in Appellant’s claim 1, as a method of removing solvents used in the preparation of radiopharmaceuticals. Lemaire 63. Lemaire explains that, “[b]ecause of the short half-lives of the radionuclides used in PET . . ., 18F (T= 110 min) . . . and of the radioactive decay throughout the procedure, time is an important constraint in the synthesis.” Id. Lemaire discloses that one of the radiotracer compounds used in its methods, [18F]altanserin, “is very sensitive to radiolytic decomposition.” Lemaire 69. Lemaire’s experiment involved an initial HPLC step, followed by application of the HPLC-treated [18F]altanserin to the SPE cartridge. See id. at 66. Lemaire discloses that, because of [18F]altanserin’s high sensitivity to radiolytic decomposition, the radioprotectant compound ascorbic acid was included in the [18F]altanserin-containing buffer before the buffer was applied to the SPE cartridge, as recited in Appellant’s claim 1. See Lemaire 69 (“As high specific radioactivity [18F]altanserin may be sensitive to radio- decomposition on the support, the same saline/[0.1%] ascorbic solution as for the [SPE cartridge] conditioning was used for the dilution of the fraction collected from the HPLC.”). Appeal 2020-004379 Application 15/102,511 10 In addition to disclosing inclusion of a radioprotectant in the radiotracer-containing formulation buffer applied to the SPE cartridge, Lemaire also discloses including a radioprotectant in the washing solution applied to the SPE cartridge having the radiotracer adsorbed thereon, as recited in step (d) of Appellant’s claim 1, before elution from the SPE cartridge material. See Lemaire 66 (“The SPE cartridge was washed twice with 0.9% NaCl/0.1% ascorbic acid (20 mL) and [18F]altanserin eluted with ethanol (600 μL)”). Thus, to summarize, Barnett teaches that adding its pABA radioprotectant to an [18F]fluciclatide-containing solution after synthesis via conjugation of [18F]-Fluorobenzaldehyde to Precursor 1, but before subsequent purification steps, significantly inhibits the loss of RCP in [18F]fluciclatide preparations. Lemaire, moreover, teaches that because of potential radiolysis “on the support” used in SPE purification of an [18F]radiotracer compound, it is desirable to include a radioprotectant in the radiotracer-containing buffer before it is applied to the SPE cartridge. Lemaire 69. Given these teachings, we agree with the Examiner that a skilled artisan had a good reason for, and a reasonable expectation of success in, including a radioprotectant in the [18F]fluciclatide-containing buffer applied to the SPE cartridge in Engell’s process. Appellant does not persuade us, therefore, that the Examiner erred in finding that a skilled artisan had motivation for including a radioprotectant in a radiotracer-containing buffer, before applying the buffer to an SPE cartridge, as recited in step (b) of Appellant’s claim 1. See Appeal Br. (Issue 1). Appeal 2020-004379 Application 15/102,511 11 Moreover, given Lemaire’s inclusion of a radioprotectant in the washing solution applied to the SPE cartridge after adsorption of the radiotracer (see Lemaire 66, 69), Appellant does not persuade us that the Examiner erred in finding that a skilled artisan had sufficient reason to include a radioprotectant in Engell’s SPE washing solution, in a manner encompassed by step (d) of Appellant’s claim 1. See Appeal Br. 3 (Issue 2). Indeed, given the disclosures in Barnett regarding the instability of [18F]fluciclatide and loss of sufficient RCP after synthesis (Barnett ¶¶ 31– 33), viewed alongside Lemaire’s disclosure that radiolysis of [18F]radiotracer compounds occurs “throughout the procedure” of preparing the compounds (Lemaire 63), we further agree with the Examiner that a skilled artisan had motivation for including a radioprotectant in the [18F]fluciclatide elution solution used in Engell’s process, in a manner encompassed by step (f) of the process of Appellant’s claim 1. We therefore also agree with the Examiner that the process recited in Appellant’s claim 1 would have been prima facie obvious. As to Issue 3 identified by Appellant, we are not persuaded that skilled artisans “had no knowledge that radiolysis was happening during the purification of a crude radiotracer on the SPE cartridge.” Appeal Br. 4; see also id. at 13 (“[N]othing in the cited references suggests that radiolytic decay occurs in-process during SPE purification, much less during the loading of a crude radiotracer as required by steps(b) and (c) of the claims.” (citing Engell Decl. ¶ 10)).7 7 Declaration Under 37 C.F.R. § 1.132 of Torgrim Engell (signed January 29, 2019). Appeal 2020-004379 Application 15/102,511 12 Contrary to Appellant’s contentions, and those of Dr. Engell, Lemaire expressly discloses that, because its radiotracer was sensitive to radiolytic decomposition, the radioprotectant compound ascorbic acid was included in the radiotracer-containing buffer before the buffer was applied to the SPE cartridge, as recited in Appellant’s claim 1. See Lemaire 69 (“As high specific radioactivity [18F]altanserin may be sensitive to radio- decomposition on the support, the same saline/[0.1%] ascorbic solution as for the [SPE cartridge] conditioning was used for the dilution of the fraction collected from the HPLC.”) (emphasis added). Thus, not only did Lemaire expressly advise skilled artisans that [18F]radiotracer compounds were likely to be susceptible to radiolysis while the compounds were in the SPE cartridge, Lemaire advised those artisans that, to inhibit that radiolysis, it is desirable to include a radioprotectant in the radiotracer composition before loading it into the SPE cartridge. Appellant does not persuade us, therefore, that skilled artisans were unaware that radiolysis would occur in Engell’s SPE cartridge, nor are we persuaded that skilled artisans were unaware that including a radioprotectant such as Barnett’s pABA in the radiotracer composition before loading it into the SPE cartridge in Engell’s process would be a useful way of inhibiting that radiolysis. This is particularly true given the general teachings in Barnett regarding the instability of [18F]fluciclatide and loss of sufficient RCP after synthesis (Barnett ¶¶ 31–33), as well as Lemaire’s disclosure that radiolysis of [18F]radiotracer compounds occurs “throughout the procedure” of synthesizing the compounds (Lemaire 63). Given Lemaire’s express teaching that, when applying [18F]radiotracer compounds to an SPE cartridge, radiolysis can occur “on the support” Appeal 2020-004379 Application 15/102,511 13 (Lemaire 69), Appellant also does not persuade us that it has discovered a problem that the prior art failed to recognize. See Appeal Br. 5; Reply Br. 2. Moreover, given Lemaire’s disclosure that, to inhibit radiolysis on the SPE support material, it was desirable to include a radioprotectant in the radiotracer composition before loading it into the SPE cartridge, we are not persuaded that the prior art failed to provide a solution to the problem of radiolysis occurring in the SPE cartridge, or that a skilled artisan lacked a reasonable expectation of success in inhibiting radiolysis in the SPE cartridge by the addition of the radioprotectant. See Appeal Br. 15. In sum, for the reasons discussed above, Appellant does not persuade us that the Examiner erred reversibly in determining that the process recited in Appellant’s claim 1 would have been prima facie obvious. For the reasons discussed below, moreover, Appellant does not persuade us that it has advanced evidence of unexpected results sufficient to outweigh the evidence of prima face obviousness presented by the Examiner. Appellant contends that the claimed process unexpectedly increases the RCP of the end product from 79% (disclosed in comparative Example 4 from the Specification) to 92% (Specification Example 7). Appeal Br. 16 (citing Engell Decl. ¶¶ 19–22); see also Reply Br. 4–5. It is well settled, however, that “any superior property must be unexpected to be considered as evidence of non-obviousness.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007) (emphasis in original). In the present case, as the Examiner contends (Ans. 9), Barnett discloses that when [18F]fluciclatide is prepared with pABA, and then evaluated using HPLC, [18F]fluciclatide maintains an RCP of 95% or greater 4 hours after preparation, whereas preparing [18F]fluciclatide in the absence Appeal 2020-004379 Application 15/102,511 14 of pABA yields a RCP of as low as 73% 4 hours after preparation. Barnett ¶ 133 (Example 5; Table 1). As discussed above, moreover, Lemaire expressly teaches adding a radioprotectant compound to inhibit radiolysis “on the support” material of an SPE cartridge. Lemaire 69. Given these teachings in Barnett and Lemaire, Appellant does not persuade us that the Examiner erred reversibly in finding that it was not unexpected that adding a radioprotectant before applying a radiotracer to an SPE cartridge would improve the radiotracer composition’s RCP. Appellant asserts that comparing the RCP values from Barnett to those obtained by Appellant “is not a fair comparison at all.” Reply Br. 5. Appellant, however, does not explain why it is unfair to compare Barnett’s results to Appellant’s results, other than the assertion that “it was the inventors’ own discovery that purification of the crude radiotracer to remove non-radioactive byproducts led to a decrease in RCP.” Id. As discussed above, Lemaire expressly discloses that radiolysis can occur in the SPE cartridge, and that combining a radioprotectant with the radiotracer compound before application to the SPE cartridge, as well as washing the SPE cartridge with a radioprotectant-containing buffer, inhibits radiolysis. We are not persuaded, therefore, that skilled artisans were unaware that radiolysis and loss of RCP would occur in an SPE cartridge, or that it was unfair to compare processes encompassed by claim 1 to processes that involve combining a radioprotectant with a radiotracer, such as Barnett’s or Lemaire’s process. In sum, for the reasons discussed, Appellant does not persuade us that the Examiner erred reversibly in determining that the process recited in Appellant’s claim 1 would have been prima facie obvious to a skilled Appeal 2020-004379 Application 15/102,511 15 artisan. For the reasons discussed, Appellant also does not persuade us that the Examiner erred reversibly in determining that the evidence advanced by Appellant to show unexpected results is insufficient to outweigh the evidence of prima facie obviousness in the cited prior art. We therefore affirm the Examiner’s rejection of claim 1 for obviousness over Engell, Barnett, and Lemaire. Claims 2–5, 8, 9, 11, 12, 14–16, 20–22, and 24–26, fall with claim 1. 37 C.F.R. § 41.37(c)(1)(iv). In rejecting claims 1–5, 8–12, 14–16, and 20–26, over Engell, Barnett, Lemaire, and Hiscock, the Examiner cited Hiscock as evidence that the Affibody 1 recited in dependent claims 10 and 23 would have been an obvious radiotracer compound purified by the process suggested by Engell, Barnett, and Lemaire. Final Act. 6–7. Appellant does not address this rejection specifically. As discussed above, moreover, we are not persuaded of reversible error in the Examiner’s conclusion of obviousness as to Appellant’s claim 1, which is also subject to this ground of rejection, and is representative of the claims subject to this rejection. See 37 C.F.R. § 41.37(c)(1)(iv). Accordingly for the reasons discussed above, we affirm this rejection as well. Appeal 2020-004379 Application 15/102,511 16 DECISION SUMMARY In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1–5, 8, 9, 11, 12, 14–16, 20–22, 24– 26 103 Engell, Barnett, Lemaire 1–5, 8, 9, 11, 12, 14– 16, 20–22, 24–26 1–5, 8–12, 14–16, 20– 26 103 Engell, Barnett, Lemaire, Hiscock 1–5, 8–12, 14–16, 20– 26 Overall Outcome 1–5, 8–12, 14–16, 20– 26 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). See 37 C.F.R. § 1.136(a)(1)(iv). AFFIRMED