BRISTOL-MYERS SQUIBB COMPANY

Patent Trials and Appeals Board

Mar 1, 2022

2021003283 (P.T.A.B. Mar. 1, 2022)

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. 16/318,209 01/16/2019 David J. Donnelly 082867.000284 / 12800-US- 6801 46339 7590 03/01/2022 BakerHostetler 1735 Market Street Suite 3300 Philadelphia, PA 19103-7501 EXAMINER DONOHUE, SEAN R ART UNIT PAPER NUMBER 1618 NOTIFICATION DATE DELIVERY MODE 03/01/2022 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): eofficemonitor@bakerlaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte DAVID J. DONNELLY, ERIN LEE COLE, RICHARD CHARLES BURRELL, WESLEY A. TURLEY, ALBAN J. ALLENTOFF, MICHAEL ARTHUR WALLACE, JAMES AARON BALOG, AUDRIS HUANG, and METTE SKINBJERG Appeal 2021-003283 Application 16/318,209 Technology Center 1600 Before TAWEN CHANG, RACHEL H. TOWNSEND, and DAVID COTTA, Administrative Patent Judges. CHANG, Administrative Patent Judge. Appeal 2021-003283 Application 16/318,209 2 DECISION ON APPEAL Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the Examiner’s decision to reject claims 1-11.2 We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. STATEMENT OF THE CASE The Specification states that indoleamine 2,3-dioxygenase (“IDO,” “IDO1,” or “hIDO”), which plays a role in immunomodulation, is implicated in cancer as well as “immunosuppression, chronic infections, and autoimmune diseases or disorders.” Spec. 1:31-32, 2:31-32. According to the Specification, [u]se of a specific PET radioligand having high affinity for IDO1 in conjunction with supporting imaging technology may provide a method for clinical evolution around both target engagement and dose/occupancy relationships of IDO1 inhibitors in tissues that express IDO1 such as the lung, gut, and dendritic cells of the immune system. The invention described herein relates to radiolabeled IDO1 inhibitors that would be useful for the exploratory and diagnostic imaging applications, both in-vitro and in-vivo, and for competition studies using radiolabeled and unlabeled IDO1 inhibitors. Spec. 3:7-13. 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 Bristol-Myers Squibb Company. Appeal Br. 1. 2 An oral hearing was held on November 15, 2021. A transcript (“Tr.”) of this hearing was entered into the record December 27, 2021. Appeal 2021-003283 Application 16/318,209 3 CLAIMED SUBJECT MATTER The claims are directed to a radiolabeled compound having the recited formula. Claim 1 is illustrative: 1. A radiolabeled compound having the following Formula I: or a pharmaceutically acceptable salt thereof. Appeal Br. 11 (Claims App.). REJECTION(S) A. Claims 1-11 are rejected under 35 U.S.C. § 103 as being unpatentable over the STN (Scientific and Technical Information Network) database,3 Underwood,4 and Henrottin.5 B. Claims 1-11 are rejected under 35 U.S.C. § 103 as being unpatentable over the STN database, Underwood, Henrottin, and Tian.6 3 STN entry for CAS Reg. No. 1923833-60-6 (2016). 4 Underwood et al., WO 2015/184099 A1, published Dec. 3, 2015. 5 Jean Henrottin et al., N1-Fluoroalkyltryptophan Analogues: Synthesis and in vitro Study as Potential Substrates for Indoleamine 2,3-Dioxygenase, 6 ACS MEDICINAL CHEMISTRY LETTERS 260 (2015). 6 Tian et al., WO 2016/040458 A2, published Mar. 17, 2016. Appeal 2021-003283 Application 16/318,209 4 C. Claims 1-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-47 of U.S. Patent No. 9,643,972 B2 (’972 patent), in view of Henrottin. D. Claims 1-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-47 of U.S. Patent No. 9,643,972 B2 (’972 patent), in view of Henrottin and Tian. E. Claims 1-11 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-66 of U.S. Patent No. 10,106,546 B2 (’546 patent), in view of Henrottin and Tian. OPINION A. Obviousness rejection over STN database, Underwood, Henrottin and Tian 1. Issue There is no dispute that a non-radiolabeled compound having the same chemical formula as Formula I, sometimes referred to as F001287, is known in the prior art. Final Act. 4.; Tr. 4:9-10. The Examiner finds that Underwood teaches that F001287 binds to and inhibits indoleamine-2,3, dioxygenase (IDO). Final Act. 4. The Examiner finds that Henrottin teaches that human IDO (hIDO) “is mainly and highly expressed in inflammatory tissues and in human tumors,” that [18F]luorine may be used for PET imaging, that “a radioactive isotopomer could be a valuable tool for the preclinical and clinical validation of new potential inhibitors,” and that “1-[18F]FETrp could . . . facilitate a more specific detection of hIDO expressing cells in cancer imaging.” Id. at 5. The Examiner finds that Tian Appeal 2021-003283 Application 16/318,209 5 similarly teaches inhibitors of IDO, “the use of 18F to PET image IDO expression,” and “the -F for -18F substitution.” Id. The Examiner asserts that a skilled artisan would have had reason to modify F001287 by radiolabeling its fluorine atom “in order [to] gain the advantage of PET imaging IDO expression in inflammatory tissues and tumors and/or preclinical and the clinical validation of new potential inhibitors.” Final Act. 5. The Examiner further asserts that “[t]he substitution of one isotope for another is not expected to change the biochemistry or pharmacology of the compound.” Id. Appellant contends that the rejection is based on impermissible hindsight. Appeal Br. 6. In particular, Appellant contends that, without Appellant’s disclosure, skilled artisans “would not have arrived at any claimed 18F-labeled compound,” and, “even if they had considered a claimed [18]F-labeled compound, they would not have reasonably predicted that diagnostic imaging using that compound would have been successful.” Id. Appellant does not separately argue the claims. Accordingly, we focus our analysis on claim 1 as representative. The issue with respect to this rejection is whether a preponderance of evidence supports the Examiner’s determination that a skilled artisan would have had reason to arrive at the 18F-labeled compound recited in claim 1, with a reasonable expectation of success. Appeal 2021-003283 Application 16/318,209 6 2. Findings of Fact 1. The STN database discloses a compound referred to as, inter alia, F001287: 2. Underwood teaches that F001287 is an inhibitor of indoleamine-2,3-dioxygenase (IDO), an immunomodulatory enzyme, and, in a method of treating cancer in a subject, may be administered to a subject as a therapeutic agent in combination with an antibody to glucocorticoid- induced TNFR family related receptor (GITR) or antigen-binding fragment thereof. Underwood ¶¶ 45, 451, claims 150, 159. 3. Henrottin teaches that hIDO “exert[s] immunosuppressive properties in inflammatory and tumoral tissues.” Henrottin Abstract. 4. Henrottin teaches that “hIDO is mainly and highly expressly (i) in placenta . . . , (ii) in inflammatory tissues, and (iii) in human tumors such as mammary, prostatic, colorectal, pancreatic, cervical, and endometrial carcinomas,” where “high expression of hIDO . . . result[s] in a local suppression of the immune response.” Henrottin 260, bridging paragraph (endnotes omitted). 5. Henrottin teaches that “a number of hIDO inhibitors have been developed” in order to “improve cancer immunotherapy and to counteract Appeal 2021-003283 Application 16/318,209 7 the local immunosuppression that protects malignancies from endogenous and drug-induced destruction,” and that, “[t]o facilitate (i) the preclinical and clinical development and validation of such compounds and (ii) the clinical detection of hIDO expressing cells in cancer imaging, the synthesis (and the radiosynthesis) of a PET imaging tracer could prove to be a highly desirable and valuable tool.” Henrottin 260-261. 6. Henrottin teaches that [18F]fluorine, a radionucleotide with a longer half-life time (t1/2 = 109.7 min) than [11C]carbon, may be better adapted for creating a radioactive hIDO substrate that would allow “following the metabolization of a radioactive substrate of hIDO through the kynurenine pathway.” Henrottin 261, left column. 7. Henrottin teaches that 1-(2-fluoroethyl)-tryptophan (1-FETrp) “is a good and specific substrate of hIDO” and, “[t]herefore, its radioactive isotopomer, 1-[18F]FETrp, should be a molecule of choice to visualize tumoral and inflammatory tissues and/or to validate new potential inhibitors.” Henrottin Abstract; see also id. at 264 (teaching that 1- [18F]FETrp “could be a valuable tool for the preclinical and the clinical validation of new potential inhibitors” and “could also facilitate a more specific detection of hIDO expressing cells in cancer imaging”). 8. Tian teaches that particularly high level IDO1 expression is observed in, inter alia, various human tumor cells. Tian 1:16-18, 8:1-3. 9. Tian teaches that IDO1 has been “implicated . . . in immune escape of tumor cells, and blockages of its activity can directly increase the ability of tumor-bearing mice to reject tumors.” Tian 1:18-21; see also id. at 6:1-2 (teaching that “[r]ecent studies indicate that tryptophan oxidation via the enzyme IDO can modulate immunoresistance of cancers”), 8:1-3. Appeal 2021-003283 Application 16/318,209 8 10. Tian teaches that molecular imaging methods such as PET “have the potential to generate IDO1 expression profile in vivo and provide valuable information on how the IDO pathway responds to the immune- modulating therapies.” Tian 1:29-31; see also id. at 6:2-4 (explaining that “[i]n vivo detection of IDO may facilitate therapeutic measures by identifying patients likely to benefit and to quantitatively monitor IDO inhibition in vivo by effectively evaluating the number of receptors”), 6:15- 18, 7:16-32, 8:6-9. 11. Tian teaches that “[a] number of medical diagnostic procedures, including PET, and Single Photon Emission Computed Tomography (SPECT) utilize radiolabeled compounds,” e.g., “[t]racers . . . radiolabeled with a radionuclide . . . such as 18F.” Tian 7:9-10, 7:14-15. 12. Tian teaches that “there is an urgent need to develop a specific PET imaging agent targeted to IDO1 for cancer imaging.” Tian 2:4-6. 13. Tian teaches 18F labeled IDO1 image constructs for PET and teaches that such constructs “are useful for imaging cancer cells in a patient.” Tian Abstract. Tian teaches 18F labeled IDO1 imaging constructs having the following structure: where the fluorine is optionally 18F, X is a halogen and R is H, C1-C8 alkyl, C1-C8 alkylcarbonyl, phenyl, phenylcarbonyl; R is optionally substituted with one or more C1-C8 alkyl, phenyl, phenylHC=N-O-; and the substituent is optionally substituted with a fluorine, where the fluorine is optionally 18F, and wherein at least one fluorine is 18F. Id. at 2:9-16; see also id. at 6:6-8 Appeal 2021-003283 Application 16/318,209 9 (“The inventors utilized 18F-labeled aniline as intermediate in [18F]- radiolabeling chemistry for the radiosynthesis of 18F-IDO5L as a novel IDO1-targeted tracer.”). 14. Tian teaches that [a]mong the potent inhibitors reported in the literature, the most potent inhibitor of IDO1 is INCB024360 (IC50 = 7.1 nM, HeLa cell assay). The carboximidamide compound IDO5L is one of the highest potent inhibitors of the IDO1 (IC50 = 19 nM, HeLa cell assay). Moreover, the reported rapid clearance rate (t1/2 <0.5 h, via oral administration) of IDO5L indicated the faster clearance rate after i.v. administration during PET imaging. This fast clearance may be preferred for 18F-PET imaging agent for less imaging background. Tian 5:26-32; see also id. at 6:8-9, 8:5-6. Tian teaches that 18F-labeled IDO1 inhibitor IDO5L, and other constructs of its invention, “can serve as novel probes for the PET imaging to generate an IDO1 activity profile in vivo that is useful to predict IDO1-related cancer diagnostic and monitor therapeutic efficacy of IDO1 inhibitors.” Id. at 6:15-18. 15. Tian teaches that “18F-IDO1 inhibitors with appropriate IC50s can be determined by hela cells assays where the level for cytotoxicity (IC50) is significantly greater than the PET-Imaging dose (about 0.1 nM) and are useful as imaging agents.” Tian 6:28-31. 16. Tian teaches that, “[u]ltimately, the effectiveness of a 18F-IDO1 imaging construct . . . can be characterized by small-animal PET/CT studies.” Tian 12:5-6. 17. Tian teaches that a solution comprising 18F labeled IDO1 imaging construct may be used in a method comprising administering Appeal 2021-003283 Application 16/318,209 10 treatment for cancer, wherein the treatment comprises administering IDO1 inhibitors such as F001287. Tian 8:30-33, 9:33-10:6, 16:13-32. 3. Analysis We agree with the Examiner that claim 1 is obvious over the combination of cited prior art. Unless otherwise noted, we adopt the Examiner’s findings of fact and reasoning regarding the Examiner’s rejection of claim 1 under 35 U.S.C. § 103 as obvious over the STN database, Underwood, Henrottin, and Tian (Final Act. 41-45, Ans. 4-5, FF1-FF17).7 Only those arguments timely made by Appellant in the briefs have been considered; arguments not so presented in the briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv) (2020); see also Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative) (“Any bases for asserting error, whether factual or legal, that are not raised in the principal brief are waived.”). We highlight the following points for emphasis. As discussed above, it is not disputed that a non-radiolabeled compound having the same chemical formula as Formula I, sometimes referred to as F001287, is known in the prior art. See, e.g., FF1. We also agree with the Examiner that the prior art teaches that F001287 is an inhibitor of IDO-an enzyme that is highly expressed in certain tumors- and may be useful in treating cancer. FF1-FF5, FF8, FF9. Finally, the prior art teaches that [18F]luorine-labeled IDO substrates and/or inhibitors may be useful for developing and validating IDO inhibitors and/or cancer imaging 7 We vacate as cumulative the rejection of the claims as obvious over STN database, Underwood, and Henrottin. Appeal 2021-003283 Application 16/318,209 11 via PET scans. FF5-FF7, FF10-FF16. Thus, as the Examiner explains, a skilled artisan would have reason to radio-label F001287 with [18F]luorine for use in developing and validating other IDO inhibitors and/or in PET imaging. Appellant contends that, without Appellant’s disclosure, a skilled artisan “would not have made any claimed 18F-labeled compound with any reasonable expectation that it would have been useful in PET imaging IDO.” Appeal Br. 7. In particular, Appellant contends that neither Underwood nor the STN database “provides any quantitative data regarding F001287’s IDO inhibition properties or other biological or pharmacokinetic properties.” Id. Appellant further contends “Henrottin does not disclose or suggest that radiolabeled IDO inhibitors make suitable imaging agents. To the contrary, Henrottin posits that IDO substrates[, such as 18F-ethylene-modified tryptophan,] might be suitable imaging agents.”8 Id.; see also Reply Br. 2 (arguing that Henrottin only discloses that radiolabeled IDO substrates, not inhibitors, “might be suitable imaging agents” and that “[n]owhere . . . in this application’s record, is there any disclosure or suggestion that a 18F- labeled IDO inhibitor would be useful for monitoring IDO metabolism”). 8 Appellant contends that “Henrottin acknowledges that no 18F-labeled tryptophan derivative had been synthesized.” Appeal Br. 8 n.5; see also Reply Br. 2 n.1. We note that prior art does not need to actually create or reduce to practice the prior art subject matter in order to render a claim obvious. Cf. Schering Corp. v. Geneva Pharms., Inc., 339 F.3d 1373, 1380 (Fed. Cir. 2003) (citing In re Donohue, 766 F.2d 531, 533 (Fed. Cir. 1985)) (“Anticipation does not require the actual creation or reduction to practice of the prior art subject matter; anticipation requires only an enabling disclosure.”). Appeal 2021-003283 Application 16/318,209 12 We are not persuaded. Although Henrottin specifically teaches use of 1-[18F]FETrp, an IDO substrate, for use in cancer imaging, FF7, it more broadly teaches the need of a radiolabeled compound to facilitate the development and validation of IDO inhibitors and detection of IDO expressing cells, FF5, and Tian teaches that radiolabeled IDO inhibitors are useful for similar purposes, FF10-FF16; see particularly FF14 (disclosing IDO5L, a “potent” inhibitor of IDO1, as a 18F-PET imaging agent). In addition, Underwood and Tian teach that F001287 is an IDO inhibitor and that it may be useful in treating cancer. FF2, FF17. The combination of these references fairly suggests the use of known IDO inhibitors for purposes of developing and validating potential IDO inhibitors as well as for imaging and detection of IDO expressing cells. In re Aslanian, 590 F.2d 911, 914 (CCPA 1979) (explaining that prior art is evaluated and applied on the basis of what they reasonably suggest to a skilled artisan, not merely what they expressly teach); In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (“Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references. . . . [The reference] must be read, not in isolation, but for what it fairly teaches in combination with the prior art as a whole.”). Appellant contends that Tian does not cure the deficiencies of STN database, Underwood, and Henrottin. Appellant contends that Tian does not suggest that “[radiolabeling] any ‘IDO-inhibitor’ would result in a compound useful for PET detection of IDO-expressing cancer cells”: To the contrary, Tian proposes that only those IDO inhibitors having a cytotoxicity that is “significantly greater than the PET-imaging dose (about 0.1 nM)” could Appeal 2021-003283 Application 16/318,209 13 be useful as imaging agents. See page 6 of Tian, lines 28- 31. There is no evidence of record regarding F001287’s cytotoxicity or IDO inhibition activity. Without cytotoxicity or IDO inhibition information, the cited art would not have informed those of ordinary skill in the art whether 18F-F001287 would have been useful for PET imaging of IDO. Appeal Br. 8-9; see also Reply Br. 3 (arguing that “the Examiner selectively ignores disclosure of Tian directed only to those IDO inhibitors that have a cytotoxicity ‘significantly greater than the PET-imaging dose (about 0.1 nM)’ could be useful as imaging agents”). We are not persuaded. Appellant’s arguments focus only on whether a skilled artisan would have had reasonable expectation of success in using the claimed compound in PET detection of IDO-expressing cancer cells. However, the prior art suggests that a radiolabeled compound that binds to IDO may be useful in the preclinical and clinical development and validation of new IDO inhibitors in addition to detection of IDO expressing cells in cancer imaging. FF5. Tian also teaches that, “[u]ltimately, the effectiveness of a 18F-IDO1 imaging construct . . . can be characterized by small-animal PET/CT studies.” FF16. Thus, a skilled artisan would have had reason to radiolabel F001287, a known IDO inhibitor (FF2, FF17), with [18F]luorine, a known radionucleotide (FF6, FF11), to, e.g., determine the effectiveness of such radiolabeled compound as a 18F-IDO1 imaging construct, or for purposes of developing and validating new IDO inhibitors. Finally, the prior art teaches that the IDO inhibition activity and cytotoxicity of F001287 is such that it is useful as a therapeutic in treating cancer. FF2, FF17. Thus, we find that the Examiner has established a prima facie case that a skilled artisan would reasonably expect F001287 radio- Appeal 2021-003283 Application 16/318,209 14 labeled with [18F]luorine to be useful as an IDO1 imaging construct. Appellant has not provided any persuasive evidence to the contrary. In the Reply Brief, Appellant disparages as “mere speculation” the Examiner’s finding that “Underwood teaches and suggest an adequate toxicity profile of F001287 for administration to subjects because Underwood teaches the administration of F001287 separately, sequentially, or concurrently with an anti-GITR antibody,” noting that “[n]o F001287 cytotoxicity data or IDO inhibition activity . . . is provided in Underwood.” Reply Br. 2; see also id. at 3 (arguing that, “[w]ithout cytotoxicity data or IDO inhibition activity information,” the cited references would not have informed a skilled artisan “whether F18-F001287 would have been useful for PET imaging of IDO” and such artisan “would not have reasonably predicated that diagnostic imaging using a radiolabeled analog of F001287 would have been successful”). We disagree with Appellant’s apparent contention that only evidence in a specific form is sufficient to establish a prima facie case of obviousness. Underwood and Tian teach administering F001287 as a therapeutic, FF2, FF17, which indicates that a skilled artisan would reasonably expect the compound to be at least sufficiently non-toxic to be administered as such. In this regard, we further note that “the expectation of success need only be reasonable, not absolute,” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007), and that “obviousness ‘does not require that the motivation be the best option, only that it be a suitable option from which the prior art did not teach away,’” Bayer Pharma AG v. Watson Labs., Inc., 874 F.3d 1316, 1328 (Fed. Cir. 2017). Appeal 2021-003283 Application 16/318,209 15 Accordingly, for the reasons discussed above, we affirm the Examiner’s rejection of claim 1 as obvious over STN database, Underwood, Henrottin, and Tian. Claims 2-11, which are not separately argued, fall with claim 1.9 B. Nonstatutory double patenting rejections The Examiner has rejected claims 1-11 on the ground of nonstatutory double patenting as being unpatentable over claims 1-47 of the ’972 patent in view of Henrottin and Tian.10 The Examiner has also rejected claims 1- 11 on the ground of nonstatutory double patenting as being unpatentable over claims 1-66 of the ’546 patent in view of Henrottin and Tian. With respect to instant claim 1 on appeal, the Examiner finds that one or more of the claims of the ’972 patent and ’546 patent claim a non- radiolabeled compound that otherwise have the same chemical formula as Formula I. Non-Final Act.11 10, 13. The Examiner acknowledges that the claims of the ’972 and ’546 patents do not claim a compound labeled with [18F]fluorine as recited in 9 Appellant contends during oral argument that there is no evidence in the record as to how “[a] skilled person [would] have gone about synthesizing the compound[] that is radiolabeled formula 1.” Tr. 3:9-19. As Appellant concedes, however, Appellant did not raise this argument in the briefs. Id. at 3:9-23. Accordingly, Appellant has waived the argument and we do not consider it for purposes of this opinion. See 37 C.F.R. § 41.41(b)(2); cf. Optivus Tech., Inc. v. Ion Beam Applications S.A., 469 F.3d 978, 989 (Fed. Cir. 2006) (argument raised for the first time in the Reply Brief that could have been raised in the opening brief is waived). 10 We vacate as cumulative the rejection of the claims on the ground of nonstatutory double patenting as being unpatentable over claims 1-47 of the ’972 patent in view of Henrottin. 11 Jan. 10, 2020 Non-Final Rejection. Appeal 2021-003283 Application 16/318,209 16 instant claim 1 on appeal. Non-Final Act. 10, 14. However, the Examiner concludes that it would have been obvious to a skilled artisan to modify the compound claimed in the ’972 and ’546 patents by substituting fluorine with [18F]fluorine as taught by Henrottin and/or Tian because it would advantageously enable “imaging and diagnosis of IDO expressing cancer cells” and “preclinical and clinical validation of . . . cancer immunotherapeutic.” Id. at 10-15. The Examiner further noted that “[t]he substitution of one isotope for another is not expected to change the biochemistry or pharmacology of the compound. Final Act. 8. Appellant relies on the same arguments as in the obviousness rejection, namely that “[n]either Henrottin nor Tian provide[s] any suggestion or motivation to those of ordinary skill in the art to modify any claimed compound of the ’972 patent or the ’546 patent to produce the claimed 18F-radiolabeled compounds” for the reasons discussed above. Appeal Br. 9; see also Reply Br. 4. We are not persuaded for the reasons already discussed.12 Accordingly, we also affirm the non-obviousness type double patenting rejections. 12 Appellant also challenges “the Examiner’s assertion [that] substitution of one isotope for another is not expected to change the biochemistry and pharmacology of the parent compound,” arguing that the ’972 patent states that “isotopic variants of the compounds of the invention can have altered pharmacokinetic and pharmacodynamic characteristics which can contribute to enhanced safety, tolerability or efficacy during treatment.” Reply Br. 4. However, Appellant raises this argument for the first in a Reply Brief, thereby denying the Board the benefit of the Examiner’s response, and no showing of good cause was made to explain why the late argument should be considered by the Board. Accordingly, this argument is waived. See 37 C.F.R. § 41.41(b)(2); Optivus Tech., 469 F.3d at 989. Appeal 2021-003283 Application 16/318,209 17 CONCLUSION In summary: Claim(s) Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1-11 103 STN database, Underwood, Henrottin13 1-11 103 STN database, Underwood, Henrottin, Tian 1-11 1-11 Nonstatutory Double Patenting: US 9,643,972 B2, Henrottin14 1-11 Nonstatutory Double Patenting: US 9,643,972 B2, Henrottin, Tian 1-11 1-11 Nonstatutory Double Patenting: US 10,106,546 B2, Henrottin, Tian 1-11 Overall Outcome 1-11 13 We vacate the rejection of claims 1-11 as obvious over STN database, Underwood, and Henrottin. 14 We vacate the rejection of claims 1-11 on the ground of nonstatutory double patenting as being unpatentable over as obvious over claims 1-47 of the ’972 patent and Henrottin. Appeal 2021-003283 Application 16/318,209 18 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