BRAINGENE AB

Patent Trials and Appeals Board

Mar 9, 2022

2021002540 (P.T.A.B. Mar. 9, 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. 15/300,686 09/29/2016 Deniz KIRIK 10400L-000053-US-NP 1459 28997 7590 03/09/2022 Harness Dickey (St. Louis) 7700 Bonhomme, Suite 400 St. Louis, MO 63105 EXAMINER POPA, ILEANA ART UNIT PAPER NUMBER 1633 NOTIFICATION DATE DELIVERY MODE 03/09/2022 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): bkamer@hdp.com stldocket@hdp.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte DENIZ KIRIK and ERIK CEDERFJÄLL1 Appeal 2021-002540 Application 15/300,686 Technology Center 1600 Before DONALD E. ADAMS, ERIC B. GRIMES, and JOHN G. NEW, Administrative Patent Judges. GRIMES, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134(a) involving claims relating to controllable gene therapy, which have been rejected based on obviousness and obviousness-type double patenting. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM. 1 Appellant identifies the real party in interest as Braingene AB. Appeal Br. 3. “Appellant” refers to “applicant” as defined in 37 C.F.R. § 1.42. Appeal 2021-002540 Application 15/300,686 2 STATEMENT OF THE CASE “Conventional symptomatic treatment for Parkinson’s disease (PD) with long term Levodopa (L-DOPA) is complicated with development of troublesome drug-induced side effects.” Spec. 4:2-4. Generation of DOPA in catecholaminergic neurons is handled by the tyrosine hydroxylase (TH) enzyme in the presence of tetrahydrobiopterin (BH4). . . . [T]ransduction of striatal neurons with transgenes encoding the TH and GTP cyclohydrolase 1 (GCH1; rate-limiting enzyme in BH4 synthesis) enzymes . . . gives rise to continuous DOPA production in these cells. Id. at 1:19-25. This gene therapy “eliminates fluctuations associated with oral administration of L-DOPA, which in turn results in dramatic beneficial effect in animal models of PD.” Id. at 4:6-12. However, “the brain alterations made with currently employed gene transfer techniques cannot be readily re-administered and are irreversible,” and clinical approaches “should have the possibility of regulating the expression to match the needs of each person and the stage of disease.” Id. at 4:12-17. “The inventors took advantage of a recently described tunable gene expression system based on the use of a destabilizing domain [DD] based on dihydrofolate reductase (DHFR).” Id. at 4:18-20. “The DD may be controlled or regulated by the use of a ligand binding and stabilizing the DD. . . . When this DD is fused to a second peptide, it destabilize[s] the whole fusion polypeptide. The whole fusion polypeptide may then be controlled” using the ligand. Id. at 11:14-19. “In some embodiments the ligand is trimethoprim (TMP),” which is “a well-known and routinely prescribed antibiotic.” Id. at 19:11-15. Appeal 2021-002540 Application 15/300,686 3 Claims 1, 6, 14-16, 19-22, 25-28, and 31-33 are on appeal. Claims 1 and 14, reproduced below, are illustrative: 1. A gene expression system comprising: a first nucleotide sequence encoding a fusion polypeptide of: a) a destabilizing domain (DD), and b) a GTPcyclohydrolase 1 (GCH1) polypeptide, or a biologically active fragment or variant thereof; and a second nucleotide sequence encoding a tyrosine hydroxylase (TH) polypeptide, or a biologically active fragment or variant thereof. 14. A method of treating a disease or condition associated with reduced dopamine level comprising administering a gene expression system and a ligand binding to a destabilizing domain (DD) to a patient in need thereof, wherein said gene expression system comprises: a first nucleotide sequence encoding a fusion polypeptide of: a) the DD, and b) a GTPcyclohydrolase 1 (GCH1) polypeptide, or a biologically active fragment or variant thereof; and a second nucleotide sequence encoding a tyrosine hydroxylase (TH) polypeptide, or a biologically active fragment or variant thereof. Appeal 2021-002540 Application 15/300,686 4 The claims stand rejected as follows: Claims 1, 6, 14-16, 19-22, 25-28, and 31-33 under 35 U.S.C. § 103 as obvious based on Björklund,2 Yan,3 Tai,4 and Kirik5 (Final Action6 5); Claims 1, 6, 14-16, 19-22, 25-28, and 31-33 under 35 U.S.C. § 103 as obvious based on Björklund, Yan, Tai, Kirik, and Furler7 (Final Action 7); and Claims 1, 6, 14-16, 19-22, 25-28, and 31-33 for obviousness-type double patenting based on claims 1-24 of U.S. Patent 9,593,312 in view of Yan, Tai, and Kirik (Final Action 3). OPINION Obviousness Claims 1, 6, 14-16, 19-22, 25-28, and 31-33 stand rejected as obvious based on Björklund, Yan, Tai, and Kirik, optionally combined with Furler. The same issue is dispositive for both rejections, so we will consider them together. 2 US 2012/0309816 A1, published December 6, 2012. 3 Effect of Levodopa Chronic Administration on Behavioral Changes and Fos Expression in Basal Ganglia in Rat Model of PD, J. HUAZHONG UNIV. OF SCIENCE AND TECHNOLOGY 23(3):258-262 (2003). 4 Destabilizing Domains Mediate Reversible Transgene Expression in the Brain, PLOS ONE 7(9):1-7 (2012). 5 Reversal of motor impairments in parkinsonian rats by continuous intrastriatal delivery of L-dopa using rAAV-mediated gene transfer, PROC. NATL. ACAD. SCI. USA 99(7):4708-4713 (2002). 6 Office Action mailed February 4, 2020. 7 Recombinant AAV vectors containing the foot and mouth disease virus 2A sequence confer efficient bicistronic gene expression in cultured cells and rat substantia nigra neurons, GENE THERAPY 8:864-873 (2001) Appeal 2021-002540 Application 15/300,686 5 The Examiner finds that Björklund teaches a gene expression system comprising nucleic acid sequences encoding GCH1 and TH, and a method of using the system to “treat[] a disease or condition associated with reduced dopamine levels (such as Parkinson’s disease . . . ).” Final Action 5-6. The Examiner finds that “Björklund et al. do not teach a DD fused to GCH1. . . . However, such use is suggested by the prior art.” Id. at 6. Specifically, the Examiner finds that Yan teaches that “prolonged treatment with DOPA results in severe complications and suggest[s] searching for novel treatments to prevent such complications,” and Tai teaches “the necessity to regulate gene expression according to clinical needs, wherein regulation takes place via using a DHFR DD and TMP administration.” Id. “Based on these teachings, one of skill in the art would have found [it] obvious to use DHFR DD in the expression system of Björklund et al. to . . . obtain[] a system that can be induced as needed by the in vivo administration of TMP.” Id. The Examiner also finds that Björklund teaches that (a) “the need for GCH1 expression may be much less than the TH expression,” (b) “GCH1 is the rate limiting enzyme in the BH4 biosynthesis pathway,” (c) “the amount of BH4 affects TH activity with too little reducing TH efficiency and too much inhibiting TH activity,” and (d) “a ratio of GCH1 to TH between 1:3 and 1:7 results in optimized TH function and efficient DOPA synthesis.” Id. Finally, the Examiner finds that “Björklund et al. teach controlling the GCH1 levels while keeping the TH levels constant to optimize TH activity.” Id. The Examiner finds that Kirik similarly teaches that administering a vector encoding TH alone does not increase DOPA production and “co- Appeal 2021-002540 Application 15/300,686 6 administration of rAAV-GCH1 is required to obtain increased DOPA production, suggesting insufficient endogenous BH4 levels for TH activity and also that TH is highly dependent on BH4 for its activity.” Id. at 6-7. The Examiner reasons that, based on Björklund and Kirik, “one of skill in the art would have reasonably concluded that DOPA levels could be controlled by controlling GCH1,” and would have found [it] obvious to keep TH expression constant and regulate GCH1 expression by attaching the DHFR DD to GCH1 with the intent of optimizing TH function/DOPA level . . . via adjusting GCH1 expression such as to achieve an in vivo therapeutic ratio of GCH1 to TH between 1:3 and 1:7 when needed. Id. at 7. We agree with the Examiner that the cited references would have made obvious the method of claim 1. Björklund discloses a “one-vector expression system comprising a sequence encoding two polypeptides, such as tyrosine hydroxylase (TH) and GTP-cyclohydrolase 1 (GCH1). The two polypeptides can be should preferentially be [sic] expressed at a ratio between 3:1 and 15:1, such as between 3:1 and 7:1.” Björklund, abstract. In Björklund’s system, “[b]oth genes were driven by the human Synapsin 1 promoter” and, “[t]o achieve an increased expression of TH over the GCH1 gene, a woodchuck hepatitis virus post-transcriptional regulatory element (WPRE) was added.” Id. ¶ 56. “WPRE regulates the expression ratio between the two polynucleotides of the invention, preferably by increasing the expression of TH.” Id. ¶ 222. Björklund states that “[t]he current treatment standard [for Parkinson’s disease] is based on substitution of dopamine by addition of L-dopa (which is converted to dopamine in the brain).” ¶ 5. “[E]ventually Appeal 2021-002540 Application 15/300,686 7 most patients start to experience diminishing treatment response and increasing adverse events. The most problematic of these is the L-dopa- induced dyskinesias.” Id. “Development of dyskinesia is believed to be associated with non-continuous delivery of L-DOPA.” Id. ¶ 22. Björklund states that “[c]ontinuous DOPA delivery depends on several factors contributing to the establishment of an environment for optimal TH enzyme functionality.” Id. ¶ 143. “The TH enzyme requires the co-factor BH4 for DOPA synthesis.” Id. ¶ 142. “One factor that affects the [TH] activity is the surrounding amount of BH4. Too little BH4 and the enzyme cannot work efficiently and too much BH4 can inhibit the function.” Id. “BH4 is synthesized from GTP in a three-step enzymatic reaction where GCH1 is the first and rate-limiting enzyme.” Id. Björklund states that its data “suggest that the activation of the TH enzyme follows a three-phase kinetic relationship to the amounts of GCH1 expressed.” Id. ¶ 144. “Taken together, the[] data show that the working range between 1:3 and 1:7 GCH1:TH ratio can result in an efficient DOPA synthesis where TH function is optimized.” Id. “Accordingly, in certain embodiments, the TH gene is expressed at about 3-7 fold higher levels than GCH1.” Id. ¶ 145. In summary, Björklund discloses (a) that continuous DOPA delivery, intended to avoid the dyskinesia that can result from conventional treatment with L-DOPA, depends on establishing an environment for optimal TH functionality; (2) that TH requires BH4 for activity, and TH function is not optimal with either too little BH4 or too much BH4; and (3) that a 1:3 to 1:7 ratio of GCH1:TH optimizes TH function and results in efficient DOPA synthesis. Björklund discloses achieving this ratio of GCH1:TH by Appeal 2021-002540 Application 15/300,686 8 increasing the expression of TH using the WPRE regulatory element. Björklund does not disclose use of a destabilizing domain (DD). Tai states that “[t]he possibility to regulate transgene expression has been [] discussed in the gene therapy field for a long time. . . . In clinical settings, regulated transgene expression would allow for increased or decreased transgene levels in response to clinical need.” Tai 1, left col. “Many different regulated gene expression systems have been developed and most operate at transcriptional levels.” Id. (reference citation omitted). Tai also states that “[g]ene therapy applications in the central nervous system represent a challenge for any gene regulation system developed so far, as the activating drug needs to cross the blood brain barrier.” Id. Tai describes a “regulation system based on a destabilizing domain (DD) derived from Escherichia coli dihydrofolate reductase (DHFR), enabling the use of the small-molecule trimethoprim (TMP) as a stabilizer. TMP is a well-characterized drug that crosses the blood-brain barrier and has been used safely as an antibiotic in humans.” Id. at 2, left col. (reference citation omitted). Tai’s study “evaluated the feasibility of using destabilizing domains fused to transgenes to regulate levels of transgene product.” Id. at 6, left col. Tai summarizes its results as follows: The DHFR DD used in our study showed reversible and dose- dependent expression of YFP [yellow fluorescent protein] in the striatum of animals. Furthermore, our study indicates that the DD system can be considered a viable alternative to currently inducible systems based on transcriptional regulation of gene expression for transgene regulation in the brain. Id. at 6, right col. Appeal 2021-002540 Application 15/300,686 9 Kirik states that “[r]estoration of striatal dopamine by peripheral administration of L-dopa can provide efficient symptomatic relief in patients with Parkinson’s disease (PD).” Kirik 4708, left col. “Intrastriatal delivery of the tyrosine hydroxylase gene by viral vectors is being explored as a tool for local delivery of L-dopa.” Kirik 4708, abstract. Kirik “defined a critical threshold level of L-dopa, 1.5 pmol/mg of tissue, that has to be reached to induce any significant functional effects.” Id. Kirik states that “levels of striatal L-dopa production exceeding this threshold can be obtained provided that tyrosine hydroxylase is coexpressed with the cofactor synthetic enzyme, GTP-cyclohydrolase-1.” Id. More specifically, “initial attempts to use viral vectors for direct intrastriatal delivery of the TH enzyme have failed to achieve any significant functional effects beyond partial reductions in apomorphine rotation.” Id. at 4712, left col. “Significant increases in L-dopa production, however, were observed when the rAAV-TH vector was injected together with the rAAV- GCH1 vector . . . , suggesting that the transduced striatal neurons contain insufficient endogenous levels of the BH4 cofactor.” Id. Kirik states that its data show that the activity of the TH enzyme . . . is very low when the rAAV-TH vector is injected alone. Coinjection of the rAAV-TH and rAAV-GCH1 vectors increased the in vivo activity of the TH enzyme 6-8-fold, resulting in a high level of L-dopa production and a significant 3-fold increase in striatal dopamine concentration. Id. Appeal 2021-002540 Application 15/300,686 10 The above teachings would have made obvious the system of claim 1 to a person of ordinary skill in the art.8 Specifically, both Björklund and Kirik teach increasing patients’ DOPA production in order to treat Parkinson’s disease through the use of a gene expression system encoding both TH and GCH1. Björklund teaches a single-vector system that encodes both enzymes; Kirik teaches that expression of TH alone was inadequate to restore function and co-expression of TH and GCH1 was required. Björklund also teaches that TH activity requires the cofactor BH4, and the amount of BH4 affects TH activity: “Too little BH4 and the enzyme cannot work efficiently and too much BH4 can inhibit the function.” Björklund ¶ 142. Björklund teaches that “TH function is optimized” when the GCH1:TH ratio is between 1:3 and 1:7. Id. Björklund thus teaches that “the TH gene is expressed at about 3-7 fold higher levels than GCH1.” Id. ¶ 145. Björklund “achieve[s] an increased expression of TH over the GCH1 gene [using] a woodchuck hepatitis virus post-transcriptional regulatory element (WPRE)” to increase TH expression. Id. ¶ 56. However, Tai teaches that the destabilizing domain (DD) from E. coli DHFR fused to a transgene caused “reversible and dose-dependent expression” of the transgene. Tai 6, right col. Tai teaches that its DD is stabilized by trimethoprim (TMP), which crosses the blood-brain barrier and has been safely used in humans. Id. at 2, left col. 8 The Examiner cites Yan for its disclosure that prolonged treatment with L-DOPA causes complications and different treatments are desirable. Final Action 6. Both Björklund and Kirik disclose the same thing, however, so Yan is cumulative and we need not discuss it further. Appeal 2021-002540 Application 15/300,686 11 Thus, it would have been obvious to modify Björklund’s gene expression system by fusing Tai’s DHFR DD to the GCH1-encoding sequence, because Björklund teaches the use of its system to treat Parkinson’s disease (Björklund ¶ 22 (“The present invention relates primarily to the treatment of Parkinson’s disease.”)) and Tai teaches that “regulated transgene expression would allow for increased or decreased transgene levels in response to clinical need” (Tai 1, left col.). Tai also teaches that the activity of its DD was dose-dependent; thus, a skilled worker would understand that the level of active GCH1 could be adjusted in vivo by changing the amount of TMP administered. See Tai 6, left col. (“[G]iving increasing doses of TMP to the animals revealed a dose- dependent stabilization of the YFP-DD.”). Therefore, it would have been obvious to add Tai’s DD to the GCH1-encoding sequence in Björklund’s gene expression system to provide a means to adjust GCH1 activity in vivo to ensure a GCH1:TH ratio between 1:3 and 1:7, as taught by Björklund to be necessary for optimal TH activity. Appellant argues that “Tai is the only reference of the cited art that discloses a DD. Tai reports fusing a DD with glial cell derived neurotrophic factor (GDNF).” Appeal Br. 8. But, Appellant argues, “[j]ust because a DD is known does not mean it would have been obvious to include with GCH1.” Id. at 9. Appellant reasons that “GDNF is a secreted protein unrelated to dopamine synthesis” and “[f]usion of a DD to GDNF directly regulates GDNF expression.” Id. at 10. “In contrast, dopamine production is more complicated than regulation of GDNF expression,” and involves both BH4 synthesis and conversion of tyrosine to dopamine via L-DOPA. Id. at 11. Appeal 2021-002540 Application 15/300,686 12 This argument is unpersuasive. Fusion of a DD to another protein, such as GDNF or GCH1, directly regulates the activity (not expression) of the fusion protein. And, even though dopamine synthesis involves both BH4 production and conversion of tyrosine to L-DOPA, the activity of a GCH1 transgene is required in order for a TH transgene to provide a significant functional effect in a rodent model of Parkinson’s disease (PD). See Kirik 4708, abstract: “[A] critical threshold level of L-dopa, 1.5 pmol/mg of tissue . . . has to be reached to induce any significant functional effects. . . . [L]evels of striatal L-dopa production exceeding this threshold can be obtained provided that tyrosine hydroxylase is coexpressed with the cofactor synthetic enzyme, GTP-cyclohydrolase-1.” Thus, a skilled worker would reasonably expect that regulating GCH1 activity via a DD would effectively regulate dopamine production. Appellant cites the Kirik Declaration9 as support for the following reasoning: (a) “It is generally known that when inhibiting or enhancing molecular synthesis in a multi-step pathway (such as the dopamine synthesis pathway), the rate-limiting step is the best choice to regulate”; (b) the rate- limiting step in dopamine synthesis is the TH-catalyzed conversion of L-tyrosine to L-DOPA; (c) “[d]estabilization of GCH1 would be an ‘inferior choice’ because GCH1 is constitutively expressed”; and thus, (d) “it would not have been obvious to fuse a DD to GCH1.” Appeal Br. 11-12. Appellant argues that “the Kirik Declaration . . . directly counters the Examiner’s unsupported assertions.” Id. at 12. Specifically, Appellant argues that Dr. Kirik declares that “even if the ordinarily skilled artisan decided to 9 Declaration under 37 C.F.R. § 1.132 of Deniz Kirik, filed July 29, 2019. Appeal 2021-002540 Application 15/300,686 13 affect dopamine synthesis by attaching a DD to an enzyme in the synthetic pathway, ‘this person would have no way of knowing which enzyme to destabilize.[’]” Id. at 13. Appellant also argues that Dr. Kirik “contradicts the Examiner’s assertion that Björklund suggests a GCH1:TH ratio of 1:3 to 1:7 to achieve optimal dopamine.” Id. at 14. “Moreover, the Kirik Declaration represents expert objective evidence beyond attorney argument.” Id. Appellant argues that this “objective evidence directly counter[s] the premise of the Examiner’s conclusions” that “it would have been obvious to fuse a DD to GCH1.” Id. We have considered Appellant’s arguments and the Kirik Declaration but do not find them persuasive of nonobviousness. We acknowledge that Dr. Kirik is well-qualified, by virtue of education and experience, to provide an expert opinion regarding Appellant’s claimed invention. Kirik Decl. ¶¶ 2, 3. We also acknowledge that Dr. Kirik is both a co-inventor of the Björklund application and a co-author of the Kirik reference cited by the Examiner. Thus, Dr. Kirik is well-positioned to opine on the authors’ thinking when these references were written. However, obviousness under 35 U.S.C. § 103 is not assessed based on the subjective intention of a reference’s authors, but on how the reference would be viewed by a hypothetical person of ordinary skill in the art. See In re Rouffet, 149 F.3d 1350, 1357 (Fed. Cir. 1998) (“Obviousness is determined from the vantage point of a hypothetical person having ordinary skill in the art to which the patent pertains.”). Dr. Kirik states that “modulating the relative expression levels of the two proteins [i.e., TH and GCH1] was not the purpose of the constructs reported in the . . . [Björklund] publication. We did not measure the ratio of Appeal 2021-002540 Application 15/300,686 14 expression between the TH and GCH1. . . . Also, we did not attempt to differentially express TH and GCH1.” Kirik Decl. ¶ 11. These statements, however, are flatly contradicted by Björklund itself. Björklund states that “[t]he present invention relates to viral vector constructs . . . comprising polynucleotide sequences encoding two polypeptides to be differentially expressed in a target cell.” Björklund ¶ 2 (emphasis added). Björklund also states that “the present invention relates to a one-vector expression system comprising two polynucleotides encoding two polypeptides designed to be differentially expressed. . . . The two encoded polypeptides, tyrosine hydroxylase (TH) and GTP-cyclohydrolase 1 (GCH1), can preferentially be expressed at a ratio between 3:1 and 7:1.” Id. ¶ 151. See also id. ¶ 342 (“To achieve a superior expression of the TH gene over GCH1, the trafficking of the TH mRNA was improved by the addition of a woodchuck hepatitis virus post-transcriptional regulatory element (WPRE).”). Dr. Kirik also states that [t]he ratios described [in Björklund] (1:3 and 1:7) highlight the relationship between GCH1 expression and TH expression for saturation of TH enzyme activity, and importantly not the dynamic range. These statements do not, and were never intended to be, suggestions that expression systems should generate a three- to seven-fold excess of TH over GCH1. Id. ¶ 12. Regardless of what the statements in Björklund were intended to suggest, however, in our view they would have unambiguously suggested a GCH1:TH ratio between 1:3 and 1:7. Björklund states that conventional treatment of Parkinson’s disease patients with L-DOPA eventually gives rise to adverse events, “[t]he most problematic of [which] is the L-dopa-induced Appeal 2021-002540 Application 15/300,686 15 dyskinesias.” Björklund ¶ 5. “[T]he current hypothesis is that dyskinesias develop, at least in part, due to the intermittent, pulsatile supply of DA [dopamine] that the oral L-DOPA delivery paradigm gives rise to. These patients benefit from continuous DA stimulation.” Id. ¶ 6. However, “[c]ontinuous DOPA delivery depends on several factors contributing to the establishment of an environment for optimal TH enzyme functionality.” Id. ¶ 143 (emphasis added). Björklund states that “the[] data show that the working range between 1:3 and 1:7 GCH1:TH ratio can result in an efficient DOPA synthesis where TH function is optimized.” Id. ¶ 144 (emphasis added). “Accordingly, in certain embodiments, the TH gene is expressed at about 3-7 fold higher levels than GCH1.” Id. ¶ 145. In our view, a person of ordinary skill in the art would have read these teachings to mean that continuous DOPA delivery can avoid the dyskinesias that results from pulsatile L-DOPA administration, and can be provided by co-expression of TH and GCH1, but depends on optimal TH enzyme functionality; a GCH1:TH ratio between 1:3 and 1:7 optimizes TH function; and therefore TH should be expressed at levels 3-7-fold higher than GCH1. Appellant also argues that the Specification provides evidence of unexpected results. Appeal Br. 15. Specifically, Appellant argues that, in “a multi-step synthetic pathway . . . , the state of the art suggests manipulating the rate-limiting step,” which “[i]n the dopamine synthesis pathway . . . is the conversion of L-tyrosine to L-DOPA by TH.” Id. Appellant argues that the in vitro results shown in the Specification show that “293 cells transfected with a nucleotide encoding the DD-TH fusion polypeptide and a separate nucleotide encoding GCH1 . . . show an enhanced reduction in DOPA synthesis upon removal of TMP as compared Appeal 2021-002540 Application 15/300,686 16 to 293 cells transfected with a nucleotide encoding the DD-GCH1 fusion polypeptide and a separate nucleotide encoding TH.” Id. Appellant argues that, based on these results, “it was expected that fusing the DD to TH would similarly regulate dopamine synthesis in vivo,” but “[u]nexpectedly, the opposite was discovered.” Id. at 16. Dr. Kirik declares that an “ordinary artisan would predict that destabilizing GCH1 to be an inferior choice because it is constitutively expressed. . . . Enzymes that are constitutively expressed, such as GCH1, will continue to be constitutively expressed, even in the presence of exogenously added destabilized GCH1.” Kirik Decl. ¶ 19. Dr. Kirik states that, [s]urprisingly, . . . we found that administering DD-GCH1 with unmodified TH . . . [resulted in] elevated dopamine production in the presence of TMP (the GCH1 was stabilized) that was equivalent to constitutive co-expression of unmodified TH and unmodified GCH1. The DD-TH (+GCH1) construct exhibited five-fold lower levels dopamine production in the presence of TMP. These results are described in the Experiments section of the pending application. Id. ¶ 20. Dr. Kirik states that, in his opinion, “the results obtained by the in vivo experiments were surprising . . . because the accepted theory, supported by in vitro evidence, directed one to the attaching the DD to TH, not GCH1.” Id. ¶ 21. We have considered the data presented in Appellant’s Specification, and Dr. Kirik’s discussion of those data, but are not persuaded that a preponderance of the evidence supports Appellant’s position. With regard to Dr. Kirik’s statement that, compared to TH, GCH1 would have been thought to be an inferior choice for regulation, the Kirik reference states that “the Appeal 2021-002540 Application 15/300,686 17 level of L-dopa production in the transduced striatum is very low unless expression of TH is combined with exogenous administration of BH4 or coexpression of . . . GTP-cyclohydrolase-1 (GCH1[)].” Kirik 4708, bridging sentence. Thus, it was known that overexpression of both TH and GCH1 was required in order to increase dopamine production in vivo, and a skilled artisan would reasonably have expected that destabilization of the exogenous nucleic acid encoding either enzyme would effectively diminish L-DOPA synthesis. In addition, the Specification discloses that both DD-GCH1 and DD- TH effectively regulated control of DOPA in vitro. The Specification states that [c]ombining constitutively expressed TH and DD-GCH1 resulted in efficient DOPA production when the DD was coupled on the N-terminal side of the enzyme and in the presence of TMP. In the absence of TMP, DOPA levels were similar to what were observed in TH only transfected cells. . . . Regulation of TH by coupling the DD on the N-terminal side gave DOPA levels comparable to the constitutively expressed vector combination in presence of TMP. . . . [T]he lowest basal activity and leakage was achieved by controlling the TH enzyme. Spec. 37:22-26. In short, both constructs were effectively stabilized by TMP and, in the absence of TMP, DD-TH gave “the lowest basal activity” but DD-GCH1 without TMP resulted in L-DOPA levels as low as seen with TH only. As noted above, the Kirik reference states that TH expression alone results in very low L-DOPA production in vivo. Kirik 4708, bridging sentence. Appeal 2021-002540 Application 15/300,686 18 With regard to in vivo results, the Specification states: Surprisingly, we found that contrary to observations in cell lines, and the results that would have been anticipated by skilled person, treatment with the DD-TH+GCH1 vector combination resulted in 5-fold lower levels of HVA, as compared with the constitutively active vectors. Next, we tested whether TH combined with DD-GCH1 would have the same limitation as the DD-TH+GCH1 combination. Unexpectedly, the inventors found that the DD-mediated control of GCH1 stability and therefore the availability of BH4 was very effective. Spec. 38:15-22 In other words, the DD-TH construct combined with constitutively expressed GCH1 resulted in 5-fold less HVA10 than constitutively expressed TH and GCH1, contrary to what was found in vitro. The in vivo results for DD-GCH1, on the other hand, were consistent with the in vitro results: in vitro, “[c]ombining constitutively expressed TH and DD-GCH1 resulted in efficient DOPA production when the DD was coupled on the N-terminal side of the enzyme and in the presence of TMP” (Spec. 37:22-24), while in vivo, “TH combined with DD-GCH1 . . . [provided] DD-mediated control of GCH1 stability and therefore the availability of BH4 was very effective” (id. at 38:19-22). Thus, the Specification’s in vivo results are inconsistent with its in vitro results only with respect to the DD-TH construct, which performed “[s]urprisingly” (Spec. 38:15) poorly in vivo. The Specification does not 10 The Specification does not appear to define “HVA” or specify its relationship with DOPA or dopamine, but the Kirik Declaration states that the Specification’s data show that “[t]he DD-TH (+GCH1) construct exhibited five-fold lower levels dopamine production” (Kirik Decl. ¶ 20), which presumably refers to the above-quoted passage. Appeal 2021-002540 Application 15/300,686 19 provide further explanation of why the in vivo performance of DD-GCH1 was considered “[u]nexpected[]” (id. at 38:21), except to the extent that it was different from that of the DD-TH construct, when the DD-GCH1 construct’s in vivo performance is consistent with its in vitro performance. In summary, we conclude that a preponderance of the evidence demonstrates that claim 1 would have been obvious based on the cited references. We affirm the rejection of claim 1 under 35 U.S.C. § 103 based either on Björklund, Yan, Tai, and Kirik or on Björklund, Yan, Tai, Kirik, and Furler. Claims 6, 14-16, 19-22, 25-28, and 31-33 were not argued separately and therefore fall with claim 1. 37 C.F.R. § 41.37(c)(1)(iv). Obviousness-type double patenting Claims 1, 6, 14-16, 19-22, 25-28, and 31-33 stand rejected for obviousness-type double patenting based on claims 1-24 of U.S. Patent 9,593,312 in view of Yan, Tai, and Kirik. The Examiner finds that the claims on appeal are not patentably distinct from the claims of the ’312 patent because “because both claim sets are drawn to a method of treating a disease or disorder associated with reduced dopamine levels” using a gene expression system comprising nucleic acids encoding GCH1 and TH. Final Action 3. “The only difference is that the [’312] patent claims do not recite a DD-GCH1 fusion.” Id. at 4. The Examiner concludes, however, that it would have been “obvious to use DHFR DD in the expression system recited in the patent claims to achieve the predictable result of obtaining a system that can be induced as needed by the in vivo administration of TMP,” based on Yan, Tai, and Kirik, for the reasons discussed above in regard to obviousness. Id. We agree with, and adopt, the Examiner’s reasoning and conclusion. Appeal 2021-002540 Application 15/300,686 20 Appellant argues that “[t]he ’312 patent claims a method for treating a condition associated with catecholamine dysfunction with a gene expression system comprising GCH1- and TH-encoding nucleotides, but no DD. This method is a different statutory category than the composition of matter of pending Claims 1, 6, and 33.” Appeal Br. 17. We agree with Appellant that the Examiner has not shown that the products of instant claims 1, 6, and 33 are obvious variants of the method claimed in the ’312 patent. “[O]bviousness-type double patenting encompasses any use for a compound that is disclosed in the specification of an earlier patent claiming the compound and is later claimed as a method of using that compound.” Sun Pharm. Industries Ltd. v. Eli Lilly & Co., 611 F.3d 1381, 1386 (Fed. Cir. 2010). Here, however, the earlier patent is to a method and, while that method requires use of a product, it is a different product from that of the instant claims. We therefore reverse the rejection of claims 1, 6, and 33 for obviousness-type double patenting. As the Examiner has pointed out (Ans. 26), however, the remaining claims on appeal are directed to methods. With respect to those claims, Appellant argues that, “[a]s discussed at length above, Yan, Tai, and Kirik do not demonstrate that fusing a DD to GCH1 would be an obvious modification. Therefore, the pending claims are not directed to an obvious modification of the invention claimed in the ’312 patent.” Appeal Br. 18. This argument is unpersuasive for the reasons discussed above with regard to the rejections under 35 U.S.C. § 103. Appeal 2021-002540 Application 15/300,686 21 DECISION SUMMARY In summary: Claims Rejected 35 U.S.C. § Reference(s)/Basis Affirmed Reversed 1, 6, 14-16, 19-22, 25- 28, 31-33 103 Björklund, Yan, Tai, Kirik 1, 6, 14- 16, 19-22, 25-28, 31- 33 1, 6, 14-16, 19-22, 25- 28, 31-33 103 Björklund, Yan, Tai, Kirik, Furler 1, 6, 14- 16, 19-22, 25-28, 31- 33 1, 6, 14-16, 19-22, 25- 28, 31-33 Obviousness-type double patenting 14-16, 19- 22, 25-28, 31, 32 1, 6, 33 Overall Outcome 1, 6, 14- 16, 19-22, 25-28, 31- 33 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