Ex Parte BerggrenDownload PDFPatent Trial and Appeal BoardFeb 11, 201510834525 (P.T.A.B. Feb. 11, 2015) 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. 10/834,525 04/29/2004 Per-Olof Berggren 03-390-US 8527 20306 7590 02/12/2015 MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP 300 S. WACKER DRIVE 32ND FLOOR CHICAGO, IL 60606 EXAMINER EWOLDT, GERALD R ART UNIT PAPER NUMBER 1644 MAIL DATE DELIVERY MODE 02/12/2015 PAPER 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. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE __________ BEFORE THE PATENT TRIAL AND APPEAL BOARD __________ Ex parte PER-OLOF BERGGREN _________ Appeal 2012-008361 Application 10/834,525 Technology Center 1600 __________ Before DONALD E. ADAMS, SCOTT E. KAMHOLZ, and CHRISTOPHER G. PAULRAJ, Administrative Patent Judges. PAULRAJ, Administrative Patent Judge. DECISION ON APPEAL This is an appeal1 under 35 U.S.C. § 134 involving claims to a method of identifying candidate compounds for the treatment of type 1 diabetes. The Examiner rejected the claims for lack of enablement. We have jurisdiction under 35 U.S.C. § 6(b). We reverse. STATEMENT OF THE CASE Background According to the Specification: Voltage-gated L-type Ca2+-channels have an important physiological role in pancreatic β-cell (“β- 1 Appellant identifies the Real Party in Interest as Biocrine AB (see App. Br. 3). Appeal 2012-008361 Application 10/834,525 2 cell”) signal-transduction (1). These channels constitute an essential link between transient changes in membrane potential and insulin release from β-cells. Changes in cytoplasmic free Ca2+ concentration ([Ca2+]i) in the β-cell are associated with the activation of a spectrum of intracellular signals and are strictly regulated, as prolonged high [Ca2+]i is harmful to the cells. In type 1 diabetes (T1D), there is a specific destruction of the insulin secreting pancreatic β-cell. Sera from newly diagnosed type I diabetic (TID) patients have been shown to increase the activity of voltage-gated L-type Ca2+-channels in β-cells resulting in increased [Ca2+]i upon depolarization and β-cell apoptosis, effects that can be prevented by Ca2+ channel blockers (2). However, it has not been determined what factor in TID serum is responsible for the changes in [Ca2+]i. (Spec. 1 ll. 9–20). The Specification purports to “demonstrate that apolipoprotein CIII (apoCIII) is increased in serum from TlD patients and that this serum factor both induces increased cytoplasmic free Ca2+ concentration ([Ca2+]i) and β-cell death” (id. at 1 ll. 21–23). The Claims Claims 1–3 are under appeal. Independent claim 1 is representative, and reads as follows: 1. A method of identifying candidate compounds for the treatment of type 1 diabetes comprising (a) contacting pancreatic β-cells with (i) one or more test compounds and (ii) an amount of human apolipoprotein CIII ("apoCIII") according to SEQ ID NO: 2 that would be effective to increase intracellular calcium concentration in the pancreatic β-cells in the absence of the one or more test compounds, and Appeal 2012-008361 Application 10/834,525 3 (b) identifying those test compounds that inhibit an apoCIII-induced increase in intracellular calcium concentration in the pancreatic β-cells, wherein such test compounds are candidate compounds for the treatment of type 1 diabetes. The Rejection The Examiner rejected the claims under U.S.C. § 112, ¶ 1 for failing to satisfy the enablement requirement. In particular, the Examiner asserts that “the specification provides insufficient evidence that the method of the instant claims would function for identifying compounds for the treatment of type 1 diabetes (TID)” (Ans. 5). FINDINGS OF FACT FF1. The Specification teaches the following method for the measurement of [Ca2+]i: Cells, attached to coverslips, were pretreated with the different compounds as described in the results and thereafter incubated in basal medium with 2 µM fura- 2AM (Molecular Probes, Eugene, OR) for 30 min. The coverslips were mounted as the bottom of an open chamber and cells were perfused with medium. Fluorescence signals were recorded with a SPEX Fluorolog-2 system connected to an inverted Zeiss Axiovert epifluorescence microscope. The excitation and emission wavelengths were 340/380 and 510 nm, respectively. The results are presented as 340/380 excitation ratios, directly representative of [Ca2+]i (7). (Spec. 13 ll. 12–19). The Specification further teaches that “[w]hole-cell Ca2+ currents were recorded by using the perforated- Appeal 2012-008361 Application 10/834,525 4 patch variant of the whole-cell patch-clamp recording technique to eliminate the loss of soluble cytoplasmic components” (id. at 13 ll. 21–23). FF2. The Specification teaches that “[t]he concentration of apoCIII has been reported to be between 6-14 mg/dl in control subjects and 9- 27 mg/dl in diabetics,” and “[w]e have tested concentrations from 1-50 µg/ml and with 1, 3 and 6 µg/ml we did not see any effects, but with the concentrations 10-50 µg/ml we had responses” (id. at 16 ll. 18–24). The Specification reports that: “There was a higher percentage of dead cells in the cell population exposed to T1D serum. This effect was prevented by the addition of anti-apoCIII (Fig. 3E). Furthermore, the addition of pure apoCIII to culture medium with control serum resulted in an increased cell death” (id. at 17 ll. 16–19). ANALYSIS The Examiner asserts: The mechanism by which the claimed method would function relies on the assertion of the specification that apoCIII causes type I diabetes by inducing apoptosis in pancreatic β cells, and that a reduction of apoCIII in a diabetic patient would effectively treat the diabetes. On its face this treatment would seem to be flawed in that diabetes is generally diagnosed only after the loss of essentially all pancreatic β cells, thus, there would be no pancreatic β cells left to protect from apoptosis and the treatment could not be effective. As set forth by the Inventor in Dekki et al. (2007), the treatment could at best, “result in less aggressive development of β cell destruction and thereby delayed onset of type 1 diabetes”. Appeal 2012-008361 Application 10/834,525 5 For this reason alone the assay method of the instant claims is not enabled for identifying candidate compounds for the effective treatment of type I diabetes. (Ans. 6–7). The Examiner further finds that “[a] review of the prior art reveals that the role of apoCIII in diabetes is questionable” (id. at 7). Based on our review of the cited prior art and Appellant’s Specification, we determine that the Examiner has not made a prima facie case of non-enablement. As an initial matter, we note that the claims on appeal do not require the actual treatment of type I diabetes, but rather only the identification of “candidate compounds for the treatment of type I diabetes” (Cl. 1 (emphasis added). The Specification discloses a particular protocol for the measurement of intracellular calcium concentration ([Ca2+]i) in pancreatic β cells, and further discloses results wherein “[t]here was a higher percentage of dead cells in the cell population exposed to T1D serum,” and “[t]his effect was prevented by the addition of anti-apoCIII (Fig. 3E),” and “[f]urthermore, the addition of pure apoCIII to culture medium with control serum resulted in an increased cell death” (FF1–2). We find this disclosure to be sufficiently enabling for the claimed screening method. It has been held that the in vitro screening for compounds that exhibit a pharmacological activity “may establish a practical utility for the compound in question” because “[s]uccessful in vitro testing will marshal resources and direct the expenditure of effort to further in vivo testing of the most potent compounds, thereby providing an immediate benefit to the public, analogous to the benefit provided by the showing of an in vivo utility.” Cross v. Iizuka, 753 F.2d 1040, 1051 (Fed. Cir. 1985); see also Nelson v. Bowler, 626 F.2d 853, 856 (CCPA 1980) (“[T]ests evidencing Appeal 2012-008361 Application 10/834,525 6 pharmacological activity may manifest a practical utility even though they may not establish a specific therapeutic use.”). Accordingly, the need for further research to elucidate the specific mechanism by which ApoCIII might play a role in type I diabetes does not negate the enablement of the claimed screening method. See In re Wands, 858 F.2d 731, 736–37 (Fed. Cir. 1988) (“Enablement is not precluded by the necessity for some experimentation such as routine screening.”); see also In re Brana, 51 F.3d 1560, 1568 (Fed. Cir. 1995) (“Usefulness in patent law, and in particular in the context of pharmaceutical inventions, necessarily includes the expectation of further research and development.”). The Examiner has not identified any evidentiary basis on the record to support the assertion “that diabetes is generally diagnosed only after the loss of essentially all pancreatic β cells,” and “there would be no pancreatic β cells left to protect from apoptosis” and thus, a method of inhibiting β cell death (apoptosis) by inhibiting apoCIII could not be an effective treatment for Type 1 Diabetes (TID) (Ans. 6–7). Indeed, the Examiner previously acknowledged during prosecution that “[u]pon reconsideration it is agreed that some T1D patients have some residual β cell mass and the protection of these residual β cells may be of value to the T1D patients” (1/11/2011 Fin. Act., at 3). Furthermore, the cited prior art references do not support the Examiner’s position. The Examiner asserts that Maeda2 “establishes that apoCIII knock-out mice suffer no identifiable alterations in glucose 2 N. Maeda et al., Targeted Disruption of the Apolipoprotein C-III Gene in Mice Results in Hypotriglyceridemia and Protection from Postrprandial Hypertiglyceridemia. 269(38) J. BIOL. CHEM. 23610–23616 (1994). Appeal 2012-008361 Application 10/834,525 7 metabolism,” and that similar findings were reported by Ginsberg3 after studying apoCIII deficient humans. However, as noted in the Declaration of Per-Olof Berggren under 37 C.F.R. § 1.132, neither Maeda and Ginsberg specifically assessed glucose metabolism or otherwise called into question the role of apoCIII in T1D (Beggren Decl. ¶¶ 16–17). The Examiner further asserts that Ito4 and Reaven5 “establish that apoCIII knock-in mice, i.e., mice wherein apoCIII is overexpressed, are not diabetic (as would be expected)” (Ans. 7). We do not find support for that assertion in either reference. To the contrary, Ito specifically teaches that “overexpression of apoliporotein CIII can be a primary cause of hypertriglyceridemia [HTG] in vivo,” and that “HTG can . . . be associated with conditions such as diabetes . . . .” (Ito, Abstract, p. 790). Although Table I of Reaven discloses that glucose and insulin concentrations were comparable for control mice and transgenic hypertriglyceridemic mice, we find no basis to conclude that the authors of the study specifically assessed whether the transgenic mice developed 3 H. N. Ginsberg et al., Apolipoprotein B Metabolism in Subjects with Deficiency of Apolipoprotein CIII and AI. 78 J. CLIN. INVEST. 1287–1295 (1986). 4 Y. ITO et al., Hypertriglyceridemia as a Result of Human ApoCIII Gene Expression in Transgenic Mice. 249 SCIENCE 790–793. (1990). 5 G. M. Reaven et al., Hypertriglyceridemic mice transgenic for the human apolipoprotein C-III gene are neither insulin resistant nor hyperinsulinemic, 35 J. LIPID RES. 820–824 (1994). Appeal 2012-008361 Application 10/834,525 8 diabetes. The Examiner also relies upon Chen6 and Blackett.7 However, Chen specifically teaches that “apoC-III mRNA levels are elevated in insulin-deficient diabetic mice and that these levels are lowered after insulin treatment,” and postulates a correlation between apoC-III expression and Type I diabetes (IDDM) (Chen, pp. 1919, 1922–1923). Likewise, Blackett concludes that “the Apo C-III level tends to be higher in diabetics than in normal subjects” (Blackett, Abstract). We therefore do not agree with the Examiner’s assessment of the prior art, as it largely supports a role for apoCIII in Type I Diabetes. As such, we find that the claimed screening method for candidate compounds that inhibit apoCIII-induced increase in intracellular calcium concentration has a practical utility that satisfies the requirements of 35 U.S.C. § 112, ¶ 1. We thus reverse the rejection of the claims for lack of enablement. REVERSED lp 6 M. Chen et al., Transcriptional regulation of the apoC-III gene by insulin in diabetic mice: correlation with changes in plasma triglyceride levels. 35 J. LIPID RES. 1918–1924 (1994). 7 P. Blackett et al., Plasma Apolipoprotein C-III Levels in Children With Type I Diabetes, 81(4) SOUTHERN MED. J., 469–473 (1988). Copy with citationCopy as parenthetical citation