Ex Parte Bar-Or

Patent Trial and Appeal BoardMar 7, 2019

12820325 (P.T.A.B. Mar. 7, 2019)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE FIRST NAMED INVENTOR 12/820,325 06/22/2010 David Bar-Or 22442 7590 03/11/2019 Sheridan Ross PC 1560 Broadway Suite 1200 Denver, CO 80202 UNITED ST A TES OF AMERICA 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 ATTORNEY DOCKET NO. CONFIRMATION NO. 6134-107 1954 EXAMINER SZNAIDMAN, MARCOS L ART UNIT PAPER NUMBER 1628 NOTIFICATION DATE DELIVERY MODE 03/11/2019 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): e-docket@sheridanross.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte DAVID BAR-OR Appeal2018-004406 Application 12/820,325 Technology Center 1600 Before ULRIKE W. JENKS, TIMOTHY G. MAJORS, and MICHAEL A. VALEK, Administrative Patent Judges. VALEK, Administrative Patent Judge. DECISION ON APPEAL Pursuant to 35 U.S.C. Â§ 134(a), Appellant submits this appeal under 35 U.S.C. Â§ 134(a) involving claims to a method of treating diabetic macular edema. 1 Examiner rejected claims 1, 16, 19, 20, 23, 63----67, and 72-75 as obvious. We have jurisdiction under 35 U.S.C. Â§ 6(b). We REVERSE. 1 Appellant identifies Ampio Pharmaceuticals, Inc. as the real party in interest. App. Br. 3. Herein we refer to the Non-Final Office Action mailed September 26, 2016 ("Non-Final Act."); Appeal Brief filed Oct. 24, 2017 ("App. Br."); Examiner's Answer, mailed Jan. 25, 2018 ("Ans."); and Reply Brief filed March 22, 2018 ("Reply Br."). Appeal2018-004406 Application 12/820,325 STATEMENT OF THE CASE Appellant's invention relates to treating edema by administering an amount of danazol to inhibit vascular hyperpermeability and a second drug effective to treat the condition. Spec 1, 11. 7-10. According to the Specification, "Danazol compounds have previously been reported to inhibit angiogenesis," but [ s ]urprisingly and quite unexpectedly, it has been found that danazol compounds can be used in the practice of the present invention at optimum doses that are about 100-1000 times lower than those previously reported for inhibiting angiogenesis and substantially less than those amounts currently administered to patients for the treatment of other diseases and conditions. Id. at 16, 1. 30- 17, 1. 5. "Uses of these lower doses of danazol compounds should avoid any significant side effects, perhaps all side effects, which will be especially advantageous for early or prophylatic [sic] treatment of diseases and conditions." Id. at 17, 11. 5-7. Claims 1, 16, 19, 20, 23, 63----67, and 72-75 are on appeal and can be found in the Claims Appendix of the Appeal Brief. App. Br. 18-19. Claim 1 is the only independent claim and representative of the claims on appeal. It reads as follows: 1. A method of treating diabetic macular edema in an animal, the method comprising administering to the animal a vascular- hyperpermeability-inhibiting amount of danazol or a pharmaceutical acceptable salt thereof, wherein the vascular- hyperpermeability-inhibiting amount is from 1 mg to 100 mg per day and an amount of a second drug selected from the group consisting of an angiotensin converting enzyme (ACE) inhibitor and an ACE receptor antagonist effective to treat diabetic macular edema. App. Br. 18 (Claims Appendix). 2 Appeal2018-004406 Application 12/820,325 Appellant seeks review of Examiner's rejection of claims 1, 16, 19, 20, 23, 63----67, and 72-75 under 35 U.S.C. Â§ 103 as unpatentable over Liu,2 in view of Funatsu. 3 App. Br. 8-16. The issue is: Has Examiner established a prima facie case of obviousness, and if so has Appellant provided evidence of unexpected results that, upon reweighing the entire merits of the case, demonstrates that the preponderance of the evidence does not support Examiner's determination that the claims are obvious over the cited prior art? Findings of Fact FF 1. Liu teaches the treatment of various conditions, including diabetic macular edema, by administering "a therapeutic amount of an angiogenesis- inhibiting compound" such as danazol. Liu ,r,r 16, 102. Liu teaches that the dosage regimen is based on a variety of factors and "may vary widely, but can be determined routinely using standard methods." Id. ,r 218. Liu teaches that the "dosage form usually ranges from slightly less than about 0.025 mg/kg/day to about 2.5 g/kg/day, preferably about 0.1 mg/kg/day to about 100 mg/kg/day." Id. ,r 220. FF2. Funatsu teaches the use of lisinopril as an angiotensin-converting enzyme (ACE) inhibitor to treat diabetic macular edema. Funatsu, Abstract. Funatsu concludes that "treatment with the ACE inhibitor lisinopril was able to reduce the macular thickness in patients with [ diabetic macular edema] ... 2 Jun Liu et al., US 2008/0193499 Al; published Aug. 14, 2008 ("Liu"). 3 Hideharu Funatsu et al., Quantitative Measurement of Retinal Thickness in Patients With Diabetic Macular Edema is Useful for Evaluation of Therapeutic Agents, DIABETES RESEARCH AND CLINICAL PRACTICE, Vol. 66, 219-227 (2004) ("Funatsu"). 3 Appeal2018-004406 Application 12/820,325 suggesting that ACE inhibitors may be effective for this condition." Funatsu at 226. Analysis Examiner determines that it would be obvious to combine Liu's teachings regarding danazol with Funatsu' s disclosure of the ACE inhibitor lisinopril because each "is taught by the prior art to be useful for the same purpose (treating diabetic macular edema)." Non-Final Act. 6. Moreover, Examiner finds that the danazol dosage range in Appellant's claims is prima facie obvious because it overlaps with the range taught in Liu. Non-Final Act. 6; Ans. 12. Specifically, Examiner relies on Liu's disclosure of a range between 0.1 to 100 mg/kg/day, which equates to a dose of7 to 7,000 mg per day for a 70 kg human adult. Non-Final Act. 6; Ans. 5---6. Appellant contends that "the skilled person would not understand Liu as disclosing the use of danazol in a vascular-hyperpermeability-inhibiting amount" because Liu' s broader range of 7 mg to 7,000 mg per day does not disclose the narrower claimed range of 1 mg to 100 mg per day with "sufficient specificity" to establish a prima facie case of obviousness. App. Br. 10. Even assuming a prima facie case, Appellant argues that there is evidence of unexpected results in both "the novel finding that the [ claimed] low concentrations of danazol inhibit vascular hyperpermeability" and the "synergistic result" achieved by combining danazol with an ACE inhibitor that rebut any prima facie showing of obviousness. Id. at 11, 14--15. Upon considering the evidence cited by the Examiner, and the evidence of unexpected results presented by Appellant, we determine that the preponderance of the evidence on this record does not support the Examiner's conclusion of obviousness. As discussed below, Appellant's 4 Appeal2018-004406 Application 12/820,325 evidence of unexpected results is sufficient to outweigh the evidence of obviousness. Regarding Examiner's prima facie case, we agree that Liu teaches the administration of danazol to treat diabetic macular edema and a dosage range that overlaps with the claimed range. FF 1. Appellant does not dispute Examiner's finding that Liu discloses a danazol dosage range of 7 mg to 7,000 mg per day, which overlaps with the claimed range of 1 mg to 100 mg per day. These facts are sufficient to establish a prima facie case of obviousness. See In re Peterson, 315 F.3d 1325, 1329 (Fed. Cir. 2003) ("[W]e and our predecessor court have consistently held that even a slight overlap in range establishes a prima facie case of obviousness."). While Liu does not expressly state that this a "vascular-hyperpermeability-inhibiting amount," one of skill in the art would reasonably expect the same compound at a dosage within the overlapping range to exhibit the same therapeutic properties. See In re Dillon, 919 F.2d 688, 692-93 (Fed. Cir. 1990) (en bane). Because we agree that a prima facie case of obviousness has been established, we tum to Appellant's rebuttal. In doing so, we are careful to consider the evidence as a whole, reweighing "the entire merits of the matter" in light of Appellant's rebuttal evidence. In re Hedges, 783 F.2d 1038, 1039 (Fed. Cir. 1986). To establish unexpected results, Appellant relies on the surprising discovery that "low concentrations of danazol inhibit vascular hyperpermeability and conversely, at higher concentrations of danazol ... vascular permeability is increased." App. Br. 12 ( emphasis in original). This argument is supported by data from assays set forth and analyzed in the 5 Appeal2018-004406 Application 12/820,325 Specification. Spec. 46, Table 2. These data show that lower concentrations of danazol (0.1 ÂµM - 10.0 ÂµM) inhibited vascular permeability, whereas higher concentrations of danazol (25.0 ÂµMor higher) had the opposite effect and "actually increased vascular permeability." Id. at 44. Conversely, higher concentrations (50 ÂµM- 100 ÂµM) are "optimal ... for inhibiting angiogenesis," but the "optimal concentrations for use to inhibit vascular permeability (0.1 ÂµM to 0.5 ÂµM) have insignificant effects on angiogenesis." Id. at 45. To establish a nexus between the data in the Specification and the claimed dosage range, Appellant relies on testimony from the inventor, Dr. David Bar-Or. App. Br. 13 (citing Declaration of Dr. David Bar-Or, submitted under 37 C.F.R. Â§ 1.132 and dated April 15, 2012 ("April 2012 Deel.")). Based on his testing, Dr. Bar-Or testified that a 50 mg dose equates to a plasma concentration of 1. 7 ÂµM, which is "well within the low concentration range (0.1 ÂµM - 10.0 ÂµM) correlated with effects of enhancing vascular barrier function (i.e., decreasing vascular permeability) as shown in Table 2." April 2012 Deel. ,r 6. Dr. Bar-Or further testified that "a 100 mg dose would be expected to produce a blood concentration falling within this low concentration range." Id. Examiner maintains that the evidence in the Specification and the April 2012 Declaration is irrelevant because it pertains only to the "mechanism of action," i.e., inhibiting vascular hyperpermeability, which would "naturally flow from the teachings of the prior art." Ans. 15. We disagree. The claims specifically require danazol in a "vascular- hyperpermeability-inhibiting amount ... from 1 mg to 100 mg per day" and Appellant's evidence shows that a dose in that range has such activity, 6 Appeal2018-004406 Application 12/820,325 whereas higher concentrations of the drug unexpectedly have the opposite effect. This distinction is a "differen[ ce] in kind" as opposed to merely "degree." See In re Applied Materials, Inc., 692 F.3d 1289, 1297 (Fed. Cir. 2012) ("The outcome of optimizing a result-effective variable may still be patentable if the claimed ranges are critical and produce a new and unexpected result which is different in kind and not merely in degree from the results of the prior art.") (internal citation and quotation marks omitted). Moreover, Appellant's evidence suggests that danazol is effective for inhibiting angiogenesis at higher, but not lower concentrations. This tends to show that one of ordinary skill, following Liu's teaching to use danazol as an angiogenesis inhibitor, would pursue higher dosages in Liu's range that would not achieve the claimed vascular-hyperpermeability-inhibiting effect, which Appellant's data shows is observed only at low dosages. This is especially true considering that the claimed range only overlaps with the extreme lower end of Liu' s much broader range, which mostly provides dosages that are at least an order of magnitude greater than even the highest dosage permitted by Appellant's claims. For these reasons, we determine that Appellant has overcome the prima facie case of obviousness with evidence that the claimed low dosage range is "critical" because it "achieves unexpected results relative to the prior art range." Peterson, 315 F.3d at 1330 (internal citation and quotation marks omitted). Accordingly, we reverse Examiner's obviousness rejection. 7 Appeal2018-004406 Application 12/820,325 SUMMARY We reverse the rejection of claims 1, 16, 19, 20, 23, 63-67, and 72-75 under 35 U.S.C. Â§ 103 over Liu and Funatsu. REVERSED 8