Ex Parte Bar-Or

Patent Trial and Appeal Board

Mar 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. § 134(a), Appellant submits this appeal under
35 U.S.C. § 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. § 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).
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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. § 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").
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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
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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
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Specification. Spec. 46, Table 2. These data show that lower concentrations
of danazol (0.1 µM - 10.0 µM) inhibited vascular permeability, whereas
higher concentrations of danazol (25.0 µMor higher) had the opposite effect
and "actually increased vascular permeability." Id. at 44. Conversely,
higher concentrations (50 µM- 100 µM) are "optimal ... for inhibiting
angiogenesis," but the "optimal concentrations for use to inhibit vascular
permeability (0.1 µM to 0.5 µM) 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. § 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 µM, which is "well within the low
concentration range (0.1 µM - 10.0 µM) 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,
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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.
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SUMMARY
We reverse the rejection of claims 1, 16, 19, 20, 23, 63-67, and 72-75
under 35 U.S.C. § 103 over Liu and Funatsu.
REVERSED
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