AMPIO PHARMACEUTICALS, INC.

Patent Trials and Appeals Board

Jun 10, 2020

2019005422 (P.T.A.B. Jun. 10, 2020)

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.
14/353,833 04/24/2014 David Bar-Or 6134-118-PUS 6556
22442 7590 06/10/2020
Sheridan Ross PC
1560 Broadway
Suite 1200
Denver, CO 80202
EXAMINER
BERRIOS, JENNIFER A
ART UNIT PAPER NUMBER
1613
NOTIFICATION DATE DELIVERY MODE
06/10/2020 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
__________

Appeal 2019-005422
Application1 14/353,833
Technology Center 1600
__________

Before DONALD E. ADAMS, RICHARD M. LEBOVITZ, and
RACHEL H. TOWNSEND, Administrative Patent Judges.

TOWNSEND, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a method
of reducing the severity of symptoms of allergic rhinitis, which have been
rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b).
We reverse.

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 AMPIO
PHARMACEUTICALS, INC. (Appeal Br. 3.)
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STATEMENT OF THE CASE
“Rhinitis is caused by chronic or acute inflammation of the mucous
membranes of the nose due to viruses, bacteria or irritants.” (Spec. 1.)
“Allergic rhinitis is a proinflammatory immune response to outdoor or
indoor allergens, such as dust or pollen.” (Id.) “The inflammation results in
the generation of excessive amounts of mucous, commonly producing a
runny nose, nasal congestion and post-nasal drip.” (Id.) Appellant’s
invention is a method to reduce the severity of symptoms of allergic rhinitis.
Claims 1, 2, 4–7, and 9–13 are on appeal. Claim 1 is representative
and reads as follows:
1. A method of reducing the severity of the symptoms of
allergic rhinitis comprising administering an effective amount
of a pharmaceutical composition comprising a diketopiperazine
with amino acid side chains of aspartic acid and alanine (DA-
DKP), to an animal in need thereof, wherein the DA-DKP is in
a composition prepared by removing albumin from a solution of
a human serum albumin composition, wherein the effective
amount of the DA-DKP in the composition is from about 100
μg to about 3000 μg per day.
(Appeal Br. 19.)

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The prior art relied upon by the Examiner is:
Name Reference Date
Alkeret al. US 5,358,953 Oct. 25, 1994
Bar-Or et al. US 6,555,543 B2 Apr. 29, 2003
Ivanova et al. US 2004/0048795 A1 Mar. 11, 2004
Bonner US 2009/0038416 A1 Feb. 12, 2009
D. H. Albert et al., ABT-491, a highly potent and selective PAF
antagonist, inhibits nasal vascular permeability associated with
experimental allergic rhinitis in Brown Norway rats, 46(Suppl. 2)
Inflammation Res. S133–34 (1997)
E. O. Meltzer, Efficacy and Patient Satisfaction with Cromolyn Sodium
Nasal Solution in the Treatment of Seasonal Allergic Rhinitis: A Placebo-
Controlled Study, 24(6) Clin. Therap. 942–52 (2002)
D. Bar-Or et al., Commercial human albumin preparations for clinical
use are immunosuppressive in vitro, 34(6) Crit. Care Med. 1707–12
(2006) (Bar-Or 2006)

The following grounds of rejection by the Examiner are before us on
review:
Claims 1, 2, 4, and 9–13 under 35 U.S.C. § 103(a) as unpatentable
over Bar-Or, Albert, and Alker.
Claims 5–7 under 35 U.S.C. § 103(a) as unpatentable over Bar-Or,
Albert, Alker, Bonner, and Meltzer.
Claims 1, 2, 4, and 9–13 under 35 U.S.C. § 103(a) as unpatentable
over Bar-Or, Albert, Bar-Or 2006, Ivanova, and Alker.
Claims 5–7 under 35 U.S.C. § 103(a) as unpatentable over Bar-Or,
Albert, Bar-Or 2006, Ivanova, Alker, Bonner, and Meltzer.

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DISCUSSION
Non-Obviousness Bar-Or, Albert, Alker
The Examiner finds that Bar-Or discloses a method of inhibiting the
effects of platelet activating factor (PAF) with DA-DKP where the suitable
daily dose of DA-DKP “will be the amount of the compound which is the
lowest dose effective to produce a therapeutic effect” and “will be
determined by an attending physician or veterinarian within the scope of
sound medical judgement.” (Final Action 3–4.) The Examiner further finds
that Bar-Or teaches that a disease “mediated by PAF (particularly
inflammation) can be treated” (id. at 3) by administration of the compound
“until an acceptable response is achieved” (id. at 4). The Examiner explains
that Bar-Or’s method is based “on the discovery that [DA-DKP] inhibits
PAF activity” which “inhibition appears to be due to the binding of DA-
DKP to both PAF and PAF receptors.” (Id. at 3.)
The Examiner recognizes that Bar-Or does not teach using DA-DKP
to treat allergic rhinitis, which is required by all the claims. (Id. at 4.)
However, the Examiner finds that such would have been obvious from the
combined teachings of Bar-Or, Albert, and Alker. (Id.; Ans. 18.) In
particular, the Examiner finds that Albert teaches that “PAF is perhaps the
most potent for inducing vascular permeability, a response that may
contribute to rhinorrhea formation” and “[t]he role of PAF in allergic rhinitis
has also been supported by studies reported with several PAF antagonists in
animal models of the disease.” (Id. at 4–5.) In addition, Albert teaches that
“ABT-491 exhibited potent [antagonist] activity” against nasal vascular
permeability in an animal model that resulted from an acute inflammatory
response after administration of PAF. (Id. at 5; Ans. 18.) The Examiner
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further notes that “[w]hile Albert specifically teaches the use of ABT-491,
Albert makes the conclusion that PAF plays an important role in antigen-
induced increased nasal vascular permeability in the rat and supports the
potential clinical utility of [any] PAF antagonist for the treatment of this
disease.” (Ans. 18; see also Final Action 5 (“Albert concludes that a PAF
antagonist has the potential for treatment of [allergic rhinitis].”).)
The Examiner concludes that because DA-DKP is a potent PAF
antagonist, it would have been expected by one of ordinary skill in the art to
function in the same manner as ABT-491 in treating rhinitis “absent
evidence to the contrary” and one of ordinary skill in the art would have
been motivated to use the compositions of Bar-Or for the treatment of
allergic rhinitis in a person in need. (Id.; Final Action 5.) In further support
of this conclusion, the Examiner notes that Alker teaches imidazopyridine is
a PAF antagonist that has “a structure very different from ABT-491 and DA-
DKP, however, these structurally different compounds are capable of
treating allergic rhinitis.” (Ans. 18; see also Final Action 7–8 (describing
the teachings of Alker).)
Regarding the claimed dosage amount, the Examiner notes that Alker
teaches using the imidazopyridine PAF/H1 antagonists at dose levels of
from 0.1-50 mg by intranasal administration and that a physician will
determine the actual dose that is most suitable for an individual patient.
(Final Action 7–8.) The Examiner concludes that “one of skill in the art
would recognize 0.1-50mg of DA-DKP to be starting point for optimization
to determine the ideal quantity of DA-DKP to be administered, as both Alker
and Bar-Or teaches that the amount of drug used to achieve a therapeutic
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effect depends on the individual patient and will vary with weight, age and
response of the patient.” (Id.)
Finally, regarding the claimed manner by which the DA-DKP is
obtained, the Examiner explains that in light of the fact that Bar-Or appears
to teach the same claimed compound, even though it may be produced by a
different process, “the burden shifts to applicant to come forward with
evidence establishing an unobvious difference between the claimed product
and the prior art product.” (Final Action 5–7.)
We conclude that the record does not support the Examiner’s
conclusion of obviousness as to the motivation and reasonable expectation
of success of treating allergic rhinitis with DA-DKP.
Appellant submitted Abu-Zidan2 in support of the unreasonableness
of the Examiner’s conclusion that just because two compounds have been
determined to be a PAF antagonist is not sufficient for one of ordinary skill
in the art to draw a conclusion that they would reasonably be expected to
treat the same inflammatory condition. The Examiner discounts any
relevance of this reference because the reference is concerned with PAF
antagonists in ischemic shock, which the Examiner indicates “does not
appear to be related to allergic rhinitis and inflammation and the prior art
shows that PAF antagonists, specifically DA-DKP and ABT-149, act against
inflammation mediated by PAF.” (Ans. 19.) We disagree with the
Examiner that Abu-Zidan is not relevant evidence contradicting the
Examiner’s reasonable expectation assertion.

2 F. M. Abu-Zidan et al., Lexipafant (BB-882): A Potent New Platelet-
Activating Factor Receptor Antagonist, 15(3) Cardiovascular Drug Reviews
232–43 (1997).
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Abu-Zidan teaches that there are “different PAF receptor subtypes in
the same animal” and that “different tissues respond differently to PAF” and
notes that there may be “subtype-selectivity of different PAF receptor
antagonists.” (Abu-Zidan 238.) Abu-Zidan also indicates that different PAF
antagonist compounds, particularly those that have different structures, may
give rise to different effects due to blocking different PAF receptors. (Id.)
Indeed, Abu-Zidan observed a difference in effect of different PAF
antagonist compounds (lexipafant and WEB 2086) in models of sepsis,
which Abu-Zidan indicates is a condition characterized by systemic
inflammation. (Id. at 232, 235–38.)
We agree with Appellant that Abu-Zidan supports the conclusion that
one of ordinary skill in the art would not have had a reasonable expectation
that DA-DKP would treat the same condition as ABT-491 just because both
ABT-491 and DA-DKP have PAF antagonist activity. (Appeal Br. 12–13.)
We note that the PAF antagonist activity Bar-Or studied is with respect to
IL-8 secretion in bronchial epithelial cells. (Bar-Or 13:30–67.) The PAF
antagonist activity studied in Albert was antigen-induced nasal vascular-
permeability. (See, e.g., Albert S133 (Materials and methods: noting
perfusion of the nasal mucosa) and id. at S134 (Results and discussion:
noting potent activity as an antagonist of PAF provoked increased nasal
vascular permeability).) In other words, different inflammatory responses
were analyzed and in different tissues.
Furthermore, as Appellant explains, ABT-491 and DA-DKP have
significantly different structures (Appeal Br. 11), which the Examiner
acknowledges (Ans. 19).
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Albert indicates that its studies, which were directed at observing a
reduction in increased vascular permeability provoked by PAF, “support the
potential clinical utility of a PAF antagonist for the treatment” of allergic
rhinitis. (Albert S134.) Albert itself suggests that it is not simply the fact of
any PAF antagonist activity that is important to suggest potential utility, but
rather PAF antagonist activity that results in reducing increased vascular
permeability. The Examiner has not established that DA-DKP has PAF
antagonist activity that results in reducing increased vascular permeability.
Abu-Zidan provides a reason to doubt that one of ordinary skill in the
art would have considered Albert to suggest that any PAF antagonist would
reasonably be expected to work just because it is a PAF antagonist. That is
because as noted above, Abu-Zidan teaches that it was known that different
compounds with PAF antagonist activity may act on different receptor
subtypes. The Examiner does not assert that it was known that DA-DKP
and ABT-491 act on the same PAF receptor subtype. Moreover, the studies
conducted in Bar-Or and Albert were on different tissues and involved
studying different activity. Given that DA-DKP and ABT-491 have a
significantly different structure, we find that it is not reasonable to conclude
in the absence of the foregoing evidence that both compounds will act on the
same PAF receptor in the same tissue.
The Examiner contends that because Alker teaches a different PAF
antagonist compound than Albert that also is taught to have utility in treating
allergic rhinitis, that the difference in structure between ABT-491 and DA-
DKP would not counsel against a reasonable expectation of success. (Ans.
19.) We disagree. That is because the bulky multiple ring structure of the
Alker compound is much closer to the bulky multiple ring structure of ABT-
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491 described in Albert than it is to the single ring structure of DA-DKP.
(Compare Alker 2 with Appeal Br. 11.)
For the foregoing reasons, we reverse the Examiner’s rejection of
claims 1, 2, 4, and 9–13 under 35 U.S.C. § 103(a) as unpatentable over Bar-
Or, Albert, and Alker.
The Examiner’s reliance on Bonner and Meltzer in rejecting claims 5–
7 does not address the deficiencies of Bar-Or, Albert, and Alker just
discussed. Consequently, we also reverse the Examiner’s rejection of claims
5–7 under 35 U.S.C. § 103(a) as unpatentable over Bar-Or, Albert, Alker,
Bonner, and Meltzer.
Non-Obviousness Bar-Or, Albert, Bar-Or 2006, Ivanova, Alker
The Examiner relies on Bar-Or, Albert, and Alker for the teachings
discussed above. (Final Action 12–14.) The Examiner relies on Bar-Or
2006 for its teaching of DA-DKP being extracted from HSA (human serum
albumin) commercial preparations, and that the compound is “partially
responsible for the immunosuppressive effects of H[SA] on activated
PBMCs and T-lymphocytes” and that “H[SA] preparations[, all of which
included DA-DKP,] significantly inhibited the in vitro production of
interferon-γ and tumor necrosis factor by activated PMBCs.” (Id. at 14–15.)
The Examiner notes that Ivanova teaches that “PAF, along with
interferon-γ and tumor necrosis factor are proinflammatory cytokines.” (Id.
at 15.) According to the Examiner:
As DA-DKP was shown to have inhibitory effects against the
proinflammatory cytokines interferon-γ and tumor necrosis
factor, one of skill in the art would have reasonably expected
DA-DKP prepared by the method of [Bar-Or 2006] to also be
effective against PAF, which is shown to be a functionally
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equivalent compound (proinflammatory cytokine) to both
interferon-γ and tumor necrosis factor.
(Id.) The Examiner concludes that “[t]herefore, it would have been prima
facie obvious to use the DA-DKP prepared by the method of Bar-Or NPL as
the DA-DKP used in the method of treating rhinitis made obvious [b]y Bar-
Or and Alberta.” Id.
The Examiner’s reliance on Bar-Or 2006 and Ivanova does not cure
the deficiencies discussed above. The fact that interferon-γ, tumor necrosis
factor, and PAF are all proinflammatory cytokines does not address or
suggest that DA-DKP would be expected to have PAF antagonist activity
that results in reducing increased vascular permeability. Consequently, we
also do not affirm the Examiner’s rejection of claims 1, 2, 4, and 9–13 under
35 U.S.C. § 103(a) as unpatentable over Bar-Or, Albert, Bar-Or 2006,
Ivanova, and Alker, or of claims 5–7 under 35 U.S.C. § 103(a) as
unpatentable over Bar-Or, Albert, Bar-Or 2006, Ivanova, Alker, Bonner, and
Meltzer.

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DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
1, 2, 4, 9–13 103 Bar-Or, Albert,
Alker
1, 2, 4, 9–13
5–7 103 Bar-Or, Albert,
Alker, Bonner,
Meltzer
5–7
1, 2, 4, 9–13 103 Bar-Or, Albert,
Bar-Or 2006,
Ivanova, Alker
1, 2, 4, 9–13
5–7 103 Bar-Or, Albert,
Bar-Or 2006,
Ivanova, Alker,
Bonner, Meltzer
5–7
Overall
Outcome
1, 2, 4–7, 9–
13

REVERSED