James Pipkin et al.

Patent Trials and Appeals Board

Jun 2, 2021

2020005040 (P.T.A.B. Jun. 2, 2021)

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.
12/479,576 06/05/2009 James D. Pipkin LIGAN4.063P1 1737
20995 7590 06/02/2021
KNOBBE MARTENS OLSON & BEAR LLP
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IRVINE, CA 92614
EXAMINER
MILLIGAN, ADAM C
ART UNIT PAPER NUMBER
1612
NOTIFICATION DATE DELIVERY MODE
06/02/2021 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.
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PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte JAMES D. PIPKIN,
RUPERT O. ZIMMERER, and JOHN M. SIEBERT
Appeal 2020-005040
Application 12/479,576
Technology Center 1600

Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
TAWEN CHANG, Administrative Patent Judges.

CHANG, Administrative Patent Judge.

DECISION ON APPEAL
Pursuant to 35 U.S.C. § 134(a), Appellant1 appeals from the
Examiner’s decision to reject claims 1, 2, 6, 7, 11, 12, 16, and 28–33.2 We
have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

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 CyDex
Pharmaceuticals, Inc. Appeal Br. 3.
2 An oral hearing was held on May 6, 2021. A transcript (“Tr.”) of this
hearing was entered into the record May 25, 2021.
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STATEMENT OF THE CASE
According to the Specification,
[t]he present invention is directed to methods of treating nasal
and/or ophthalmic diseases, symptoms, or disorders that are
therapeutically responsive to corticosteroid therapy by
delivering aqueous solution formulations comprising a
corticosteroid to nasal and ophthalmic tissues. The invention is
also directed to methods, systems, devices, and compositions
for delivering aqueous solution formulations comprising a
corticosteroid and an antihistamine to nasal and ophthalmic
tissues.
Spec. 1:16–21.
CLAIMED SUBJECT MATTER
The claims are directed to methods for treating an allergic symptom or
disorder, an ocular symptom or disorder, or ocular inflammation. Claim 1 is
illustrative:
1. A method for treating an allergic symptom or
disorder in a subject in need thereof, comprising: nasally
administering by a pump sprayer to the subject a corticosteroid
solution comprising a therapeutically effective amount of
budesonide, SAE-CD, an antihistamine, and a pharmaceutically
acceptable aqueous liquid carrier, wherein the ratio of SAE-CD
to budesonide is from 16:1 to 500:1, wherein the budesonide is
present in an amount of 25 μg to 66 μg per unit dose, and
wherein the antihistamine is present in an amount of 130 μg to
275 μg per unit dose;
wherein the therapeutically effective amount is
administered in one or two unit doses per nostril;
wherein the allergic symptom or disorder includes a non-
nasal symptom selected from the group consisting of
itchy/gritty eyes, tearing/watery eyes, red/burning eyes, itchy
ears/palate and combinations thereof;
wherein the antihistamine is azelastine, pharmaceutically
acceptable salts thereof, pharmaceutically active metabolites
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thereof, optically active isomers or racemates, or mixtures
thereof,
wherein the SAE-CD is sulfobutylether ß-cyclodextrin,
wherein the method provides more rapid relief from the
allergy symptom or disorder compared to a budesonide
suspension at the same unit dose.
Appeal Br. 17 (Claims App.).

REJECTION(S)3
A. Claims 1, 2, 6, 7, 11, 12, 16, and 28–33 are rejected under 35 U.S.C.
§ 103(a) as being unpatentable over Stern,4 Plaut,5 and Pipkin.6 Ans.
3.
B. Claims 1, 2, 6, 7, 11, 28, 29, 31, and 327 are rejected under 35 U.S.C.
§ 112 (pre-AIA), second paragraph, as being indefinite. Ans. 3.

3 The Examiner has withdrawn the rejection of claims 1, 2, 6, 7, 11, 12, 16,
and 28–33 on the ground of nonstatutory double patenting as being
unpatentable over claims 1–3 of U.S. Patent No. 9,827,324 and claims 1–14
of U.S. Patent No. 10,159,752. Ans. 6. The Examiner states in the February
26, 2019 Non-Final Action (“Non-Final Action”) that, “[i]n the case of
rejoinder, claims 1-21 of U.S. Patent No. 10,207,008 may be added to the
double patenting rejection.” Non-Final Act. 9. As the Examiner does not
appear to have made any actual rejection based on the ’008 patent thus far,
we do not address the merits of any such hypothetical rejection.
4 Martin A. Stern et al., Nasal Budesonide Offers Superior Symptom Relief in
Perennial Allergic Rhinitis in Comparison to Nasal Azelastine, 81 ANNALS
ALLERGY, ASTHMA, & IMMUNOLOGY 354 (1998).
5 Marshall Plaut & Martin D. Valentine, Allergic Rhinitis, 353 NEW ENG. J.
MED. 1934 (2005).
6 Pipkin et al., WO 2005/065435 A2, published July 21, 2005.
7 In the Non-Final Action, the Examiner also rejected claims 12, 16, 30, and
33 under 35 U.S.C. § 112 (pre-AIA), second paragraph, as being indefinite.
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OPINION
A. Obviousness rejection over Stern, Plaut, and Pipkin (claims 1, 2, 6,
7, 11, 12, 16, and 28–33)
1. Issue
The Examiner finds that Stern teaches treating allergic rhinitis using
nasal antihistamines, such as azelastine hydrochloride, or nasal steroids,
including budesonide. Ans. 3–4. The Examiner finds “Stern demonstrates
that once-daily administration of 256µg of intranasal budesonide aqueous
suspension reduced nasal symptoms better than twice daily intranasal
administration of 280µg azelastine hydrochloride . . . and that both showed
improvement over the placebo.”8 Id. (citation omitted).
The Examiner finds that Plaut teaches that “allergic rhinitis symptoms
. . . include ocular symptoms such as itchy, red, water eyes” and that, “while
nasal corticosteroids are more effective than antihistamines for treating nasal
congestion and sneezing, there is no significant difference in the treatment of

Non-Final Act. 2. As Appellant points out, however, claims 12, 16, 39, and
33 do not recite any of the phrases the Examiner asserts to be indefinite. In
the Answer, the Examiner did not explicitly withdraw the rejection of claims
12, 16, 30, and 33 as indefinite. Ans. 6. However, the Examiner
acknowledged that “Appellant[] note[s] that the [indefiniteness] rejection
does not apply to claims 12, 16, 30, and 33” and listed the claims rejected
under this ground as “[c]laims 1, 2, 6–7, 11, 28, 29, 21 [sic] and 32.” Id. at
3, 6. We presume the reference to claim 21 to be a typographical error and,
accordingly, understand that the claims rejected as indefinite by the
Examiner are claims 1, 2, 6, 7, 11, 28, 29, 31, and 32.
8 We note that Stern did not appear to find the difference between azelastine
hydrochloride and placebo to be statistically significant. Stern 354
(Results). However, as discussed below, the Examiner also finds that Plaut
teaches using both azelastine and budesonide to treat allergic rhinitis.
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ocular symptoms when administering nasal corticosteroids or oral
antihistamines.” Ans. 4.
The Examiner finds that neither Stern nor Plaut teaches the addition of
sulfoalkylether-cyclodextrin (“SAE-CD”). Ans. 4. However, the Examiner
finds that Pipkin teaches a composition comprising SAE-CD, budesonide,
and an aqueous carrier, and further teaches that “the nebulization of
solutions containing SAE-CD provided a higher budesonide output rate than
nebulization of suspensions without SAE-CD.” Id. The Examiner finds that
Pipkin teaches an embodiment comprising 2 ml of budesonide and 50 mg of
SAE-CD, and further teaches that, in general, a single-use suspension will
contain 0.125–2 mg of corticosteroid suspended in about 50 µl to 10 ml of
carrier. Id.
The Examiner concludes that
[i]t would have been prima facie obvious to one of ordinary
skill in the art to treat allergic rhinitis, particularly the ocular
symptoms, by administering a combination of 280μg azelastine
hydrochloride and 256μg of intranasal budesonide, given that
Plaut[9] teaches these amounts of antihistamine and nasal

9 We understand that the specific amounts of 280µg azelastine hydrochloride
and 256µg of intranasal budesonide are taught in Stern rather than Plaut.
However, Plaut does teach that azelastine (Astelin) and budesonide
(Rhinocort) are both indicated for “[r]educ[ing] sneezing, ocular and
nasopharyngeal itching, [and] rhinorrhea,” and that budesonide (Rhinocort)
is additionally indicated for reducing mucosal congestion. Plaut 1936, Table
1. Plaut also teaches that, “[b]ecause antihistamines and nasal
corticosteroids influence different pathogenetic mechanisms, patients with
moderate or severe symptoms are commonly treated with both,” that “[i]n
practice, combination therapy is often used for patients who do not have a
response to a single agent,” and that, “[i]n a study testing an algorithm for
management, such therapy was the standard for patients with moderate or
severe rhinitis.” Id. at 1938, bridging paragraph.
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corticosteroid are individually effective in treating ocular
symptoms of allergic rhinitis. See MPEP 2144.06.
Further, it would have been prima facie obvious to one of
ordinary skill in the art at the time the application was filed to
solubilize the budesonide in SAE-CD given Pipkin teaches that
budesonide compositions containing SAE-CD have a higher
budesonide output than solutions[10] without SAE-CD. The
addition of SAE-CD would be expected to improve the delivery
of budesonide. Accordingly, there is an expectation that the
instantly claimed composition comprising azelastine and
budesonide solution would provide more rapid relief from an
ocular symptom than a budesonide suspension, given the output
rate difference taught by Pipkin.
Ans. 4–5.
With regard to the claimed range of azelastine, the Examiner further
finds that a skilled artisan “would have found it obvious to optimize the
amount of an active agent based on the desired level of response required
and side effects tolerated” and that “[s]uch a modification is routine in
pharmaceutics.” Ans. 5.
Appellant contends that a skilled artisan would not have had reason to
modify the prior art to arrive at the claimed inventions. Appeal Br. 9–12.
Appellant further contends that the claimed subject matter exhibits
unexpected results commensurate with the scope of the claims. Id. at 12–14.
Appellant does not separately argue the claims. We therefore focus
our analysis on claim 1 as representative. The issues with respect to this
rejection are (1) whether a skilled artisan would have had a reason to
combine the prior art to arrive at the invention of claim 1, with a reasonable

10 We note that the comparison described in Pipkin, as the Examiner points
out earlier in the Answer, is between an SAE-CD-containing solution and a
suspension without SAE-CD. Ans. 4.
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expectation of success and, if so, (2) whether Appellant has provided
evidence of unexpected results commensurate with the scope with the claim
that, when considered together with the evidence of obviousness, shows the
claims to be non-obvious.11
2. Analysis
Unless otherwise noted, we agree with and adopt the Examiner’s
findings summarized above, and determine that the Examiner has
established a prima facie case that claim 1 is obvious over Stern, Plaut, and
Pipkin. We address Appellant’s arguments below. Only those arguments
timely made by Appellant in the briefs have been considered; arguments not
so presented in the briefs are waived. See 37 C.F.R. § 41.37(c)(1)(iv); see
also Ex parte Borden, 93 USPQ2d 1473, 1474 (BPAI 2010) (informative)
(“Any bases for asserting error, whether factual or legal, that are not raised
in the principal brief are waived.”).

Motivation to combine/Reasonable Expectation of Success
Appellant contends that a skilled artisan at the time of the invention
would not have had reason to combine the teachings in the cited references
to arrive at a composition comprising both SAE-CD and azelastine. Appeal

11 In the briefs, Appellant also argues that the combination of cited prior art
does not teach a composition “wherein the sulfobutyl ether-ß-cyclodextrin
with budesonide [is] in a molar ratio of from 16:1 to 500:1” as required by
claim 1. Appeal Br. 8–9; Reply Br. 3–4. However, Appellant is no longer
relying on this argument. Tr. 17:2–18. In any event, as discussed below in
the context of whether a skilled artisan would have had reason to arrive at
the claimed ratio of sulfobutyl ether-ß-cyclodextrin with budesonide, we
find that Pipkin discloses and/or renders this ratio obvious.
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Br. 9–10. More particularly, Appellant notes the high equilibrium binding
constant of azelastine with cyclodextrin as compared to that of budesonide
with cyclodextrin. Id. at 10; Reply Br. 4. Appellant contends that a skilled
artisan would have expected the cyclodextrin to reduce the freely available
azelastine in solution, particularly in a composition having a high
cyclodextrin to azelastine ratio, and, accordingly, slow the availability of
azelastine when azelastine is administered in a composition with both
budesonide and cyclodextrin as compared to when it is sequentially
administered in free solution form with budesonide. Appeal Br. 9–10; Reply
Br. 4–5. Appellant contends that, furthermore, a skilled artisan “would
expect that the problem of reduced availability of free drug to be
exacerbated by the low fluid environment of the nasal cavity.” Appeal Br.
10; Reply Br. 6.
We are not persuaded. Appellant relies on the two Pipkin
declarations12 in support of its arguments. Reply Br. 4–5. Dr. Pipkin in turn
relies on Stella13 to support his assertion that a skilled artisan would have
expected cyclodextrin complexes to slow onset of action because “effective
binding of drugs to cyclodextrin could result in a slower release of the free
drug from the complex in vivo.” Pipkin Decl. ¶ 4.
However, Stella teaches that “drug release from cyclodextrin
complexes is rapid and quantitative in most cases” and that “[i]n aqueous

12 Declaration of J.D. Pipkin, Ph.D. under 37 C.F.R. § 1.132 (June 13, 2012)
(“Pipkin Declaration”) and Declaration of James D. Pipkin (Dec. 28, 2017)
(“Second Pipkin Declaration”).
13 Valentino J. Stella et al., Mechanisms of Drug Release from Cyclodextrin
Complexes, 36 ADV. DRUG DELIV. REV. 3 (1999).
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solution, drug/cyclodextrin complexes are continually forming and
dissociating with lifetimes in the range of milliseconds or less.” Stella
Abstr. Stella further states that, “[a]though the stronger the binding, the
slower the relative kinetics of dissociation, the rates are still fast and
essentially instantaneous.” Id.; see also id. at 4, left col. (stating that
“cyclodextrins do NOT appear to substantially alter the intrinsic
pharmacokinetics of drugs”); 5, left col. (stating that “the association and
dissociation of molecules to and from cyclodextrins . . . occur at very rapid
rates for both strong and weak complexes” and that “the KINETICS of
release of a drug molecule from the cyclodextrin cavity should not be a
limiting factor”); 6, left col. (stating that extensive reviews “have concluded
that cyclodextrins have little or no effect on the intrinsic pharmacokinetics of
drugs”).
Furthermore, even though Stella teaches that dilution—“the major
driving force for dissociation of weakly to moderately bound drugs” after
parenteral administration—is minimal when a drug/cyclodextrin is
administered ophthalmically (Stella Abstr.; 10, left col.), we are not
persuaded that Stella suggests a skilled artisan would thereby lack
motivation to, or reasonable expectation of success in, incorporating a
cyclodextrin in an intranasal formulation with azelastine. In particular,
Stella teaches that “[t]he literature is rich with examples of cyclodextrin
complexes administered at . . . sites” where “dilution is minimal, e.g., after
ocular, nasal, sublingual, pulmonary, dermal or rectal administration,” and
further suggests that mechanisms other than dilutions may contribute to drug
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release at those sites. Id. at 10–12; see also Spec. 2:17–21 (“Cyclodextrins
have been included in nasal or ophthalmic compositions.”).14
Finally, as the Examiner points out, azelastine is poorly soluble. Ans.
7. As taught in Pipkin, “[s]olubilization of drugs by cyclodextrins and their
derivatives is well known,” and “inclusion complexation [with
cyclodextrins] may result in increased apparent aqueous solubility and
stability for the complexed drug.” Pipkin 6:26–7:5. Thus, it is not clear why
a skilled artisan would have necessarily expected SAE-CD to decrease the
availability of azelastine in an intranasal formulation.
Appellant contends that “the package insert for Astelin indicates that
azelastine is ‘slightly soluble’ and not ‘poorly soluble’” and that “Astelin
provides azelastine as an aqueous solution at a concentration of 1 mg/mL to
deliver a dose of 137 micrograms in a metered-spray dispenser.” Reply Br.
5. Appellant contends that, “[t]hus, azelastine is fully soluble at
concentrations sufficient to deliver a nasal spray dose.” Id. Appellant
contends that, “[i]n any case, one of skill in the art would readily understand
that when no cyclodextrin is present, azelastine is in a completely free form
and available to be absorbed” and that, therefore, “[t]he presence of any
sulfobutylether ß-cyclodextrin, let alone large amounts, would be expected

14 Although we do not rely on the following to affirm the rejection, we note
that Roger A. Rajewski & Valentino J. Stella, Pharmaceutical Applications
of Cyclodextrins, 85 J PHARMACEUTICAL SCI. 1142 (1996), attached to the
Appeal Brief as Appendix 4 of the Evidence Appendix, also states that,
“[u]nlike solution administration to the precorneal area, there is probably
greater contact time between the drug or the cyclodextrin complex of the
drug and the nasal mucosal surface to allow for greater dissociation” of the
drug and cyclodextrin. Rajewski 1159, left col.
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to lower the amount of free azelastine in solution due to its significantly
higher affinity for sulfobutylether ß-cyclodextrin.” Id.; see also id. at 5–6.
We are not persuaded. The package insert for Astelin indicates that
azelastine is “sparingly soluble.” Appeal Br., Evidence App. 7, at 1. As
Stella explained,
[w]hen evaluating in vivo studies which suggest that
cyclodextrins either do or do not appear to alter drug
pharmacokinetics/pharmacodynamics, the question of
appropriate controls can and should be raised. Consider the
issue of a poorly soluble drug formulated in either a
cyclodextrin solution or some other dosage form for parenteral
administration. Traditionally, poorly water soluble drugs have
been formulated through the use of co-solvents, pH adjustments
for weak electrolytes, surfactants, emulsion and liposome
formulations, etc. or a combination of these techniques. In all
of these strategies the question becomes, ‘is it safe to assume
that the dosage form, itself, or a component of the formulation
may not affect the pharmacokinetics/ pharmacodynamics?’
Stella 5, bridging para. In the case of Astelin, for example, the formulation
appears to contain benzalkonium chloride, which may act as a
surfactant/solubilizer. Appeal Br., Evidence App. 7, at 1. Appellant does
not explain why a skilled artisan would expect azelastine solubilized by
SAE-CD to be less than available than the azelastine as formulated in
Astelin. For instance, in apparent contradiction to Appellant’s assertion that
a skilled artisan “would readily understand that when no cyclodextrin is
present, azelastine is in a completely free form and available to be
absorbed,” Astelin’s package insert in fact states that, “[a]fter intranasal
administration, the systemic bioavailability of azelastine hydrochloride is
approximately 40%.” Id.
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In the Reply Brief, Appellant cites to Ono15 to support its argument
regarding decreased availability of azelastine. We note as
an initial matter that Appellant did not rely on Ono in the opening brief,
thereby denying the Board the benefit of the Examiner’s response, and no
showing of good cause was made by Appellant to explain why the late
argument should be considered by the Board. Accordingly, Appellant’s
arguments relating to Ono are waived. See 37 C.F.R. § 41.41(b)(2); Cf.
Optivus Tech., Inc. v. Ion Beam Appl’ns S.A., 469 F.3d 978, 989 (Fed. Cir.
2006) (argument raised for the first time in the Reply Brief that could have
been raised in the opening brief is waived).
In any event, we note that, while Ono indeed teaches that “[o]nly the
free form of the drug, which is in equilibrium with the complexed form in
solution, is capable of penetrating . . . mucosal epithelia . . . and eventually
entering the systemic circulation,” and that addition of certain cyclodextrin
(“CyD”) decreased the permeation and absorption rate of the drug
phenacetin (Ono 93, left col.; 94, right col.; 95, right col.), Ono does not
thereby conclude that phenacetin should not be formulated with
cyclodextrin. Instead, Ono teaches that the absorption and permeation rate
of the drug was restored by the addition of a competition agent (id.), and
concludes that “[t]he bioavailability parameters of a drug after oral
administration of a preparation containing drug/CyD complexes may be
modified by formation of competitive inclusion complexes” and that the
results of the study “may be useful not only for prediction of intestinal

15 Naomi Ono et al., Model Analysis for Oral Absorption of a
Drug/Cyclodextrin Complex Involving Competitive Inclusion Complexes, 44
J INCLUSION PHENOMENA & MACROCYCLIC CHEM. 93 (2002).
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absorption of drugs from CyD preparations, but also for formulation design
of CyD preparations containing multi-components” (id. at Abstr.). See also
id. at 93, left col. (“The rate and extent of bioavailability of a poorly water-
soluble drug from its cyclodextrin (CyD) complex can be optimized by
adjusting various factors affecting the dissociation equilibrium of the
complex in both the formulation and the biophase in which the complex is
administered.).
In light of the above, we are not persuaded by Appellant’s argument
that a skilled artisan would have lacked motivation, or reasonable
expectation of success, in including SAE-CD in a composition comprising
both azelastine and budesonide, particularly when Plaut teaches that patients
are commonly treated with both antihistamines (such as azelastine) and
corticosteroids (such as budesonide) (Plaut 1938, left para.) and Pipkin
teaches the advantages of a composition comprising SAE-CD and a
corticosteroid (Pipkin 17:19–31). In this regard, we note that “‘[t]he fact
that [a] motivating benefit comes at the expense of another benefit . . .
should not nullify its use as a basis to modify the disclosure of one reference
with the teachings of another. Instead, the benefits, both lost and gained,
should be weighed against one another.’” Medichem S.A. v. Rolabo S.L.,
437 F.3d 1157, 1165 (Fed. Cir. 2006) (quoting Winner Int’l Royalty Corp. v.
Wang, 202 F.3d 1340, 1349 n.8 (Fed. Cir. 2000)). We also note that, for
purposes of an obviousness analysis, “the expectation of success need only
be reasonable, not absolute.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348,
1364 (Fed. Cir. 2007).
Appellant also contends that a skilled artisan would have had no
reason to select the claimed ratio of SAE-CD to budesonide of from 16:1 to
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500:1. Appeal Br. 11. More particularly, Appellant contends that neither
Stern nor Plaut teaches a composition comprising SAE-CD, “while Pipkin
only provides a broad general disclosure of corticosteroid to SAE-CD ratios
without providing any guidance to the person of ordinary skill in the art to
select any particular ratio, much less the high ratio of 16:1 to 500:1.”
Appeal Br. 11. Appellant contends that a skilled artisan would have been
motivated “to use as little SAE-CD as possible in order to avoid adding
unnecessary bulk and mass to the formulation and to reduce formulation
ionic strength and salt load,” to avoid prohibitive expense, and “to avoid the
use of excessive foreign agents in pharmaceutical formulations because large
amounts of foreign agents increase the risk of toxic side effects.” Id. at 11–
12.
We are not persuaded. Pipkin teaches embodiments “wherein . . . the
budesonide to SAE-CD molar ratio is 0.5 to 0.0001 (1:2 to 1:10,000), 1:1 to
1:100, 1:1 to 1:10,000, or 0.1 to 0.03 [(1:10 to 1:33)].”16 Pipkin 19:21–23.
Thus, Pipkin teaches a range of ratios that overlaps the claimed ratio of
SAE-CD to budesonide of from 16:1 to 500:1. Appellant concedes that

16 In the Answer, the Examiner cites specifically to Pipkin’s disclosure of
using “2mg budesonide . . . and 50mg Captisol® SAE-cyclodextrin” as
disclosing a ratio of 25:1 SAE-CD to budesonide, which the Examiner
asserts “falls squarely within the recited range of 16:1 to 500:1.” Ans. 7.
We do not agree with this portion of the Examiner’s Answer. Nevertheless,
as discussed below, we agree with the Examiner that the limitation relating
to the ratio of SAE-CD to budesonide is obvious because, as the Examiner
points out, “the amounts taught by the prior art generally overlap with the
amounts instantly claimed” and “[a] skilled artisan would have been
motivated to optimize the amount of cyclodextrin solubilizer in order to
provide the desired budesonide solubilization and corresponding
nebulization output rate.” Id. at 7–8.
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Pipkin teaches ranges of budesonide to SAE-CD, but contends that they are
“extremely broad ranges” that “provides no teaching to the person of
ordinary skill in the art to select a molar ratio of SAE-CD to budesonide of
at least 16:1.” Appeal Br. 9. However, as noted above, Pipkin teaches
embodiments that provide narrow ranges of budesonide to SAE-CD ratios
(e.g., 1:1 to 1:100 and 1:10 to 1:33).
Moreover, “[i]n cases involving overlapping ranges, [our reviewing
court and its] predecessor court have consistently held that even a slight
overlap in range establishes a prima facie case of obviousness,” and “shifts
the burden to the applicant to show that his invention would not have been
obvious.” In re Peterson, 315 F.3d 1325, 1329–30 (Fed. Cir. 2003). As
further noted below, Appellant has not persuasively shown that its claimed
range is “critical, [e.g.,] by showing that the claimed range achieves
unexpected results relative to the prior art range.” In re Woodruff, 919 F.2d
1575, 1578 (Fed. Cir. 1990) (citations omitted, emphasis in original).17
Neither are we persuaded by Appellant’s argument that a skilled
artisan would not have “directed to methods of treating allergic symptoms
using the formulations recited by Claims 1, 7, and 12, wherein the molar

17 At oral argument, Appellant asserted that “Pipkin is directed primarily to
inhalation [to the lungs] rather than nasal.” Tr. 9:15–19; see also id. at
17:13–17. However, Appellant does not appear to have made this argument
in the briefs. Id. at 12:5–8. Accordingly, Appellant has waived the
argument. We further note that, while Pipkin teaches a method of
administering its formulation by inhalation, it also teaches that its
formulation “can . . . be administered by conventional nasal delivery
apparatus.” Pipkin Abstr.; see also id. at 37:25–27 (“The present invention
can be used with other suspension-based aqueous formulations, which
formulations may be adapted for nasal delivery or pulmonary delivery.”).
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ratio of cyclodextrin to corticosteroid is from 16:1 to 500:1” because “the art
heavily taught against using excessive amounts of cyclodextrin.” Appeal Br.
11–12. As discussed above, Pipkin teaches overlapping ranges of SAE-CD
to budesonide ratios. Moreover, Appellant did not provide persuasive
evidence that the specific amounts of SAE-CD claimed would have been
considered excessive or toxic by a skilled artisan at the time of the invention.
In the same vein, with respect to Appellant’s argument regarding the
expense of the use of cyclodextrin, our reviewing court has explained that
the fact “a given combination would not be made by businessmen for
economic reasons does not mean that persons skilled in the art would not
make the combination because of some technological incompatibility. Only
the latter fact would be relevant.” In re Farrenkopf, 713 F.2d 714, 718 (Fed.
Cir. 1983) (citing Orthopedic Equip. Co. v. U.S., 702 F.2d 1005, 1013 (Fed.
Cir. 1983)).

Unexpected Results
Appellant contends that, even if the Examiner has established a prima
facie case of obviousness, Appellant has provided evidence of unexpected
results commensurate with the scope of claim 1 by showing that CDX-313, a
composition within the scope of claim 1, “increased onset of action for nasal
symptoms as well as [Total Nasal Symptom Score] and [Total Ocular
Symptom Score] when compared to Astelin [(comprising azelastine)] and
Rhinocort [(comprising budesonide)] administered separately.” Appeal Br.
12–14.
We are not persuaded. Appellant’s alleged unexpected results is
based on data relating to a single embodiment (i.e., CDX-313), which as
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described in the Second Pipkin Declaration contains 30 µg of budesonide
solubilized with sulfobutylether ß-cyclodextrin and 137 µg azelastine HCl
per spray with a ratio of cyclodextrin to budesonide of 46.9:1. Second
Pipkin Decl. ¶ 5. Similarly, the data is based on a single method in which
“[e]ach patient was administered successive single sprays in each nostril
from two bottles: (1) CDX-313 followed by [a] placebo; (2) Astelin
followed by Rhinocort Aqua; or (3) placebo followed by placebo.” Id.
Claim 1, however, recites budesonide in an amount of 25 to 66 per
unit dose, azelastine in an amount of 130 to 275 per dose, and a ratio of
SAE-CD to budesonide from 16:1 to 500:1. Appeal. Br. 17 (Claims App.).
Claim 1 further encompasses methods wherein the therapeutically effective
amount is administered in one or two unit doses per nostril. Id.
Accordingly, we agree with the Examiner that Appellant has not shown
unexpected results commensurate with the scope of the claim. Ans. 8; In re
Lindner, 457 F.2d 506, 508 (CCPA 1972) (“It is well established that the
objective evidence of nonobviousness must be commensurate in scope with
the claims.”).
Appellant contends that CDX-313 administered as a single spray in
each nostril “corresponds closely to the lower bound of effective dosages of
budesonide and azelastine as disclosed on the package inserts for Rhinocort
and Astelin.” Appeal Br. 13; Reply Br. 7–8. Appellant contends that “the
package inserts for Rhinocort and Astelin list a range of effective dosage
amounts.” Appeal Br. 14; Reply Br. 8. Appellant contends that a skilled
artisan would expect, “upon reading the 2017 Pipkin Declaration, that the
inventive formulation to also be effective and safe at the upper range of
doses for the [Rhinocort] and Astelin package inserts.” Appeal Br. 14. We
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are not persuaded. As the Examiner explained, the issue is not whether the
claimed range of dosages would be safe or effective, but whether they would
exhibit unexpected results. Ans. 10–11.
Appellant contends that,
upon becoming aware of the unexpected effects of CDX-313 at
the administered dosages, the person of ordinary skill in the art
would expect that the effects of the inventive formulation
would also exist at higher doses. In other words, if the
unexpected effectiveness is exhibited at one dose, it would also
be expected at higher doses.
Appeal Br. 14. Appellant similarly contends that “there is no reason to
expect that the instantly claimed composition would not result in the same
effects at dosages of budesonide and/or azelastine other than those tested.”
Reply Br. 7; see also id. at 8 (stating that “if the unexpected effectiveness [of
the claimed formulation] is exhibited at one dose, it would also be expected
at higher doses”).
We remain unpersuaded. It is true that, “[i]f an applicant
demonstrates that an embodiment has an unexpected result and provides an
adequate basis to support the conclusion that other embodiments falling
within the claim will behave in the same manner, this will generally
establish that the evidence is commensurate with [the] scope of the claims.”
In re Kao, 639 F.3d 1057, 1068 (Fed. Cir. 2011). However, Appellant has
cited no evidence in support of its conclusory statement above. “Attorneys’
argument is no substitute for evidence.” Johnston v. IVAC Corp., 885 F.2d
1574, 1581 (Fed. Cir. 1989).
We acknowledge that Dr. Pipkin states in his declaration that he
believes the results achieved by CDX-313 to “illustrate an unexpected
improvement” as compared to sequential treatment with Rhinocort Aqua and
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Astelin and that such result “can be reasonably representative of results that
can be obtained with other combinations of corticosteroid, SAE-CD and
antihistamine.” Pipkin Decl. ¶¶ 4–6; Second Pipkin Decl. ¶¶ 5–12.
However, Dr. Pipkin does not provide any persuasive factual basis for his
belief that CDX-313 is representative, stating merely that “[b]ecause the
skilled artisan is now aware . . . that combinations of SAE-CD,
corticosteroid and antihistamine can be selected so as to achieve results that
are synergistic, he will identify and select such combinations with a standard
or normal amount of experimentation.” Id. (emphasis added). This
statement, however, does not provide the requisite basis for concluding that
all of the solutions encompassed by claim 1 will behave in the same manner
as CDX-313 (i.e., that the evidence of alleged unexpected results is
commensurate with the scope of the claims).
Accordingly, although we have carefully considered the Pipkin
Declaration, we decline to give it controlling weight in light of the totality of
the evidence of record before us. In this regard, we note that
[t]he Board has broad discretion as to the weight to give to
declarations offered in the course of prosecution. See Velander
v. Garner, 348 F.3d 1359, 1371 (Fed.[]Cir.[]2003)
(‘[A]ccord[ing] little weight to broad conclusory statements [in
expert testimony before the Board] that it determined were
unsupported by corroborating references [was] within the
discretion of the trier of fact to give each item of evidence such
weight as it feels appropriate.’).
In re American Acad. of Sci. Tech Ctr., 367 F.3d 1359, 1368 (Fed. Cir.
2004) (alterations in original); see also In re Beattie, 974 F.2d 1309, 1313
(Fed. Cir. 1992) (opinion evidence in declarations has little value without
factual support); Perreira v. Sec. of the Dept. of HHS, 33 F.3d 1375, 1377
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n.6 (Fed. Cir. 1994) (“An expert opinion is no better than the soundness of
the reasons supporting it.”).18
Finally, Appellant’s heavy reliance on Ex parte Lee, 2007 WL
1766990, Appeal 2007-1033 (BPAI June 19, 2007) is misplaced. Appeal Br.
12–13; Reply Br. 7–8. The claim at issue in Ex parte Lee recites a method
of treating various types of cancer in a mammal, comprising “administering
. . . a therapeutically-effective combination of (1) a dosage unit of
capecitabine and (2) a dosage unit of Compound (1) . . . wherein the
administration will provide a greater anti-cancer effect than the effect
obtainable with either the dosage unit of capecitabine or the dosage unit of
Compound (1) alone.” Ex parte Lee, 2007 WL 1766990, at *1.
As an initial matter, Ex parte Lee is not binding on this panel.
Moreover, in Ex parte Lee the data in the declaration submitted by Appellant

18 During oral argument, Appellant points to the limitations in claim 1,
“wherein the method provides more rapid relief from the allergy symptom or
disorder compared to a budesonide suspension at the same unit dose.” Tr.
17:1–11. Appellant contends that the limitation imposes “a functional
constraint . . . on the amounts” of solution ingredients encompassed by claim
1. Id. This argument was not presented in the briefs and is thus waived.
Moreover, to the extent Appellant is arguing that all of the solutions that
meet the functional limitation will also exhibit the alleged unexpected results
exhibited by CDX-313 (i.e., allegedly unexpected superior performance
when compared to sequential administration of Rhinocort Aqua and
Astelin), Appellant has pointed to no adequate basis for such a conclusion.
To the extent Appellant is arguing that the functional limitation itself recites
an unexpected result, we are not persuaded. As the Examiner points out in
the prima facie case, Pipkin teaches that a solution comprising budesonide
and SAE-CD provides a higher budesonide output rate than budesonide
suspensions without SAE-CD. Ans. 4; Pipkin 43:3–10. Accordingly, the
functional limitation recited in claim 1 would not be unexpected.
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showed unexpected synergism when capecitabine and Compound (1) were
administered together, and the majority in Ex parte Lee found that “the
Examiner has not provided any reason why, in view of the Declaration, a
synergistic effect would not also be expected for other cancers and at
different dosages.” Id. at *3–*4. In this case, however, the Examiner not
only pointed out the scope of claim 1 as compared to the tested formulation,
but also provided reasons why a skilled artisan would not have expected all
of the formulations encompassed by claim 1 to exhibit the same allegedly
unexpected results. For example, the Examiner states:
In the instant application, Appellants[’] claims encompass
many distinct compounds and a wide range of amounts of these
compounds as well as a wide ranges of budesonide and
cyclodextrin. The single test performed is drawn to a
combination of [azelastine], budesonide and cyclodextrin in
specific amounts. This single test is insufficient to lead one of
skill in the art to believe that all claimed compounds at all
claimed amounts would exhibit the same result as the single
tested formulation. The instant claims permit not just azelastine,
but active metabolites, isomers and racemates and Appellants
have made no showing or argument that these compounds
behave the same as one another. The claims also include a wide
variety of amounts of cyclodextrin solubilizer, budesonide
steroid and . . . antihistamine (including potentially less
effective or salts, metabolites, isomers and racemates), but no
rationale as to why one of skill in the art would expect a similar
result for the very different amounts and agents included within
the scope of claims 1, 7 and 12 when only a single formulation
was tested. . . .
. . . . Based on the current single data point, one of skill in
the art would not expect a ratio of 16:1 cyclodextrin to
budesonide to solubilize to the same extent as a ratio of 46.9:1.
Nor would a skilled artisan expect all azelastine metabolites,
isomers, and racemates to provide the same treatment
effectiveness as azelastine. Thus, the skilled artisan would not
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expect the entire claimed range to achieve the same result as the
single formulation tested. Accordingly, Appellants have not met
their burden of placing the claims commensurate in scope with
the demonstrated results.
Ans. 10–11.19
Accordingly, for the reasons discussed above, we affirm the
Examiner’s rejection of claim 1 as obvious over Stern, Plaut, and Pipkin.
Claims 2, 6, 7, 11, 12, 16, 28–33, which are not separately argued, fall with
claim 1.

B. Indefiniteness rejection (claims 1, 2, 6, 7, 11, 28, 29, 31, and 32)
The Examiner concludes that “the recitation of itchy/gritty,
tearing/watery, itchy ears/palate are unclear because one of skill in the art
would not know whether the recited ‘/’ represents an ‘and’ or an ‘or’ and
thus whether both conditions are required or just one.” Ans. 3.
Appellant contends that “the term ‘/’ was not given any special
definition in the specification as originally filed,” and “[t]he term ‘/’ may be

19 During oral argument, Appellant took issue with the Examiner’s statement
that, “[b]ased on the current single data point, one of skill in the art would
not expect a ratio of 16:1 cyclodextrin to budesonide to solubilize to the
same extent as a ratio of 46.9:1.” Tr. 12:19–13:7. Appellant contends that
Figure 11B of the Specification shows that at the lower end of the claimed
SAE-CD to budesonide ratio (i.e., 16:1), solubility of budesonide would still
be maintained. Id. Putting aside the fact that this argument was not made in
the Reply Brief, Appellant has not provided an adequate explanation why
the fact that budesonide could be solubilized by SAE-CD at a ratio of 1:16
would lead a skilled artisan to conclude that such a formulation would also
exhibit unexpected results. We further note that, based on Figure 11B, it
appears that the solubility of budesonide in SAE-CD appear to depend in
part on the concentration of azelastine in the formulation.
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used in the English language to represent ‘and,’ ‘or,’ or ‘and & or.’” Reply
Br. 3; see also Appeal Br. 8 (stating that “it is well-known that the term ‘/’
can represent ‘and’ or ‘or’” in the sense that “the person of ordinary skill in
the art would understand the term ‘itchy/gritty’ to mean ‘itchy or gritty or
both’”).
“A claim is indefinite if, when read in light of the specification, it
does not reasonably apprise those skilled in the art of the scope of the
invention.” Amgen, Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313,
1342 (Fed. Cir. 2003). We agree with Appellant that a skilled artisan,
reading the claims in light of the Specification, would understand the “/” to
encompass both “and” as well as “or.” That is, as Appellant states, a skilled
artisan, reading the claims in light of the Specification, would understand a
claim phrase such as “itchy/gritty” to mean “itchy or gritty or both” (i.e.,
itchy and gritty).20 Accordingly, we reverse the rejection of indefiniteness.

20 See, e.g., “slash.” MERRIAM-WEBSTER, https://www.merriam-
webster.com/dictionary/slash (last visited May 21, 2021) (defining slash as
“a mark / used typically to denote ‘or’ (as in and/or), ‘and or’ (as in
straggler/deserter), or ‘per’ (as in feet/second)”); see also Spec. 116:23–33
(stating that TSS (total symptom score) was “the sum score of 4 nasal
symptoms . . . [,] 3 ocular symptoms (TOSS): redness, itching, tearing[;] and
1 non-nasal, non-ocular [symptom]: itchy ears/palate” and that “[p]atients
rated . . . non-nasal symptoms (itchy/gritty eyes, tearing/watery eyes,
red/burning eyes, itchy ears and palate”).
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CONCLUSION
In summary:
Claim(s)
Rejected
35
U.S.C. §
Reference(s)/Basis Affirmed Reversed
1, 2, 6, 7, 11, 12,
16, 28–33
103(a) Stern, Plaut, Pipkin 1, 2, 6, 7,
11, 12, 16,
28–33

1, 2, 6, 7, 11, 28,
29, 31, 32
112 Indefiniteness 1, 2, 6, 7,
11, 28, 29,
31, 32
Overall
Outcome
1, 2, 6, 7,
11, 12, 16,
28–33

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