ALLERGAN, INC.

Patent Trials and Appeals Board

May 4, 2020

2020000021 (P.T.A.B. May. 4, 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.
14/139,519 12/23/2013 Terrence J. Hunt 17859-CON2 (BOT) 7909
51957 7590 05/04/2020
ALLERGAN, INC.
2525 DUPONT DRIVE, T2-7H
IRVINE, CA 92612-1599
EXAMINER
LYONS, MARY M
ART UNIT PAPER NUMBER
1645
NOTIFICATION DATE DELIVERY MODE
05/04/2020 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):
blake.morgan@allergan.com
pair_allergan@firsttofile.com
patents_ip@allergan.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
__________

Ex parte TERRENCE J. HUNT
__________

Appeal 2020-000021
Application1 14/139,519
Technology Center 1600
__________

Before ERIC B. GRIMES, RACHEL H. TOWNSEND, and
CYNTHIA M. HARDMAN, Administrative Patent Judges.

TOWNSEND, Administrative Patent Judge.

DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134 involving claims to a
lyophilized or vacuum dried pharmaceutical composition, which claims have
been rejected as obvious and for obviousness-type double patenting. We
have jurisdiction under 35 U.S.C. § 6(b).
We affirm.
STATEMENT OF THE CASE
“For storage stability and convenience of handling, a pharmaceutical
composition can be formulated as a lyophilized (i.e. freeze dried) or vacuum

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 Allergan, Inc.
(Appeal Br. 3.)
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dried powder which can be reconstituted with a suitable fluid.” (Spec. 2.)
Such compositions can include active ingredients that are proteins. (Id.)
Stabilizing such active ingredients to minimize loss of biological activity in
such a composition is important. (Id.) “Various excipients, such as albumin
and gelatin have been used with differing degrees of success to try and
stabilize a protein active ingredient present in a pharmaceutical
composition.” (Id.) “[D]espite their known stabilizing effects, significant
drawbacks exist to the use of protein excipients, such as albumin or gelatin,
in a pharmaceutical composition.” (Id. at 4.)
“Various proteins such as albumin and gelatin have been used to
stabilize a botulinum toxin present in a pharmaceutical composition.” (Id. at
2.) The claimed invention relates to botulinum toxin pharmaceutical
compositions stabilized with a non-protein excipient. (Id. at 21.)
Claims 15, 24–26, and 30 are on appeal. Claim 15 is representative
and reads as follows:
15. A lyophilized or vacuum dried pharmaceutical composition
comprising: (a) a botulinum toxin, wherein the botulinum toxin
is not stabilized by a protein excipient, (b) a poloxamer; and (c)
a disaccharide selected from sucrose or trehalose.
(Appeal Br. 41.)

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The prior art relied upon by the Examiner is:
Name Reference Date
Friedman et al. US 5,472,706 Dec. 5, 1995
Hunt US 2002/0064536 A1 May 30, 2002
Donovan US 2004/0086532 A1 May 6, 2004
K. Johnson, Preparation of peptide and protein powders for inhalation,
26 Adv. Drug Delivery Reviews, 3–15 (1997)
J. Carpenter et al., Rationale Design of stable protein formulations-theory
and practice: Rational Design Of Stable Lyophilized Protein
Formulations: Theory And Practice, 109–133 (Carpenter and Manning
eds. 2002).

The following grounds of rejection by the Examiner are before us on
review:
Claims 15, 24–26, and 30 under 35 U.S.C. § 103(a) as unpatentable
over Donovan, Johnson, Friedman, and Carpenter.
Claims 15, 24–26, and 30 on the ground of non-statutory obviousness-
type double patenting as being unpatentable over claims 4–6 of U.S. Patent
No. 8,642,047, Johnson, Friedman, and Carpenter.
Claims 15, 24–26, and 30 on the ground of non-statutory obviousness-
type double patenting as being unpatentable over claims 1–2 of U.S. Patent
No. 8,168,206, Johnson, Friedman, and Carpenter.
Claims 15, 24–26, and 30 on the ground of non-statutory obviousness-
type double patenting as being unpatentable over claims 1–12 of U.S. Patent
No. 8,137,677, Johnson, Friedman, and Carpenter.
Claims 15, 24–26, and 30 on the ground of non-statutory obviousness-
type double patenting as being unpatentable over claim 1 of U.S. Patent No.
9,981,022, Johnson, Friedman, and Carpenter.
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Claims 15, 24–26, and 30 on the ground of non-statutory obviousness-
type double patenting as being unpatentable over claim 11 of U.S. Patent
No. 9,044,477, Johnson, Friedman, and Carpenter.
Claims 15, 24–26, and 30 on the ground of non-statutory obviousness-
type double patenting as being unpatentable over claims 1–3 of U.S. Patent
No. 9,265,722, Johnson, Friedman, and Carpenter.
Claims 15, 24–26, and 30 on the ground of non-statutory obviousness-
type double patenting as being unpatentable over claims 1–28 of U.S. Patent
No. 7,419,676, Johnson, Friedman, and Carpenter.
Claims 15, 24–26, and 30 on the ground of non-statutory obviousness-
type double patenting as being unpatentable over claims 1–9 of U.S. Patent
No. 6,203,794, Johnson, Friedman, and Carpenter.
Claims 15, 24–26, and 30 on the ground of non-statutory obviousness-
type double patenting as being unpatentable over claims 1–16 of U.S. Patent
No. 9,629,904, Johnson, Friedman, Carpenter, and Hunt.
Claims 15, 24–26, and 30 on the ground of non-statutory obviousness-
type double patenting as being unpatentable over claims 1–6 of U.S. Patent
No. 8,580,250, Johnson, Friedman, Carpenter, and Hunt.
Claims 15, 24–26, and 30 on the ground of non-statutory obviousness-
type double patenting as being unpatentable over claims 1–5 of U.S. Patent
No. 9,107,815, Johnson, Friedman, Carpenter, and Hunt.
Claims 15, 24–26, and 30 on the ground of non-statutory obviousness-
type double patenting as being unpatentable over claims 1–6 of U.S. Patent
No. 8,323,666, Johnson, Friedman, Carpenter, and Hunt.
Claims 15, 24–26, and 30 provisionally on the ground of non-statutory
obviousness-type double patenting as being unpatentable over claims 20–41
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and 43–46 of copending Application No. 13/427,582, Johnson, Friedman,
and Carpenter.2
DISCUSSION
Obviousness
The Examiner finds that Donovan teaches a lyophilized
pharmaceutical composition that includes a botulinum toxin complex “(e.g.,
see [0034-35, 0073, 0131-0135, 0144-0149)” where that “neurotoxin can be
mixed with emulsifiers and stabilizing agents, including sucrose, (e.g. [0119,
0131, 0176–0177]. . .).” (Final Action 3–4.) The Examiner also finds that
Donovan teaches “the compositions may be formulated for inhalation
administration.” (Id. at 4 (citing Donovan ¶ 2).) The Examiner finds that
Donovan does not disclose the use of poloxamer 188 as an emulsifier or
trehalose as a stabilizing agent, but “does not require the composition be
stabilized by a protein excipient.” (Id. at 4.) The Examiner notes, though,
that Donovan does teach a suitable stabilizing agent is needed for use of the
toxin at dilute nanogram per milliliter concentrations, as well as when the
toxin is not used pharmaceutically until months or years after the
composition with the toxin is formulated. (Ans. 36 (citing Donovan ¶ 36).)
The Examiner finds three references concerning lyophilization of
proteins teach or suggest the use of poloxamer 188 and trehalose or sucrose

2 Appellant does not argue the merits of this rejection, nor has a terminal
disclaimer been filed to obviate the rejection. Therefore, we summarily
affirm this rejection. Hyatt v. Dudas, 551 F.3d 1307, 1314 (Fed. Cir. 2008)
(“When the appellant fails to contest a ground of rejection to the Board, . . .
the Board may treat any argument with respect to that ground of rejection as
waived.”).
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in the lyophilized composition of Donovan that includes botulinum toxin.
(Id. at 4–6). In particular, the Examiner finds that Johnson teaches
lyophilization is one of the most common and successful methods for
stabilizing proteins and that poloxamer 188 and sucrose are glass forming
excipients commonly used in that process with proteins. (Id. at 4) The
Examiner also finds that Friedman teaches, in lyophilizing compositions that
include neuromuscular blocking agents, essential components of the
composition include emulsifiers and cryoprotectant stabilizers, and the
emulsifier enhances the composition. (Id. at 4–5.) Poloxamer 188 is one
such emulsifier set forth in Friedman. (Id. at 5.) The Examiner further finds
that Friedman teaches that there are advantages to lyophilized submicron
emulsions, including better stability for long term storage. (Id.)
The Examiner finds that Carpenter teaches that there are “minimum
criteria for successful lyophilization of a protein-containing pharmaceutical
formulation [which] includes protection of the protein during freezing and
drying; and a high glass transition temperature.” (Final Action 5.) The
Examiner notes that Carpenter teaches formulators include sugars as
cryoprotectant stabilizers, and that “the best choice for stabilizing proteins
are sucrose and trehalose (e.g. page 117. . . ).” (Id.) Indeed, those sugars are
noted to be preferred “for inhibiting lyophilization-induced protein
unfolding and provide a glassy matrix with acceptably high glass transition
temperatures (e.g. see page 113)” as well as for minimizing aggregation.
(Id.)
The Examiner concludes that, in light of the foregoing, it would have
been obvious to modify the lyophilized “compositions comprising botulinum
toxin, stabilizing excipients including sucrose, and emulsifiers, as taught by
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Donovan, by using stabilizing cryoprotectants, including sucrose and/or
trehalose along with emulsifiers, including poloxamer 188” with a
reasonable expectation of success as “each element performs the same
function as it does individually.” (Id. at 5–6.) The Examiner explains that
the reason to include poloxamer 188 along with sucrose and/or trehalose
would have been to achieve a “stable, appropriately-sized, therapeutic
composition, fit for human use.” (Id. at 6.)
We agree with the Examiner’s conclusion of obviousness. In
particular, we agree with the Examiner that Donovan does not require the
stabilizing agent be a protein (Ans. 35), as will be addressed below.
The Examiner contends that Donovan specifically teaches sucrose is a
stabilizing agent for use in a composition of botulinum toxin that is to be
lyophilized. The Examiner points to the following passage in Donovan to
arrive at that conclusion:
To stabilize a neurotoxin, both in a format which renders the
neurotoxin useful for mixing with a suitable polymer which can
form the oral formulation matrix (i.e. a powdered neurotoxin
which has been freeze dried or lyophilized) as well as while the
neurotoxin is present or incorporated into the matrix of the
selected polymer, various pharmaceutical excipients can be
used. Suitable excipients can include starch, cellulose, talc,
glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica
gel, magnesium stearate, sodium stearate, glycerol
monostearate, sodium chloride, albumin and dried skim milk.
The neurotoxin in a neurotoxin oral formulation can be mixed
with excipients, bulking agents and stabilizing agents, and
buffers to stabilize the neurotoxin during lyophilization or
freeze drying.
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(Donovan ¶ 131; Final Action 43.) We agree with the Examiner that
Donovan can be so interpreted.
We conclude this portion of Donovan teaches that the lyophilized or
freeze dried botulinum toxin used to make the oral formulation that includes
a polymer matrix, can be stabilized by the addition of an excipient either (a)
by addition of the stabilizing agents in formation of the lyophilized product
or (b) after that lyophilized product is formed, or both. The stabilization is
such that the toxin is stable for mixing with the polymer, and when
incorporated into the matrix of the selected polymer. We do not read this
paragraph to limit the list of suitable excipients to arrive at a stabilized
neurotoxin to use only with a component that has already been lyophilized
that is to then be mixed with polymer matrix, particularly because Donovan
indicates that many different types of compounds can be used “to stabilize
the neurotoxin during lyophilization or freeze drying,” namely “excipients,
bulking agents and stabilizing agents, and buffers.” (Donovan ¶ 131.)
We agree with Appellant (Appeal Br. 12) that Donovan teaches the
necessity of diluting the toxin for use in a pharmaceutical composition, and
that such dilution is known to “result [] in rapid detoxification of the toxin
unless a suitable stabilizing agent is present.” (Donovan ¶ 36.) But we
disagree with Appellant that because Donovan (a) describes albumin and
gelatin as examples of such suitable stabilizing agents that can be used
(Appeal Br. 12 (citing Donovan ¶ 36)), (b) refers to obtaining botulinum
toxin type A using the Schantz process and “incorporates by reference” the

3 Although the Examiner also cites paragraphs 119 and 176–177, those
paragraphs do not refer to specific stabilizing compounds.
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article4 describing that process (Appeal Br. 11–12), and (c) provides
examples of using commercially available botulinum toxin, which is
stabilized with a protein (id. at 14), that Donovan requires that the toxin to
be used in its formulation is necessarily stabilized with a protein excipient.
First, we agree with the Examiner that Schantz cited by Appellant
(Appeal Br. 12; Ans. 37) discloses that human serum albumin use in
lyophilized botulinum toxin “presents potential problems.” See Schantz 81.
In particular, Schantz teaches that “[a]lthough the commercial botulinum
type A product is prepared in the presence of human serum albumin, the use
of human serum albumin presents potential problems in that certain stable
viral agents carried through from donors could contaminate the toxin.” (Id.)
Furthermore, Schantz teaches that loss of toxicity when storing a lyophilized
botulinum toxin stabilized with human albumin is significant at pH 7.3 (i.e.,
neutral pH) and “research” to develop a medium and conditions to overcome
losses on drying was being studied. (Id. at 83.)
Furthermore, we agree with the Examiner (Ans. 36), that in describing
known “stabilizing agents such as albumin and gelatin” (Donovan ¶ 36),
Donovan was not limiting stabilization of botulinum toxin to only those
agents, as evident by the use of the term “such as.” In fact, Donovan teaches
that “[i]t has been discovered that a stabilized neurotoxin can comprise
biologically active, non-aggregated neurotoxin complexed with at least one
type of multivalent metal cation which has a val[e]ncy of +2 or more.” (Id.
¶ 132.) Donovan notes that “[a] preferred metal cation used to stabilize a

4 E. Schantz and E. Johnson, Properties and Use of Botulinum Toxin and
Other Microbial Neurotoxins in Medicine, 56 Microbiological Reviews 80–
99 (1992).
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botulinum toxin is Zn++ because the botulinum toxin[s] are known to be zinc
endopeptidases.” (Id. ¶ 135.)5 Donovan describes how the “[t]he suitability
of a metal cation for stabilizing neurotoxin can be determined” with a
number of “stability indicating techniques” including “potency tests on
neurotoxin lyophilized particles containing metal cations to determine the
potency of the neurotoxin after lyophilization and for duration of release
from microparticles.” (Id. ¶ 136.) Donovan further explains:
In stabilized neurotoxin, the tendency of neurotoxin to
aggregate within a microparticle during hydration in vivo
and/or to lose biological activity or potency due to hydration or
due to the process of forming a sustained release composition,
or due to the chemical characteristics of a sustained release
composition, is reduced
(Id.)6 The conditions for preparing such a stable toxin are described,
including appropriate pH and suitable aqueous solvent and then lyophilizing
to form particulates of stabilized neurotoxin. (Id. ¶¶ 144–149.)7
Consequently, we conclude that Donovan’s references to using a stabilized
neurotoxin do not require that the neurotoxin be stabilized with a protein

5 We note that the Examiner relies on these cited paragraphs in the rejection.
(See Final Action 3–4.)
6 Donovan also notes that “[i]t is known that a significant water content of
lyophilized tetanus toxoid can cause solid phase aggregation and inactivation
of the toxoid once encapsulated within microspheres.” (Id. ¶ 168.)
Donovan explains that
the manufacturing process for BOTOX® results in a freeze
dried botulinum toxin type A complex which has a moisture
content of less than about 3%, at which moisture level nominal
solid phase aggregation can be expected.
(Id.)
7 We note that the Examiner also relies on these cited paragraphs in the
rejection. (See Final Action 4.)
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excipient, but do require the stabilization of a lyophilized neurotoxin such
that loss of biological activity during hydration is reduced, as well as a
reduction in the tendency of the neurotoxin to aggregate within a
microparticle during hydration or due to the process of forming, or chemical
characteristics of, a sustained release composition.
Moreover, we agree with the Examiner that Johnson, Friedman, and
Carpenter collectively teach or suggest the use of poloxamer 188 along with
sucrose and/or trehalose, without the use of albumin, for obtaining a stable
lyophilized botulinum toxin composition, which Donovan teaches can be
used to make the controlled release oral formulation of botulinum toxin
(Donovan ¶¶ 119, 142, 165). None of these references teach that a protein
excipient is necessary to obtain a stabilized lyophilized macromolecule.
And as discussed above, we conclude that Donovan does not require
albumin or another protein stabilizer. Thus, we disagree with Appellant’s
argument the “[t]he cited references are not combinable, as at least one of
the cited references teaches away from the claimed composition.” (Appeal
Br. 17–18.)
Although Johnson is “a review of ‘formulations for delivering
therapeutic aerosols to the lungs’” (Appeal Br. 15), and Donovan is
primarily concerned with making a biodegradable botulinum toxin oral
formulation (Donovan ¶ 169)8, Johnson is analogous art in that it recognizes

8 We disagree with the Examiner that Donovan teaches inhalation of its
composition. The citation relied on by the Examiner for such a teaching
(Donovan ¶ 2) mentions inhalation administration as one route of
administration of pharmaceutical compositions generally, but proceeds
thereafter to describe advantages of oral administration.
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the susceptibility of proteins to chemical and physical degradation in a
formulation or during the manufacturing process, or even during storage,
and provides information on common techniques used to stabilize these
“macromolecules,” particularly when they “must be stabilized in the solid
state.” (Johnson 7.) Johnson explains that “[o]ne of the most common” and
a “successful technique” for stabilizing proteins in the solid state is
lyophilization, which incorporates the protein into amorphous glasses, and
lists ten excipients commonly used in stabilizing proteins in the solid state.
(Id. (including Table 3).) Two of the commonly used compounds are
surfactants, one being poloxamer 188, the other being polysorbate 80 (also
known as TWEEN 80). (Id.) And two of them are carbohydrates, one being
sucrose and the other lactose. (Id.) The list also includes two polyols, two
amino acids, one chelating agent, and one protein. (Id.)
Carpenter teaches that for rational design of stable lyophilized protein
formulations there are “five criteria [that] define the minimal conditions
necessary for a successful lyophilized protein formulation,” and provides
“prototypic rational formulations . . . in Table 2.” (Carpenter 111, 117.)
The first criterion of importance is inhibiting protein unfolding, which can
lead to non-native aggregates, and the second is to ensure the glass transition
temperature (Tg) exceeds the planned storage temperature, which is
“essential for optimal protein stability.” (Id. at 111–13 and Table 1.)
Carpenter discloses that “[a]ggregation can be minimized by including
stabilizing excipients (e.g., sucrose or trehalose) in the formulation to inhibit
lyophilization-induced unfolding” and further that “[f]ortunately, sucrose
and trehalose, which are the preferred excipients for inhibiting
lyophilization-induced protein unfolding. . . , also provide a glassy matrix
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with acceptably high Tg values.” (Id. at 112–13.) Carpenter further notes
that “[f]rom a regulatory standpoint . . . the formulation scientist should
choose from among excipients that are already used in approved parenteral
products. For protein stabilizers, the best choices are the disaccharides,
sucrose and trehalose,” especially where the protein is a “therapeutic
protein.” (Id. at 117, 120.)
Carpenter also notes that in the case where a “structurally perturbed
protein molecule[]” might have arisen during lyophilization, “fostering
refolding during rehydration (e.g., with surfactants) can reduce aggregation.”
(Id. at 112.) Thus, inclusion of a nonionic surfactant to reduce protein
aggregation, where aggregation is known to be an issue, is considered in
addition to the use of trehalose or sucrose in rational lyophilized protein
formulations. (Id. at 118 (Table 2).) From a regulatory standpoint,
Carpenter indicates that “[f]or surfactants, usually the Tweens (20, 40 or 80)
are preferred.” (Id. at 117.)
The Examiner relies on Friedman for teaching “advantages of
lyophilized submicron emulsions.” (Final Action 5.) We do not agree,
because Friedman includes an oily component to make an oil-in-water
emulsion, and because Friedman’s composition “are formulated for
parenteral administration.” (See e.g., Friedman 2:31–42, 10:53–54.) We do
not find the Examiner has established a prima facie case for the obviousness
of such a lyophilized emulsion for the botulinum toxin used in Donovan that
is combined with a polymer to make an oral formulation. Nevertheless, we
rely on Friedman for its suggestion that poloxamer 188, like TWEEN and
TYLOXAPOL, is compatible with neuromuscular blocking agents. (Id. at
5:12–29, 6:2–9.)
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In light of the foregoing, we agree with the Examiner that it would
have been obvious to one having ordinary skill in the art to have selected
sucrose and poloxamer 188 as excipients to aid in the stabilization of the
botulinum toxin that is lyophilized and used in the Donovan oral
formulation, without the need for a protein stabilizer. Donovan suggests that
stabilization using a protein is not necessary as discussed above.9
Johnson provides a list of ten excipients for use in stabilizing proteins
during lyophilization, and Carpenter provides two strong reasons to include
a carbohydrate and a surfactant which are two categories of compounds in
the Johnson list. “Reading a list [such as is provided in Johnson] and
selecting a known compound to meet known requirements is no more
ingenious than selecting the last piece to put into the last opening in a jig-
saw puzzle. It is not invention.” Sinclair & Carroll Co. v. Interchemical
Corp., 325 U.S. 327, 335 (1945); see also Merck & Co. Inc. v. Biocraft
Laboratories, Inc., 874 F.2d 804, 807 (Fed. Cir. 1989). Indeed, in light of
Carpenter’s teachings regarding the rational design of stable lyophilized
protein formulations and the importance of preventing protein unfolding and
non-native aggregation, and its teaching that nonionic surfactant and sucrose
and trehalose are useful in that regard, we conclude that one of ordinary skill

9 Moreover, Schantz notes that there are potential contamination problems
by stable viral agents carried through from donors associated with the use of
human serum albumin as a stabilizing agent. (Schantz 81.) Although
Schantz mentions stabilization of the neurotoxin with a protein being
“required” (id.; Appeal Br. 12), that disclosure is limited to stabilization in
liquid medium for long term storage, not with respect to a lyophilized
botulinum neurotoxin. Schantz discloses that it was researching mediums
and conditions to overcome toxicity losses on drying of toxin, such as by
lyophilization. (Schantz at 83.)
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in the art “would have selected and combined th[e] prior art elements [in
Table 3 of Johnson] in the normal course of research and development to
yield the claimed invention” that includes sucrose and poloxamer 188 as
excipients to stabilize the botulinum toxin taught for use in the oral
composition of Donovan. Unigene Labs., Inc. v. Apotex, Inc., 655 F.3d
1352, 1360 (Fed. Cir. 2011).
While it is true that Carpenter indicates that usually Tweens are
preferred for the surfactant (Appeal Br. 16), Johnson provides another
commonly used surfactant, one that Friedman teaches is also compatible
with neurotoxins. Regarding the selection of poloxamer 188 over TWEEN
from Johnson’s list, “[t]he prior art’s mere disclosure of more than one
alternative does not constitute a teaching away from . . . alternatives because
such disclosure does not criticize, discredit, or otherwise discourage the
solution claimed.” In re Fulton, 391 F.3d 1195, 1201 (Fed. Cir. 2004). We
conclude that the claimed excipients are no more than a combination of
familiar elements yielding no more than predictable stabilization results.
Such a combination is unpatentable for obviousness. KSR Int’l Co. v.
Teleflex Inc., 550 U.S. 398, 416 (2007). For the foregoing reasons, we do
not agree with the Appellant that the Examiner has not established a rational
underpinning to support the conclusion of obviousness (Appeal Br. 18–19).
We thus affirm the Examiner’s rejection of claim 15 as being obvious
over Donovan, Johnson, Friedman, and Carpenter.
Claims 24–26 and 30 have not been argued separately and therefore
fall with claim 15. 37 C.F.R. § 41.37(c)(1)(iv).
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II
Non-Statutory Obviousness-type Double Patenting
1. Rejections relying on Johnson, Friedman, and Carpenter
The Examiner contends that the claims on appeal are “not patentably
distinct” from the claims identified in the ’047, ’206, ’677, ’022, ’477, ’722,
’676, and ’794 patents “because they are both drawn to substantially similar
compositions comprising the same active ingredient, i.e., botulinum toxin,
stabilized with commonly used non-protein ingredients.” (Final Action 16,
21, 24, 28, 32, 36, 38, 41.)
In particular, the Examiner states with respect to each of the noted
patents, that the toxin recited in those claims is a botulinum toxin (’047,
’677, ’022, ’477, ’722, ’676) (id. at 16, 25, 28, 32, 36, 38) or a genus of
toxins that is defined to encompass botulinum toxins (’206, ’794) (id. at 21,
41), and that either (1) the toxin is required to not be stabilized by a protein
excipient (’047, ’206, ’677 ) (id. at 16, 21, 25), or (2) the Examiner’s
position relies on the fact that the claims of the patent do not positively
recite the inclusion of a protein excipient (’022, ’477, ’722, ’676, ’794) (id.
at 28–29, 32, 36, 38, 41).
Regarding additional components in the compositions of the foregoing
patents, the Examiner finds:
a) Poloxamer and a dissacharide are included (’047) (id. at 16–17),
b) A dissacharide and a non-protein polymer excipient are included
(’206) (id. at 21),
c) Lactose and polyvinylpyrrolidone are included (’677) (id. at 25),
d) Trehalose and a thermo-reversible thermoplastic poloxamer are
included (’022) (id. at 28–29),
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e) Cross-linked, polymeric, hyaluronic acid carrier is included (’477)
(id. at 32),
f) the toxin is encapsulated in a polymer matrix carrier (’722) (id. at
36), and
g) the toxin is necessarily in a composition (’676) (id. at 38).
In view of the foregoing, the Examiner concludes that with respect to the
differences between the appealed claims and the patent claims that:
1) For the ’047 patent “the difference between the instant claims and
the patent claims is lyophilization” but “lyophilizing a protein containing
composition is prima facie obvious in view of the teachings of Johnson et
al., Friedman et al., and Carpenter et al. for the same reasons as set forth [in
the obviousness rejection discussed above].” (Final Action 17.)
2) For the ’206, ’677, ’477, ’676, and ’794 patents “the difference
between the instant claims and the patent claims is lyophilization with the
use of poloxamer 188 and trehalose” but “that lyophilizing a composition,
including the use of commonly employed, non-protein, stabilizing
excipients, emulsifiers, and/or cryoprotectants is prima facie obvious in view
of the teachings of Johnson et al., Friedman et al., and Carpenter et al., for
the same reasons set forth above.” (Id. at 21–22, 25, 32–33, 38–39, 41–42.)
3) For the ’022 patent “the difference between the instant claims and
the patent claims is lyophilization with the use of poloxamer 188” but “that
lyophilizing a composition, including the use of commonly employed, non-
protein, stabilizing excipients, emulsifiers, and/or cryoprotectants is prima
facie obvious in view of the teachings of Johnson et al., Friedman et al., and
Carpenter et al., for the same reasons set forth above.” (Id. at 29.)
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4) For the ’722 patent “the difference between the instant claims and
the patent claims is lyophilization with the use of poloxamer 188, sucrose
and/or trehalose” but “that lyophilizing a composition, including the use of
commonly employed, non-protein, stabilizing excipients, emulsifiers, and/or
cryoprotectants is prima facie obvious in view of the teachings of Johnson et
al., Friedman et al., and Carpenter et al., for the same reasons set forth
above.” (Id. at 36.)
Thus, in light of the foregoing, the Examiner concludes that “the
claims are not patentably distinct as being obvious variants of the
compositions in the patent claims.” (Id. at 17–18, 22, 26, 29, 33, 37, 39, 42.)
We agree with the Examiner’s position as to the ’047, ’206, ’677, and
the ’022 patents, but not as to the ’477, ’722, ’676, and ’794 patents.
Appellant first argues that the rejections are improper because the
Office has issued two different restrictions based on distinctness of certain
compositions. (Appeal Br. 21–22.) Appellant states that the restriction
dated August 18, 2014 concluded that “the pharmaceutical compositions
comprising a botulinum toxin and the following excipients are distinct:
polyvinylpyrrolidone (PVP), sugars/sugar alcohols, polyethylene glycol
(PEG), amino acids (e.g. methionine).” (Id. at 21.) Appellant states that the
restriction dated April 6, 2009 concluded that “a pharmaceutical
composition comprising a botulinum toxin (combination) is distinct from a
pharmaceutical composition comprising a botulinum toxin, wherein the
botulinum toxin is not stabilized by a protein excipient (subcombination).”
(Id. at 21–22.) Appellant argues that “it is improper for the Office to apply
one standard to determine whether the claims are distinct for restriction
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practice and another contradictory standard for purposes of obviousness-type
double patenting.” (Id. at 22.)
We do not find this argument persuasive as to any of the patents for
the reasons set forth by the Examiner in the Answer (Ans. 45–46), which
Appellants do not respond to.
a. The ’047, ’206, ’677, and the ’022 patents
Appellant argues with respect to these patents, that none refer to a
lyophilized composition. (Appeal Br. 23, 30, 36–37, 38.) This argument is
not persuasive. The Examiner recognized the absence of this limitation and
explained that such would have been an obvious variant of a botulinum toxin
composition including the excipients recited by these patent claims in light
of the cited prior art. (See, e.g., Final Action 21–22, Ans. 51.)
Appellant further argues that the Examiner has failed to provide a
rational underpinning for the selection of poloxamer 188. (Appeal Br. 22)
Regarding the ’677 patent, Appellant states the Examiner “has not explained
why a skilled artisan would have randomly chosen a poloxamer instead of
the claimed non-protein polymer excipient.” (Id. at 24.) Regarding the ’022
patent, Appellant states that the Examiner has failed to provide a reason why
a skilled artisan would have randomly selected poloxamer 188
from Johnson among a long list of commonly used stabilizing
agents, or poloxamer 188 from Friedman’s long list of
surfactants, when both Friedman and Carpenter both teach that
TWEEN surfactants are most preferred.
(Id. at 31.) Appellant argues similarly regarding the ’206 patent. (Id. at 37.)
We do not find this argument persuasive for the reasons discussed above
regarding the obviousness rejection and the obviousness of using known
excipients for their recognized purpose in stabilizing proteins for
lyophilization.
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Regarding the ’047 patent, Appellant asserts that one of ordinary skill
in the art would not have reasonably expected success in obtaining a toxin
having the recovery potency of the patent claims. (Id. at 38.) We do not
find this argument persuasive because the asserted potency is not an aspect
of the patented invention. Whether or not obtaining that potency would have
been obvious, has no bearing on whether the claims on appeal, which do not
require a particular potency, would have been obvious from the patented
claim which recites a composition that includes a botulinum toxin that is not
stabilized by a protein excipient, but does include a poloxamer and also
includes sucrose or trehalose. Regarding potency, we note that a later-
claimed genus is always obvious over an earlier claimed species. In re
Slayter, 276 F.2d 408, 411 (CCPA 1960) (“A generic claim cannot be
allowed to an applicant if the prior art discloses a species falling within the
claimed genus.”)
The only difference is that the appealed claims require lyophilization
(and with respect to dependent claim 30, a particular poloxamer). We have
already addressed the obviousness of those differences above. That the
patented combination might yield a better potency does not mean that an
inferior potency would not have been obvious. In re Fulton, 391 F.3d 1195,
1200 (Fed. Cir. 2004) (a conclusion of obviousness does not require
“something in the prior art as a whole to suggest that the combination is the
most desirable combination available”).
Regarding the ’677 patent, we note that an “[e]xpress suggestion to
substitute one equivalent for another need not be present to render such
substitution obvious.” In re Fout, 675 F.2d 297, 301 (CCPA 1982). But, we
do note as to the substitution of trehalose or sucrose for lactose, Carpenter
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teaches that “[r]educing sugars, such as maltose or lactose, should not be
used” in lyophilization because these compounds “during storage in the
dried solid . . . can degrade proteins via the Maillard reaction between
carbonyls of the sugar and free amino groups on the protein.” (Carpenter
121.)
Consequently, for the reasons set forth in the Examiner’s Final Action
as well as the Answer addressing Appellant’s arguments, which Appellant
does not respond to, we affirm the Examiner’s obviousness-type double
patenting rejection with respect to the ’047, ’206, ’677, and the ’022 patents.
b. The ’477, ’722, ’676, and ’794 patents
The references relied upon by the Examiner indicate excipients are
used to stabilize lyophilized proteins, which are subject to various
degradation effects on lyophilization either through chemical and/or physical
degradation and thus are accompanied by excipients to prevent degradation.
We note that in contrast to the patents just discussed, none of the claims of
the ’477, ’722, ’676, or ’794 patents recite lyophilized toxin or the inclusion
of excipients. The ’477 patent recites botulinum toxin with a cross-linked,
polymeric hyaluronic carrier. The ’722 patent recites the botulinum toxin
“encapsulated in a carrier.” The ’676 and ’794 patents recite toxin
polypeptide structural characteristics and are silent as to any excipients.
Consequently, we find that the Examiner has not established a reason that
one of ordinary skill in the art would have modified the toxins recited in the
patented claims to include excipients used for stabilizing a lyophilized
protein.
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Thus, we do not affirm the Examiner’s obviousness-type double
patenting rejection grounded on the claims of the ’477, ’722, ’676, and ’794
patents.
2. Rejections relying on Johnson, Friedman, Carpenter, and Hunt
The Examiner contends that the claims on appeal are “not patentably
distinct” from the claims identified in the ’904, ’250, ’815, and ’666 patents
“because they are both drawn to substantially similar compositions
comprising the same active ingredient, i.e., botulinum toxin, modified to
remove an undesirable protein element and stabilized with commonly used
non-protein ingredients.” (Final Action 44, 48, 52, 56.)
The Examiner relies on Hunt as recognizing prior to 2004, that “the
presence of albumin was a serious problem and thus provided one of
ordinary skill in the art motivation to remove albumin from pharmaceutical
compositions comprising botulinum toxins (e.g. inter alia [0068]).” (See
e.g., Final Action 44.)
We do not agree with the Examiner’s rejections.
The Examiner’s position is that it would have been obvious to do
precisely the opposite of what the patented claims require. That is, the
claims of each of the ’904, ’250, ’815, and ’666 patents require botulinum
toxin and albumin, whereas the instant claims require that “the botulinum
toxin is not stabilized by a protein excipient” such as albumin. We find that
the patented compositions are the quintessential teaching away, as urged by
Appellant. (See e.g., Appeal Br. 27.) They lead one of ordinary skill in the
art in a divergent path, a polar opposite path, from the claims on appeal. It is
improper to combine references where the references teach away from their
combination. In re Grasselli, 713 F.2d 731, 743 (Fed. Cir. 1983) (The
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claimed catalyst which contained both iron and an alkali metal was not
suggested by the combination of a reference which taught the
interchangeability of antimony and alkali metal with the same beneficial
result, combined with a reference expressly excluding antimony from, and
adding iron to, a catalyst.). Thus, we do not find the claims on appeal to be
obvious variants of the patented inventions set forth in the ’904, ’250, ’815,
’666 patents.
DECISION SUMMARY
In summary:
Claims
Rejected
35 U.S.C.
§
Reference(s)/Basis Affirmed Reversed
15, 24–26,
30
103 Donovan, Johnson,
Friedman,
Carpenter
15, 24–26,
30

15, 24–26,
30
Obviousness-type
Double Patenting:
8,642,047,
Johnson,
Friedman,
Carpenter
15, 24–26,
30

15, 24–26,
30
Obviousness-type
Double Patenting:
8,168,206,
Johnson,
Friedman,
Carpenter
15, 24–26,
30

15, 24–26,
30
Obviousness-type
Double Patenting:
8,137,677,
Johnson,
Friedman,
Carpenter
15, 24–26,
30

15, 24–26,
30
Obviousness-type
Double Patenting:
15, 24–26,
30

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9,981,022,
Johnson,
Friedman,
Carpenter
15, 24–26,
30
Obviousness-type
Double Patenting:
9,044,477,
Johnson,
Friedman,
Carpenter
15, 24–26,
30
15, 24–26,
30
Obviousness-type
Double Patenting:
9,265,722,
Johnson,
Friedman,
Carpenter
15, 24–26,
30
15, 24–26,
30
Obviousness-type
Double Patenting:
7,419,676,
Johnson,
Friedman,
Carpenter
15, 24–26,
30
15, 24–26,
30
Obviousness-type
Double Patenting:
6,203,794,
Johnson,
Friedman,
Carpenter
15, 24–26,
30
15, 24–26,
30
Obviousness-type
Double Patenting:
9,629,904,
Johnson,
Friedman,
Carpenter, Hunt
15, 24–26,
30
15, 24–26,
30
Obviousness-type
Double Patenting:
8,580,250,
Johnson,
15, 24–26,
30
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Friedman,
Carpenter, Hunt
15, 24–26,
30
Obviousness-type
Double Patenting:
9,107,815,
Johnson,
Friedman,
Carpenter, Hunt
15, 24–26,
30
15, 24–26,
30
Obviousness-type
Double Patenting:
8,323,666,
Johnson,
Friedman,
Carpenter, Hunt
15, 24–26,
30
15, 24–26,
30
Provisional
Obviousness-type
Double Patenting:
Application No.
13/427,582,
Johnson,
Friedman, and
Carpenter
15, 24–26,
30

Overall
Outcome
15, 24–26,
30

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