Ex Parte Skold

Patent Trial and Appeal Board

Jan 31, 2018

11616658 (P.T.A.B. Jan. 31, 2018)

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.
11/616,658 12/27/2006 Thomas Skold SKD001 2891
39731 7590 02/02/2018
Moser Taboada / Art Jackson
1030 BROAD STREET, SUITE 203
SHREWSBURY, NJ 07702
EXAMINER
WESTERBERG, NISSA M
ART UNIT PAPER NUMBER
1618
NOTIFICATION DATE DELIVERY MODE
02/02/2018 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):
docketing@mtiplaw.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte THOMAS SKOLD1
Appeal 2016-002058
Application 11/616,658
Technology Center 1600
Before FRANCISCO C. PRATS, JEFFREY N. FREDMAN, and
TAWEN CHANG, Administrative Patent Judges.
CHANG, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal under 35 U.S.C. § 134(a) involving claims to a
systemic delivery composition and a delivery device for the composition,
which have been rejected as obvious. We have jurisdiction under 35 U.S.C.
§ 6(b).
We AFFIRM.
1 Appellant identifies the real party in interest as the inventor, Thomas
Skold. (Appeal Br. 1.)
1
Appeal 2016-002058
Application 11/616,658
STATEMENT OF THE CASE
The Specification describes “oral, pulmonary and transmucosal
delivery compositions that contain aqueous mixtures of three types of lipids:
(1) phospholipids or certain similar lipids, (2) fatty acids, and (3) bilayer-
stabilizing steroids.” (Spec. 14.) According to the Specification, “[t]he
variety of lipid structures that these lipids may form are believed to facilitate
transport across mucosal membranes or epithelial tissue of intestines.” (Id.)
The Specification further describes forming delivery compositions having a
lipid particle component and a vesicle component and states that “[t]he
bioactive agent delivery profile (i.e., pharmacokinetic profile) can be
adjusted by adjusting the amounts of the two components and the extent that
the bioactive agent is enclosed within the vesicles.” (Id. 19.)
Claims 1, 23, 24, 35, 36, 49-51, 56—61, and 64—76 are on appeal.2
Claims 1 and 35 are illustrative and reproduced below:
1. A delivery device for a transmucosal systemic delivery
composition comprising:
liquid vessel(s) containing a delivery composition; and
a sprayer situated to accept and spray the delivery
composition from the vessel, wherein the delivery composition
comprises:
an aqueous carrier;
a lipid component suspended in the aqueous carrier
comprising lipids consisting essentially of 20-60 mol
% or more type A lipid, 30-50 mol % or more fatty
acid, and 20-30 mol % or more bilayer-stabilizing
steroid(s), wherein
type A lipid is one or more of any of phospholipid,
ceramide(s), sphingomyelin(s),
2 Claim 10 has been cancelled. (Advisory Act. 1.)
2
Appeal 2016-002058
Application 11/616,658
glucocerebroside(s) and conjugate(s) of (i)
lipid-phase anchoring hydrophobic moieties
and (ii) flexible, soluble polymers, wherein the
lipid-phase anchoring hydrophobic moieties are
phospholipid, ceramide(s), sphingomyelin(s) or
glucocerebroside(s),
the lipid component formulated in the aqueous carrier
to have:
(i) a lipid particle component comprising particles
of said lipids and having average diameter of 1
micron or more, said particles being surrounded
by a lipid monolayer, and
(ii) a vesicle component comprising vesicles
enclosed by a single lipid bilayer, the bilayers
comprising said lipids; and
a bioactive agent suitable for transmucosal systemic
delivery,
wherein the type A lipid comprises (i) conjugate(s) of
lipid-phase anchoring hydrophobic moieties and flexible,
soluble polymers and (ii) other type A lipid(s),
wherein the contribution of the lipid anchor portion of the
conjugate to the lipid component is 5 mole % or less,
wherein the viscosity of the composition is selected to
allow nasal or pulmonary application by spraying,
wherein the weight contribution of the lipid component
to the composition is 3.5% or less,
wherein the delivery composition is essentially lacking in
cell-surface disruptors, and
wherein the bioactive agent has MW about 1000 or less
and an octanol-water partition coefficient of 10 or higher,
wherein 1 mole % or more of the bioactive agent is
associated with the particles of said lipids, and 1 mole % or
more of the bioactive agent is associated with the vesicles.
3
Appeal 2016-002058
Application 11/616,658
35. A systemic delivery composition comprising:
a composition formed by drying to a dry form by
lyophilization to remove water of
an intermediate composition comprising
an aqueous carrier;
a lipid component suspended in the aqueous carrier
comprising lipids consisting essentially of 20-60
mol % or more type A lipid, 30-50 mol % or more
fatty acid, and 20-30 mol % or more bilayer-
stabilizing steroid(s), wherein
type A lipid is one or more of any of
phospholipid, ceramide(s) sphingomyelin(s),
glucocerebroside(s) and conjugate(s) of (i)
lipidphase anchoring hydrophobic moieties
and (ii) flexible, soluble polymers, wherein
the lipid-phase anchoring hydrophobic
moieties are phospholipid, ceramide(s),
sphingomyelin(s) or glucocerebroside(s),
and formulated in the aqueous carrier to have:
(i) a lipid particle component comprising
particles of said lipids and having average
diameter of 1 micron or more, said particles
being surrounded by a lipid monolayer, and
(ii) a vesicle component comprising vesicles
enclosed by a single lipid bilayer, the
bilayers comprising said lipids;
a lyophilization protective agent, and
a bioactive agent suitable for transmucosal systemic
delivery,
wherein the type A lipid comprises (i) conjugate(s) of lipid­
phase anchoring hydrophobic moieties and flexible, soluble
polymers and (ii) other type A lipid(s), wherein the
contribution of the lipid anchor portion of the conjugate to
the lipid component is 5 mole % or less;
4
Appeal 2016-002058
Application 11/616,658
wherein the delivery composition has been formulated for oral
delivery by compression, encapsulation, or coating,
wherein the delivery composition is essentially lacking in cell-
surface disruptors,
wherein the bioactive agent has MW about 1000 or less an
octanol-water partition coefficient of 10 or higher,
wherein 1 mole % or more of the bioactive agent is associated
with the particles of said lipids, and 1 mole % or more of the
bioactive agent is associated with the vessicles [sic],
and
wherein, upon reconstitution with water the reconstituted
composition has (i) the lipid particle component comprising
particles of said lipids, and (ii) the vesicle component
comprising vesicles comprising said lipids.
(Appeal Br. 31, 33—34 (Claims App.).)
The Examiner rejects claims 1, 23, 24, 49—51, 56—60, 66, 68, 70, and
72 under pre-AIA 35 U.S.C. § 103(a) as being unpatentable over Skold,3
Yoshioka,4 Choi,5 and Katinger.6 (Ans. 2.)
The Examiner rejects claims 61, 67, 69, 71, and 73 under pre-AIA
35 U.S.C. § 103(a) as being unpatentable over Skold, Yoshioka, Choi,
Katinger, and Scott.7 (Id. at 8.)
The Examiner rejects claims 35, 36, 64, 74, and 75 under pre-AIA
35 U.S.C. § 103(a) as being unpatentable over Skold, Yoshioka, Choi,
Katinger, and Tardi.8 (Id. at 9.)
3 Skold, US 2004/0009213 Al, published Jan. 15, 2004.
4 Yoshioka et al., US 5,593,622, issued Jan. 14, 1997.
5 Choi et al., US 5,820,873, issued Oct. 13, 1998.
6 Katinger et al., US 5,942,245, issued Aug. 24, 1999.
7 Scott et al., US 2004/0034336 Al, published Feb. 19, 2004.
8 Tardi et al., US 2003/0124181 Al, published July 3, 2003.
5
Appeal 2016-002058
Application 11/616,658
The Examiner rejects claims 65 and 76 under pre-AIA 35 U.S.C.
§ 103(a) as being unpatentable over Skold, Yoshioka, Choi, Katinger, Tardi,
and Scott. (Ans. 11.)
I.
Issue
The Examiner has rejected claims 1, 23, 24, 49-51, 56—60, 66, 68, 70,
and 72 under pre-AIA 35 U.S.C. § 103(a) as obvious over Skold, Yoshioka,
Choi, and Katinger. The Examiner finds that Skold discloses an active agent
delivery system that meets a majority of limitations in claim 1. (Ans. 2—3.)
However, the Examiner finds that Skold does not teach “inclusion of
conjugate such as a PEG-type A lipid conjugate” or “explicitly describe the
mol % of the various ingredients.”9 (Id. at 2—3.) The Examiner further finds
that Skold does not teach “a delivery device comprising a liquid vessel
containing the composition and a sprayer situated to accept and spray
delivery composition from the vessel.” (Id. at 5.)
The Examiner finds that
Yoshioka discloses a delivery composition with liposomes
comprised of PEG[]bound to
dipalmitoylphosphatidylethanolamine, which reads on a type A
phospholipid that [comprises] a conjugate of a lipid phase
anchoring hydrophobic moiety and PEG as the flexible, soluble
polymer; cholesterol, which reads on a bilayer-stabilizing
steroid; myristic acid, a fatty acid; and an aqueous solution of
hemoglobin, which reads on the aqueous carrier and bioactive
agent.
9 A PEG-type A lipid conjugate meets the limitation in claim 1 relating to
“conjugate(s) of lipid-phase anchoring hydrophobic moieties and flexible,
soluble polymers.” (FF16.)
6
Appeal 2016-002058
Application 11/616,658
{Id. at 3.) The Examiner finds that Yoshioka teaches mixing ratios of the
PEG-bound phospholipid with liposome forming lipid, as well as weight
percentages of the phospholipid, sterols, and fatty acids. {Id. at 3 4.)
Similarly, the Examiner finds that Choi teaches “liposomes or other
lipid-based carriers comprised of PEG-ceramides ... in combination with
other lipid types such as DOPE, DODAC, DSPC, SM, cholesterol and the
like.” {Id. at 4.) The Examiner finds that Choi teaches that its compositions
“can be formulated as pharmaceutical compositions, such as in aqueous
solutions.” {Id.) The Examiner further finds that Choi teaches an example
where liposomes were prepared with 50:40:5 mol %
sphingomyelin:cholesterol:PEG-2000 ceramide as well as a “similar lipid
preparation with DSPC instead of [sphingomyelin] and either PEG-2000 or
PEG-5000.” {Id.)
Finally, the Examiner finds that Katinger “discloses the delivery of
superoxide dismutase (SOD) enclosed in protective liposomes” wherein
“[t]he liposomes can be formulated in a liquid form in a spray can or spray
bottle to apply the solution to surfaces such as bum wounds to reduce the
danger of infection.” {Id. at 6.)
The Examiner concludes that a skilled artisan would have reason to
“incorporate PEG-type A lipids conjugates [as disclosed in Yoshioka and
Choi] into the lipid particles and vesicles of Skold,” with a reasonable
expectation of success, because “the prior art teaches that such conjugates
are readily made and improve the properties of the resulting lipid particles,
including reducing dmg leaking and/or increasing the residence time of the
lipid structures.” {Id. at 5.) The Examiner further concludes that the percent
and mole percent of various ingredients as recited in claim 1 are obvious
7
Appeal 2016-002058
Application 11/616,658
because the cited prior art discloses overlapping ranges and because “[t]he
amount of a specific ingredient in a composition is clearly a result effective
parameter that a person of ordinary skill in the art would routinely
optimize.” (Id.) Finally, the Examiner concludes that it would be obvious to
prepare a liposomal composition as described in Skold in a liquid vessel
with a sprayer, because Katinger discloses that “various forms are suitable
formulations for active-ingredient containing liposomal compositions” and
“[t]he selection of the administration form for a delivery composition is
within the [skill of] one of ordinary skill [in] the art.” (Id. at 6.)
Appellant contends that a skilled artisan would not, absent hindsight,
have had reason to formulate Skold’s “thick” materials into a form
“appropriate for spraying to nasal or pulmonary tissue.” (Appeal Br. 7, 9—
12.) Appellant contends that there is similarly no reason to modify Skold’s
“mixture of particles and vesicles (liposomes)” with a PEG coating. (Id. at
8.) Appellant further contends that the claimed subject matter exhibits
unexpected results. (Id. at 13—19.)
The issues with respect to this rejection are (1) whether a skilled
artisan would have reason to (a) modify Skold’s mixture of particles and
vesicles to include the conjugates suggested by Yoshioka and Choi and (b)
formulate the composition suggested by Skold, Yoshioka, and Choi into a
form that allows nasal or pulmonary application by spraying; and, if so, (2)
whether Appellant has provided evidence of unexpected results that, when
considered together with the evidence of obviousness, show the claims to be
non-ob vious.
8
Appeal 2016-002058
Application 11/616,658
Findings of Fact
1. Skold relates to “a water-based delivery system for an active
substance, characterized by enhancing skin barrier restoration in the stratum
comeum comprising water, a fatty acid, cholesterol, [which is a bilayer
stabilizing steroid,] and a ceramide.” (Skold 110; Spec. 133 (stating that
“[t]he bilayer stabilizing steroid or steroid analog is typically cholesterol, a
fatty acyl ester of cholesterol, or an analog thereof’); see also id. 111,
Abstract.)
2. Skold teaches that active substances useful in its invention
include, e.g., steroid hormones (id. 1126), which includes bioactive agents
encompassed within claim 1 (see, e.g., Spec. 1 53; claim 60 (claim
depending from claim 1 where bioactive agent is a steroid hormone).
3. Skold teaches that, in a preferred embodiment, its delivery
system “comprises a water content exceeding 50%, such as more than 55%,
60%, 65%, 70%, 75%, 76%, 77%, 78%, 79%, 80%, 85%, 87%, 90%, 94%,
95% and 98%. Preferably, the water content is between 60-80%, more
preferably, between 70 and 80%.” (Skold 118; see also id. 1110 (stating
that “the water content of the delivery system can be as high as 80-98%”).)
4. Skold teaches that “[t]he preferred ratio of the
ceramide/phospholipid portion:cholesterol:fatty acid is in the range of
approximately 2:1:1.5 to approximately 2.95:0.5:0.5. Preferably, for
example, the ratio is approximately 2:1:1; more preferably the ratio is
approximately 2.35:1:1.” (Id. 120; see also id. H 116, 120-123 (amounts of
lipid components in a preferred embodiment and in examples.)
5. Skold teaches embodiments in which the lipophilic components
of its delivery system are in the form of “lipid particles, and gas spheres or
9
Appeal 2016-002058
Application 11/616,658
vesicles.” {Id. 111; see also id. 1133 (teaching that in a preferred
embodiment the lipophilic components of the delivery system form three
types of particles (i.e., gas spheres, vesicles, and lipid particles) within an
aqueous medium), || 138, 162—166 (providing an exemplary formulation
where the same components, including Skinflux (containing ceramide),
cholesterol, and fatty acid (palmitic acid), are used to form both the vesicle
phase (containing lipid vesicles and particles) and the foam phase
(containing gas spheres and lipid particles).)
6. Skold also teaches an embodiment of its in invention wherein
the lipid components of its delivery system form only two of the above, e.g.,
only the gas spheres and lipid particles, or only the vesicles and lipid
particles. {Id. 1155.)
7. Skold teaches that the gas spheres are lipid monolayers
enclosing air bubbles wherein the monolayers are formed from the lipophilic
components. {Id. 134.) Skold further teaches that these gas spheres are
preferably approximately 1 pm to approximately 500 pm in diameter. {Id.)
8. Skold teaches that the vesicles are “lipid bilayers enclosing a
hydrophilic core” wherein the bilayers are formed from the lipophilic
components. {Id. 135.) Skold further teaches that “[t]he vesicles can
range from approximately 0.02 /on to approximately 0.5 /on in diameter.”
{Id. 1135.)
9. Skold teaches that the lipid particles are lipid monolayers
enclosing fatty acids wherein the monolayers are formed from the lipophilic
components. {Id. 136.) Skold further teaches that the particles are “less
than approximately 1 to approximately 150 jam in diameter.” (Id.)
10. Skold teaches that
10
Appeal 2016-002058
Application 11/616,658
[t]he various particles of the delivery system provide
microcompartments with different properties. Due to these
different microcompartments, the delivery system can be used
to deliver both hydrophilic and lipophilic active substances.
For example, a water soluble active substance can be located in
the hydrophilic core of the vesicles, or can be located in the
hydrophilic phase of the system. A lipid soluble active
substance can be located within the monolayer of the gas
spheres, within the bilayer of the vesicles, or within the
monolayer or within the core of the lipid particles.
{Id. 1137.)
11. Skold teaches that
[t]he specific components of a formulation, and the formulation
process, can be varied to obtain delivery systems which allow
for different rates of the release, and degrees of penetration, of
active substance(s). For example, the phase of the system in
which an active substance is placed affects release and
penetration rates. For instance, to enhance penetration rates of
either a hydrophilic or lipophilic active substance, a major
portion of the active substance is placed within the vesicle
phase portion.
{Id. 1147; see also id. 1154.)
12. Skold teaches that its invention relates to a mucosal delivery
system for drugs or other active substance as well as to a topical delivery
system. {Id. 12.) In particular, Skold teaches that, in one embodiment,
the present invention provides a mucosal delivery system
formulated to deliver a substance to, or through, a human
mucous membrane without permanently disturbing the integrity
of the mucous membrane. The mucous membrane is the moist
tissue that lines some organs and body cavities (such as nose,
mouth, lungs, rectum, stomach and vagina) and secretes
mucous. . . . The particular formulations of the mucosal
delivery systems are varied to accommodate the particular
environment of the mucosa, as would be known by a skilled
artisan.
11
Appeal 2016-002058
Application 11/616,658
(Id. 1132.)
13. Skold teaches that “[t]he delivery system can be in any form,
such as a cream, a lotion, a gel, and an aerosol foam” and that “[t]he amount
of certain adjunct minor components used in a particular formulation varies
depending on the desired form of the delivery system, as would be known by
a skilled artisan.” (Id 1131.) For instance, Skold teaches that “thickening
agent can be included in the formulation to adjust the viscosity of the
formulation” and to prepare an aerosol foam formulation “the amount of
thickening agent used ... is about 10 to 20% of the amount used to prepare a
cream formulation” and emulsifiers are added. (Id. H 130-131; see also id.
1171 (describing how to produce an aerosol foam delivery system from the
cream form described in Example 2.)
14. Skold teaches that, in contrast to prior art dermal delivery
systems, its invention “provides an improved topical delivery system (skin
preparation) formulated to deliver a substance to, or through, the human skin
without permanently disrupting the stratum comeum’s natural barrier
function” as well as “unique skin barrier restoration properties.” (Id. H 9,
16.) In particular, Skold teaches that
[its] topical delivery system is preferably designed, in its choice
and composition of lipids, to resemble the normal lipid
organization of the stratum comeum (homy layer), as much as
possible. Upon administration, the system (formulation) blends
with the lipids naturally present in the stratum co[m]eum, and
easily penetrates the lipid bilayer of the skin. In doing so, the
system carries along with it one or more active substances to be
administered. The system enhances penetration of active
substances into and/or through the stratum comeum, while the
normal barrier properties of the stratum comeum are left intact,
and/or are even functionally enhanced.
(Id. 119; see also id. H 118—119.)
12
Appeal 2016-002058
Application 11/616,658
15. Y oshioka teaches
[ajgents for inhibiting adsorption of proteins on the liposome
surface and liposomes which are agglutination-free by binding
said inhibiting agent on the surface .... The above-mentioned
inhibiting agents comprise a hydrophobic moiety and a
hydrophilic macromolecular chain moiety. Adsorption of
plasma proteins on the liposomes is inhibited due to the
hydrophilic moiety exposed on the liposome surface with a
result that agglutination of the liposomes in plasma is
prevented. Therefore, there is no danger of embolism in blood
vessels inhibiting blood flow when the liposomes are
introduced into the living body. . . .
Moreover, when liposomes are introduced into the living
body, antibody protein (immunoglobulin) to the liposome
which is an antigen will be adsorbed on the liposome to produce
foreign body recognition in the phagocytes (macrophage) with a
result that the liposome will be included in the macrophage and
disappear within a short period of time. Thus, inhibition of the
protein adsorption on liposome can delay disappearance of the
liposome in plasma.
(Yoshioka, Abstract; see also id. at 1:15—21, 35—67; 4:8—12.)
16. Yoshioka teaches that the hydrophobic moiety and the
hydrophilic macromolecular chain moiety of the agent for inhibiting protein
adsorption on liposome surface are covalently bound, that the hydrophilic
macromolecular chain moiety may consist of a polyethylene glycol (“PEG”),
and that the hydrophilic macromolecular chain moiety may be bound with a
liposome membrane-constituting lipid, in particular a phospholipid. {Id. at
3:3—6, 11—14, 25—28, 57—61; 4:19-24 (“Especially preferable in the
invention are . . . PEG-bound phospholipids in which PEG and a
phospholipid are covalently bound.”).)
17. The Specification teaches that “[a] conjugate of a lipid-phase
anchoring hydrophobic moiety and a flexible, soluble polymer can be, for
13
Appeal 2016-002058
Application 11/616,658
example, a conjugate of a type A lipid and a polymer such as polyethylene
glycol.” (Spec. 128.)
18. Yoshioka teaches that lipids forming the liposomes of its
invention contain
as the main component phospholipids obtained from natural
materials such as egg yolk and soybean or those which are
produced by organic chemical synthesis used alone or in
combination. Representative are phosphatidylcholine,
sphingomyelin, phosphatidylethanolamine and
phosphatidylserine. In addition, sterols such as cholesterol and
cholestanol as a membrane-stabilizing agent, phosphatidic acid,
dicetyl phosphate and higher fatty acids as a charged substance
and other additives may be added. Mixing ratio of the PEG-
bound phospholipid with the liposome-forming lipid is 0.1—50
mol %, preferably 0.5—20 mol % and more preferably 1—5 mol
% in terms of the molar ratio to the phospholipid of the main
component. Below the above-defined range, the effect of
preventing agglutination of liposomes in plasma will not be
sufficiently high. Beyond the above-defined range, solubilizing
capacity of the PEG-bound phospholipid will cause instability
of the liposome.
(Id. at 5:14—31; see also 9:61—64 (stating that “[hjigher fatty acids are
preferably employed as a charge-providing substance”).)
19. Yoshioka teaches mixing ratios of liposome-forming lipids of
“0.2—1 part by weight of sterols and 0.05—0.2 parts by weight of higher fatty
acids per part by weight of the phospholipid.” (Id. at 9:64—67; see also id. at
12:44—67 (describing an exemplary composition comprising PEG-bound
phospholipid, cholesterol, myristic acid (a fatty acid), and aqueous solution
of hemoglobin).)
20. Choi teaches that “[ljipid stability is important in the
development of liposomal drug delivery systems” and that, “[tjherefore, it is
14
Appeal 2016-002058
Application 11/616,658
desirable to develop PEG-lipids that are less susceptible to hydrolysis,
thereby[] increasing the liposome circulation longevity.” (Choi 2:12—19.)
21. Choi teaches “polyethylene glycol modified ceramide lipids,”
which “can be used to form liposomes optionally containing various
biological agents or drugs.” {Id. at Abstract.)
22. Choi also teaches “liposomes or other lipid-based carriers
including the . . . PEG-Ceramide lipids,” as well as “[mjethods for
delivering therapeutic agents such as drugs and vaccines to a patient in need
thereof comprising administering to the patient a therapeutically effective
amount of such therapeutic agent in a liposome or a lipid-based carrier of the
invention.” {Id. at 2:66—3:1, 3:16—21; see also id. at 3:2—7 (describing
constructing liposomes using “mixtures of. . . PEG-Ceramide lipids ... in
combination and in conjunction with other lipid types, such as DOPE and
DODAC, as well as DSPC, SM, Choi and the like”), 13:34—14:37 (methods
of liposome preparation), 20:7—62 (describing exemplary compositions
comprising 55:45:5 mol % sphingomyelin/Chol/PEG2ooo or
DSPC/Chol/PEGsooo or PEG2000).)
23. Choi teaches that:
The PEG-modified ceramide lipids of Formula I enhance the
properties of liposomes by increasing the circulation longevity
or lifetime of the liposome; preventing aggregation of the
liposomes during covalent protein coupling, such as for
targeting; preventing aggregation of liposomes incorporating
targeting moieties or drugs, such as antibodies, and DNA;
promoting drug retention within the liposome; and/or increasing
bilayer or other stability of the liposome when low pH is
required for encapsulation of the bioactive agents.
These PEG-Ceramide lipids also reduce leakage due to
hydrolysis of the fatty acyl chains of the liposome bilayer and
are more stable than other lipid forms.
15
Appeal 2016-002058
Application 11/616,658
{Id. at 4:27—39; see also id. at 1:61—2:11 (teaching that some other PEG-
lipids such as PEG-DSPE may be susceptible to cleavage under acidic or
basic conditions), 14:60-63 (stating that “liposomes formulated from PEG-
lipids are especially advantageous, since they are more stable and have an
increased half-life in circulation over conventional liposomes”), 17:54—56
(stating that “liposomes made from PEG-Ceramide lipids are less susceptible
to hydrolysis”).)
24. Choi teaches that,
[tjypically, the PEG-Ceramide will comprise about 5 to about
30 mol % of the final liposome construction, but can comprise
about 0.0 to about 60 mol % or about 0.5 to about 5 mol %. .. .
The invention also includes lipid complexes whereby the PEG-
Ceramide lipid comprises about 0.01 to about 90 mol % of the
complex.
{Id. at 3:7-15.)
25. Katinger teaches “pharmaceutical compositions for transporting
[superoxide dismutase (SOD)], preferably [recombinant human SOD
(rhSOD)] enclosed in protective liposomes,” which may be used for
“therapeutic and/or prophylactic use against increased concentrations of
superoxide radicals and/or damage caused thereby.” (Katinger 1:5—12;
2:18-20.)
26. Katinger teaches that, particularly in the case of bum wounds or
surface inflammations, it is particularly advantageous to apply the SOD-
containing liposomes by spraying on from a spray can or spray bottle, which
avoids direct contact of the wound with fingers or another applicator and,
thus, reduce the danger of an additional infection. (Id. at 5:9-15; 6:27—33;
see also id. at 6:57—62 (describing administering formulation in the form of
sprays); 8:30-33 (describing administering liposomal SOD in a liquid
16
Appeal 2016-002058
Application 11/616,658
composition to food by means of “spray bottles, spray cans or other spray
apparatuses”).)
Analysis
Claim 1
We agree with the Examiner that claim 1 is rendered obvious by the
combination of Skold, Yoshioka, Choi, and Katinger and adopt the
Examiner’s findings of fact and reasoning regarding the scope and content of
the prior art as applied to claim 1. (Ans. 2—7, 13—19; FF1—FF26.) We
address Appellant’s arguments below.
Reason to Combine Skold and Katinger
Appellant first contends that nothing in the cited prior art suggests that
“one ought to use in a sprayer a mixed particle . . . and vesicle composition.”
(Appeal Br. 9.) Appellant contends that “[o]ne of ordinary skill in the art of
drug formulation would not... see in [Skold] a motivation to formulate the
illustrated thick materials as something appropriate for spraying to nasal or
pulmonary tissue.”10 (Id. at 7, 9-10, 12; see also Reply Br. 2—3, 6.)
Appellant contends that, indeed, “[w]hen one dilutes the [Skold] formulation
as would be needed to obtain lower viscosity for spray delivery] to nasal or
pulmonary tissue, ... the formulation fails.” (Appeal Br. 7; see also Reply
Br. 2-3, 6.)
10 Appellant also argues with respect to this rejection that Skold does not
suggest formulation its composition in lyophilized dried form. (Appeal Br.
7, 13.) We do not address this argument here because claim 1 does not
require lyophilization.
17
Appeal 2016-002058
Application 11/616,658
With respect to Katinger, Appellant contends that while the reference
teaches treating tissue with the enzyme superoxide dismutase (“SOD”) using
a spraying apparatus, it does not suggest applying SOD in a mixture of lipid
vesicles and particles and “motivates putting liposomes only in a sprayer.”
(Appeal Br. 9; see also Reply Br. 5.) Appellant also contends that SOD is
nothing like the claimed bioactive agents and is used at a low concentration
“not instructive for formulations of the recited bioactive agents.” (Id.)
We are not persuaded. Skold teaches that its invention provides “a
mucosal delivery system formulated to deliver a substance to, or through, a
human mucous membrane,” including the membranes that line the nose and
lungs. (FF12.) Skold also teaches that “[t]he particular formulations of the
mucosal delivery systems are varied to accommodate the particular
environment of the mucosa, as would be known by a skilled artisan.” (Id.)
Contrary to Appellant’s contention, therefore, Skold thus provides a skilled
artisan with the motivation to formulate its composition for spray delivery to
nasal or pulmonary tissue. Indeed, it is difficult to envision delivery of a
substance to or through the membrane lining the lungs other than through
spraying via, e.g., an inhaler.11
11 Appellant argues that, despite Skold’s disclosure of its invention providing
a mucosal delivery system formulated to deliver a substance to the mucous
membrane of the lungs, Skold does not teach a skilled artisan how to
perform such delivery. (Transcript of Oral Hearing (Oct. 3, 2017) (“Tr.”)
9:8—10:3.) However, “‘a reference must be considered not only for what it
expressly teaches, but also for what it fairly suggests.’” In re Baird, 16 F.3d
380, 383 (Fed. Cir. 1994) (quoting In re Burckel, 592 F.2d 1175, 1179
(CCPA 1979)).
18
Appeal 2016-002058
Application 11/616,658
Appellant further relies on the March 6, 2015 Supplemental
Declaration of Thomas Skold under 37 C.F.R. § 1.132 (“Skold Supplemental
Declaration” or “Skold Suppl. Decl.”), to argue that a skilled artisan would
not formulate Skold’s composition in spray form. In the declaration, Mr.
Skold, the named inventor of the application on appeal as well as the Skold
prior art reference, states that a precipitate formed when he “sought to dilute
a formulation described in Example 2 of [Skold] to a viscosity appropriate
for nasal or pulmonary application by spraying.” (Skold Suppl. Decl. 128.)
However, the statements in the declaration are conclusory. For
instance, the declaration does not provide explanations as to precisely what
Mr. Skold did in diluting Skold’s cream formulation, why a skilled artisan
attempting to adjust the viscosity of Skold’s formulation would have used
such a dilution process, or what Mr. Skold considered to be “a viscosity
appropriate for nasal or pulmonary . . . spraying.” Indeed, Skold suggests
that, to adjust the viscosity of its cream formulation (e.g., so as to prepare an
aerosol foam formulation), a skilled artisan would decrease the amount of
thickening agent used and add an emulsifier. (FF13.) This does not appear
to be what Mr. Skold did based on the brief description in the Skold
Supplemental Declaration. (Tr. 10:18—12:7.) Accordingly, we give little
weight to the conclusion in the Skold Supplemental Declaration that Skold’s
compositions cannot be used in spray form. In re Am. Acad, of Science Tech
Ctr., 367 F.3d 1359, 1368 (Fed. Cir. 2004) (“The Board has broad discretion
as to the weight to give to declarations offered in the course of
prosecution.”).12
12 The Specification also cites Skold, US 2005/129722, which claims
priority to the Skold reference cited as prior art herein. (Spec. ^ 3.) With
19
Appeal 2016-002058
Application 11/616,658
We are similarly unpersuaded by Appellant’s arguments regarding
Katinger (i.e., that Katinger does not disclose a composition of lipid particles
and vesicles or a claimed bioactive agent). “Non-obviousness cannot be
established by attacking references individually where the rejection is based
upon the teachings of a combination of references. . . . [The reference] must
be read, not in isolation, but for what it fairly teaches in combination with
the prior art as a whole.” In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir.
1986). Here, Katinger is cited only to show that spraying is “a known
manner for delivering bioactive containing compositions” (Ans. 16), while
as discussed above Skold teaches delivering bioactives, including those
encompassed by claim 1, and using a combination of lipid vesicles and
particles.
The combination of Skold and Katinger thus renders obvious using a
sprayer to deliver bioactives carried by a mixed lipid particle and vesicle
composition: Skold suggests that its delivery system may be in any form,
including a form suitable for delivering substances to the mucous membrane
of the lung, and Katinger teaches a sprayer as a known delivery system that
does not need direct contact with the area where the bioactive agent is to be
applied. KSRInt’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007) (“The
respect to US 2005/129722, the Specification states that, “no teaching
indicates that this . . . formulation can be effectively diluted to a composition
suitable for spraying, and which is . . . effective for transmucosal delivery of
bioactive agents. In fact, diluting formulations like those described in this
publication leads to the formation of unacceptable sediments.” (Id.) This
statement also appears to rely on the statements in the Skold Supplemental
Declaration discussed above and is unpersuasive for the same reasons.
20
Appeal 2016-002058
Application 11/616,658
combination of familiar elements according to known methods is likely to be
obvious when it does no more than yield predictable results.”).13
For the same reasons discussed above, we note but are not persuaded
by Appellant’s apparent argument that a skilled artisan would not have had a
reasonable expectation of success in combining Skold and Katinger.
(Appeal Br. 11 ,)14 “[T]he expectation of success need only be reasonable,
not absolute.” Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir.
2007).
13 Appellant also argues in the Reply Brief that Katinger does not suggest
that the composition delivered by the sprayer will be capable of systemic
delivery, as required by the preamble of claim 1. (Reply Br. 5.) We are not
persuaded. “Where ... the claimed and prior art products are identical or
substantially identical... the PTO can require an applicant to prove that the
prior art products do not necessarily or inherently possess the characteristics
of his claimed product. Whether the rejection is based on ‘inherency’ under
35 U.S.C. § 102, on ‘prima facie obviousness’ under 35 U.S.C. § 103,
jointly or alternatively, the burden of proof is the same, and its fairness is
evidenced by the PTO’s inability to manufacture products or to obtain and
compare prior art products.” In re Best, 562 F.2d 1252, 1255 (CCPA 1977)
(citations and footnote omitted). In this case, we find that the Examiner has
shown that the product suggested by the combination of the cited art is
substantially similar to the claimed product such that burden is shifted to
Appellant to show that systemic delivery would not occur.
14 Appellant’s citation to Ex parte Rauser is inapposite. Ex parte Rauser,
Appeal No. 2011-003681, 2011 WL 4872024 (BPAI 2011). In that case, the
Board found that the Examiner had not identified a reason why a skilled
artisan would add another (i.e., a second) exchange material to adjust the pH
of a drug solution when the pH of the solution had been previously adjusted.
Id. at *4. In this case, however, Skold explicitly provides a skilled artisan
with a reason to modify the form of the delivery system, e.g., for purposes of
delivery an active agent to the mucous membrane lining the lungs. (FF12—
13.)
21
Appeal 2016-002058
Application 11/616,658
Reason to Combine Skold, Yoshioka, and Choi
Appellant next contends that a skilled artisan would not have a reason
to combine Skold, Yoshioka, and Choi to arrive at the claimed invention.
(Appeal Br. 8—9, 12—13.) In particular, Appellant contends that (1)
“[njothing in [Skold] indicates any reason to modify the mixture of particles
and vesicles (liposomes) with a PEG coating,” (2) “[t]he lipid materials
exemplified [in Yoshioka] do not fall within the current claim recitations on
relative lipid amounts,” (3) the cited art does not suggest “adding a PEG
coating to both vesicles and lipid particles,” and the benefits taught in
Yoshioka and Choi for using PEG “are not taught for the current sprayed
composition.” (Appeal Br. 8—9, 12—13; see also Reply Br. 3—5.)
We are not persuaded. While Skold by itself might not suggest
modifying its mixtures of particles and vesicles with a PEG coating, “[non­
obviousness cannot be established by attacking references individually
where the rejection is based upon the teachings of a combination of
references.” Merck, 800 F.2d at 1097. In this case, the reason to modify
Skold by adding PEG to the ceramides in Skold’s lipid particles and vesicles
comes from Yoshioka and Choi, both of which suggest that PEGylating the
lipids in lipid-based drug carriers (e.g., liposomes) stabilizes the carrier and
increases their circulation longevity. (FF15, FF16, FF20—23.)
Neither are we persuaded by Appellant’s argument that Yoshioka
does not exemplify the claimed relative lipid amounts. Appellant has not
disputed that Yoshioka discloses relative lipid amounts that overlaps with
the claimed relative lipid amounts, albeit not in an example. (Tr. 6:13—7:11;
see also FF19.) A prior art reference is relevant for all that it teaches to
those of ordinary skill in the art, not merely what is exemplified. Cf. In re
22
Appeal 2016-002058
Application 11/616,658
Lemelson, 397 F.2d 1006, 1009 (CCPA 1968) (“The use of patents as
references is not limited to what the patentees describe as their own
inventions or to the problems with which they are concerned. They are part
of the literature of the art, relevant for all they contain.”). Furthermore,
Appellant concedes that Skold also discloses relative ratios of lipids that
overlap the claimed ratios.15 (Tr. 7:12—22.) “Aprima facie case of
obviousness typically exists when the ranges of a claimed composition
overlap the ranges disclosed in the prior art.” In re Peterson, 315 F.3d 1325,
1329-30 (Fed. Cir. 2003). As further discussed below, Appellant has not
shown that the particularly claimed relative lipid amounts exhibit
unexpected results.
Finally, we disagree with Appellant that Yoshioka and Choi do not
suggest that PEGylation is useful or needed in a spray formulation of lipid
particles and vesicles, or that the benefits taught in Yoshioka and Choi for
using PEG “are not taught for the current sprayed composition adapted to
get bioactive agent into the blood, not lipid structures.” (Appeal Br. 13.)
As discussed above, Yoshioka and Choi both teach that PEGylating
the lipids in lipid-based drug carriers stabilizes the carrier and increases their
circulation longevity within the body. (FF15, FF16, FF20—23.) To the
15 During oral hearing, an issue was raised as to whether claim 1 required the
lipid particles and vesicles to comprise each of the three types of lipids
making up the lipid component. (Tr. 7:23—9:5.) Assuming arguendo that
the lipid particles and vesicles both must comprise each of the three types of
lipids, we note that Appellant has not disputed that the lipid vesicles and
particles disclosed in Skold meets this limitation other than contending that
Skold does not disclose PEGylated ceramides. (See also FF5 (lipid
components including ceramide, fatty acid, and cholesterol used to form
both phases containing lipid particles and lipid vesicles).)
23
Appeal 2016-002058
Application 11/616,658
extent Appellant is arguing that there is no suggestion that PEGylation is
useful in a spray formulation, we note that the benefits of PEGylation
disclosed in Yoshioka and Choi—e.g., increased stability and circulation
time in the body—are not dependent on how the lipid drug carrier is
delivered into the body. Appellant also appears to argue that Yoshioka and
Choi only teach usefulness of PEGylation in intravenous compositions
because they emphasize stability of PEGylated lipid drug carriers in blood.
(Appeal Br. 9.) We note, however, that drugs enter the bloodstream even if
they are not administered intravenously. Indeed, as discussed later,
Appellant’s unexpected results arguments rely on a comparison between the
uptake of the active agent into the subject’s blood in different formulations.
(Id. at 14.) To the extent Appellant is arguing that Yoshioka and Choi do
not suggest PEGylating lipids in lipid particles as well as those in vesicles
such as liposomes (Id. at 8—9), we note that Choi explicitly teaches that
PEGylation may be beneficial to other lipid-based drug carriers and not just
liposomes. (FF22 (liposomes or other lipid-based carriers).)
For the above reasons, we are also not persuaded by Appellant’s
argument that “one of skill would not have applied the recited [] lipid ratios
to spray delivery compositions containing hydrophobically anchored
flexible, soluble polymers except by exercise of hindsight.” (Appeal Br. 11—
13; see also Reply Br. 3—5.)
Any judgment on obviousness is in a sense necessarily a
reconstruction based upon hindsight reasoning, but so long as it
takes into account only knowledge which was within the level
of ordinary skill at the time the claimed invention was made
and does not include knowledge gleaned only from applicant’s
disclosure, such a reconstruction is proper.
In re McLaughlin, 443 F.2d 1392, 1395 (CCPA 1971).
24
Appeal 2016-002058
Application 11/616,658
Unexpected Results
We next turn to Appellant’s argument that the claimed invention
exhibits unexpected results. (See, e.g., Appeal Br. 15—19.)
Appellant relies on the Skold Supplemental Declaration as well as the
March 18, 2014 Declaration of Thomas Skold under 37 C.F.R. § 1.132
(“Skold Declaration” or “Skold Deck”). Appellant argues that when
testosterone (an active agent) is carried by both lipid vesicles and particles,
particularly where it is “[ejvenly inputted into both the vesicle and the
particle fractions,” its uptake is significantly better than when it is
formulated with either a surfactant (1% Polysorbate 80) or rape seed oil.
(Appeal Br. 14.) Citing Jadhav,16 which states that “for a range of
enhancing agents . . . there is a direct correlation between the absorption
enhancing effect and the damage to the nasal mucosa,. . . particularly ... for
bile salts and surfactants” (Jadhav 28, left column), Appellant argues that the
claimed formulation exhibits unexpected results because it “shows efficacy
better than achieved with a state-of-the[-]art enhancer . . . and very little
tissue disruption.” (Appeal Br. 15 (citations omitted).)
We are not persuaded. Skold teaches that its formulation, which
contains the same lipid components as the composition of claim 1 other than
with respect to PEG conjugates, enhances the penetration of active
substances into the stratum comeum without disrupting (or even enhancing)
its barrier properties. (FF14.) In light of Skold’s disclosure, Appellant has
not persuasively shown that the results Appellant cites above, which
compare the invention to prior art formulations known to be disruptive to
16 Kisan R. Jadhav et al., Nasal Drug Delivery System-Factors Affecting and
Applications, 2 Current Drug Therapy 27-38 (2007).
25
Appeal 2016-002058
Application 11/616,658
tissue, are unexpected. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371
(Fed. Cir. 2007) (“[B]y definition, any superior property must be unexpected
to be considered as evidence of non-obviousness. . . . Thus, in order to
properly evaluate whether a superior property was unexpected, the [fact­
finder] should have considered what properties were expected.”).17
Similarly, while we do not rely on a blanket rule that “the only way to
establish unexpected results” is by “comparison to the asserted closest prior
art” (Appeal Br. 16), we note that “[t]o be particularly probative, evidence of
unexpected results must establish that there is a difference between the
results obtained and those of the closest prior art.” Bristol-Myers Squibb Co.
v. Teva Pharms. USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014); see also In
re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) (“[W]hen
unexpected results are used as evidence of nonobviousness, the results must
be shown to be unexpected compared with the closest prior art.”). In this
case, Appellant did not perform a comparison between the claimed
formulation and the formulations of Skold, which is the closest prior art.
Appellant contends that Skold “is (a) a topical composition . . . that
cannot be reasonably expected to be effective in spray-initiated trans-
mucosal transport into the blood and (b) liposome (vesicle) compositions.”
(Appeal Br. 16; see also id. at 19 (“one could not reduce the viscosity
outside a ‘cream, a lotion, a gel,’ or ‘an aerosol foam’ and stay within the
17 Appellant contends that “[njothing in [Skold] discloses or suggests that
sprayed transmucosal delivery superior to a strong enhancer-containing
composition . . . can be obtained.” (Appeal Br. 16) We are not persuaded
for the reasons discussed above: Skold teaches that its composition enhance
penetration of active substances without disrupting the barrier function of
the stratum comeum and may be formulated to be applied to mucosal
membranes of, e.g., nose and lungs. (FF12, FF14.)
26
Appeal 2016-002058
Application 11/616,658
teachings of [Skold]”).) Thus, Appellant argues that it is not a proper
comparative. {Id. at 16.) We have already discussed why Skold suggests a
mucosal delivery system in the form of a spray. We also disagree with
Appellant’s apparent argument that Skold does not suggest including active
agents in both lipid vesicles and particles. {See, e.g., FF10 (explaining that a
lipid soluble active substance can be located within the bilayers of the
vesicles or within the monolayer or core of the lipid particles).) Likewise,
we are not persuaded by Appellant’s argument that Skold could not be used
as a comparative because dilution of Skold’s exemplary formulation led to
formation of unacceptable sediments (Appeal Br. 16—17; Reply Br. 6—7), for
the reasons already discussed above: Appellant did not appear to follow
Skold’s teaching of how to adjust the viscosity of Skold’s formulation in
attempting to formulate Skold’s composition as a spray.
We further agree with the Examiner that Appellant’s alleged evidence
of unexpected results is not reasonably commensurate with the scope of
claim 1. (Ans. 17.) As the Examiner points out, the only active agent for
which data is provided is testosterone. Similarly, Appellant tested only a
single carrier formulation allegedly within claim 1 for purposes of showing
unexpected results. (Skold Suppl. Deck 13, Ex. 3.) The claim, however,
recites a wide range of active ingredients, lipid components, and relative
ratios of components.
Appellant contends in their Appeal Brief that “anything that prefers
octanol to water 10:1 is hydrophobic, and is reasonably representative of
how bioactive agents will affiliate with the lipid components of the
claim[ed] recitations,” that the amounts of lipids used in the tested
formulation are “highly similar to the amounts in the two tables on p. 16 of
27
Appeal 2016-002058
Application 11/616,658
the [Specification,” that the ranges recited in the claims are “focused . . .
and not susceptible to . . . bias,” and that, “[i]n any case, the experimental
[sic] is reasonably representative.” (Appeal Br. 17—19; see also Reply Br.
7.) Claim 1, however, is not limited to the examples provided in the
Specification. Appellant has provided no persuasive evidence that the test
data relied upon for unexpected results is in fact representative or reasonably
commensurate with the scope of claim 1. “Attorney’s argument in a brief
cannot take the place of evidence.” In re Pearson, 494 F.2d 1399, 1405
(CCPA 1974).
Finally, we agree with the Examiner in giving less weight to
conclusory statements in the declarations. In particular, as the Examiner
points out, the composition of comparative formulations used in the study
regarding cytotoxic effects on mucosal tissue were not provided, making it
difficult to evaluate meaningfully whether the data in fact evidences
unexpected results as compared to the closest prior art. (Ans. 17—18, 19;
Skold Suppl. Decl. 114.) While Appellant contends that such information is
outside of Appellant’s control (Appeal Br. 18), the Patent Office is
nevertheless entitled to give less weight where relevant underlying data is
not provided to support conclusions in Appellant’s declarations. Am. Acad,
of Science Tech Ctr., 367 F.3d at 1368.
Accordingly, we affirm the Examiner’s rejection of claim 1 as
obvious over Skold, Yoshioka, Choi, and Katinger. Claims 49-51 and 56—
59, which were not separately argued, fall with claim 1. 37 C.F.R.
§ 41.37(c)(l)(iv).
28
Appeal 2016-002058
Application 11/616,658
Claims 23 and 24
Claims 23 and 24 depend from claim 1 and further recite that the
composition is packaged with a label with directions for nasal and
pulmonary administration, respectively. (Appeal Br. 32 (Claims App.).)
Appellant contends that the additional limitations further render claims 23
and 24 patentable because
the claimed formulation is not “known” ... at least because (a)
it has anchored flexible polymers, (b) it has low viscosity for
spraying, (c) it has a low lipid component weight contribution,
and (d) it is in a delivery device with a sprayer. Further,
directions for use for nasal administration are functionally
related to the spray device claimed; and directions for use for
pulmonary administration (to the lungs) are functionally related
to the spray device claimed.
(Appeal Br. 20.)
We acknowledge that “[difference between an invention and the prior
art cited against it cannot be ignored merely because those differences reside
in the content of the printed matter.” In re Gulack, 703 F.2d 1381, 1385
(Fed. Cir. 1983). However, we are not persuaded by Appellant’s arguments.
Appellant first argues that claims 23 and 24 are distinguishable from
the claim at issue in In re Ngai, 367 F.3d 1336 (Fed. Cir. 2004), in which
our reviewing court held that a known product does not become patentable
merely by attachment of new instructions, because the formulation of claims
23 and 24 are not known. (Appeal Br. 20.) We are not persuaded because
we find the delivery device of claims 23 and 24 (i.e., the delivery device
recited in claim 1) to be obvious for the reasons discussed above.
Neither are we persuaded, as Appellant contends, that claims 23 and
24 are independently patentable because the directions for use for nasal or
29
Appeal 2016-002058
Application 11/616,658
pulmonary administration are “functionally related” to the device claimed.
(Id.)
As our reviewing court has explained, the critical question for
purposes of this argument is “whether there exists any new and unobvious
functional relationship between the printed matter and the substrate.”
Gulack, 703 F.2d at 1386 (emphasis added). The claims in Gulack involved
a band, digits imprinted on the band, and an algorithm by which the digits
are developed. Id. at 1382. The Court found that the appealed claims in that
case required a particular sequence of digits, which are related to the band
because “(a) the band supports the digits; and (2) there is an endless
sequence of digits—each digit residing in a unique position with respect to
every other digit in an endless loop.” Id. at 1386—87. The Court thus found
that “the digits exploit the endless nature of the band” and further found that
the prior art does not disclose the critical features of the invention, which are
the particular sequence of digits and their derivation. Id. at 1387.
Unlike the situation in Gulack, where “the printed matter would not
achieve its educational purposes without the band, and the band without the
printed matter would similarly be unable to produce the desired result,” in
this case as in Ngai “the printed matter in no way depends on the [delivery
device], and the [delivery device] does not depend on the printed matter”; all
that the printed matter does is teach a use for a packaged product. Ngai, 367
F.3d at 1339; see also King Pharms., Inc. v. Eon Labs, Inc., 616 F.3d 1267,
1279 (Fed. Cir. 2010) (finding no functional relationship between
administration of an active agent with food and limitation informing patient
of the benefits of administering the agent with food because “[informing a
patient about the benefits of a drug in no way transforms the process of
30
Appeal 2016-002058
Application 11/616,658
taking the drug with food”). As in Ngai, if we were to adopt Appellant’s
position, “anyone could continue patenting a product indefinitely provided
that they add” new information to the packaging of the product. Ngai, 367
F.3d at 1339.
Accordingly, we affirm the Examiner’s rejection of claims 23 and 24
as obvious over Skold, Yoshioka, Choi, and Katinger.
Claims 60, 66, 68, 70, and 72
Claims 60, 66, 68, and 70 depend directly or indirectly from claim 1
and further recites that the bioactive agent is a steroid hormone. Claim 72
indirectly depends from claim 35 and also further recites that the bioactive
agent is a steroid hormone. Appellant does not separately argue these
claims. Thus, we limit our analysis to claim 60 as representative. Appellant
argues that the data relied upon for unexpected results, which relates to a
formulation comprising testosterone, is at least representative of steroid
hormones. (Appeal Br. 20—21.) Appellant argues that, even if the Board
does not accept the data for unexpected results for all of the claims, it should
accept it as to the above-enumerated claims, including claim 60, thus
rendering the claims patentable. {Id. at 21.) We are not persuaded. As
discussed above, we do not find Appellant’s unexpected results data to be
sufficient to render the claims non-obvious, when considered together with
the evidence of obviousness, even if the data were commensurate in scope
with respect to the bioactive agent.
Accordingly, we affirm the Examiner’s rejection of claim 60 as
obvious over Skold, Yoshioka, Choi, and Katinger. Claims 66, 68, 70, and
72, which were not separately argued, fall with claim 60. 37 C.F.R.
§ 41.37(c)(l)(iv).
31
Appeal 2016-002058
Application 11/616,658
II.
Issue
The Examiner has rejected claims 35, 36, 64, 74, and 75 under pre-
AIA 35 U.S.C. § 103(a) as obvious over Skold, Yoshioka, Choi, Katinger,
and Tardi. As reproduced above, claim 35 recites “[a] systemic delivery
composition” comprising “a composition formed by . . . lyophilization to
remove water of an intermediate composition” similar to the delivery
composition recited in claim l,18 wherein “the delivery composition has
been formulated for oral delivery by compression, encapsulation, or coating”
and wherein “upon reconstitution with water the reconstituted composition
has (i) the lipid particle component comprising particles of [previously
recited] lipids, and (ii) the vesicle component comprising vesicles
comprising [previously recited] lipids.” (Appeal Br. 33—34 (Claims App.).)
The Examiner finds that Choi teaches formulations that can be
lyophilized and then combined with a sterile aqueous solution prior to
administration. (Ans. 4.) The Examiner finds that Katinger teaches that
“liposomes can be administered in oral forms such as capsules, sugar-coated
tablets or powders.” {Id. at 6.) The Examiner finds that, “[f]or these forms,
the water must be removed and for tablets, compression is employed.” {Id.)
The Examiner finds that Tardi teaches that cryoprotectants may be added to
liposome preparations to prevent detrimental effects of lyophilization, that
“disaccharides such as trehalose, sucrose, lactose, sorbitol, mannitol,
maltodextrin and dextran are the most commonly used cryoprotectants,” and
18 In addition to including a lyophilization protective agent, the intermediate
composition of claim 35 also differs from the delivery composition of claim
1 in that claim 1 requires the viscosity of the delivery composition be
“selected to allow nasal or pulmonary application by spraying.”
32
Appeal 2016-002058
Application 11/616,658
that a skilled artisan can readily determine the cryoprotectant type and
concentration that works best for a particular liposomal preparation. (Id. at
10.) The Examiner concludes that a skilled artisan would have had reason,
with reasonable expectation of success, “to incorporate a cryoprotectant
when lyophilizing the formulations taught by the combined prior art,”
because Tardis teaches that cryoprotectant protect against damage known to
occur to lipid structures during lyophilization. (Id. )
Appellant contends that the cited art does not suggest a lyophilized
“formulation with vesicles and particles, with bioactive agent associated
with both, . . . formulated for oral delivery” by “compression, encapsulation,
or coating.” (Appeal Br. 26—27.)
The issues with respect to this rejection are (1) whether the cited art
suggests a delivery composition (a) comprising a composition formed by
lyophilization of an intermediate composition comprising an active agent
associated with both lipid particles and lipid vesicles and (b) “formulated for
oral delivery by compression, encapsulation, or coating,” and, if so, (2)
whether Appellant has provided evidence of unexpected results that, when
considered together with the evidence of obviousness, show the claims to be
non-ob vious.
Findings of Fact
27. Choi teaches that
[ljiposomes comprising the lipid compounds of this invention
can be formulated as pharmaceutical compositions or
formulations according to standard techniques using acceptable
adjuvants or carriers. . . .
. . . [The] invention provides for compositions for
intravenous administration which comprise a solution of
liposomes suspended in a physiologically-acceptable adjuvant
33
Appeal 2016-002058
Application 11/616,658
or carrier, preferably an aqueous carrier, such as water, buffered
water, isotonic saline, and the like. The compositions may be
sterilized by conventional, well-known sterilization techniques,
or may be sterile filtered. The resulting aqueous solutions may
be packaged for use as is, or lyophilized; the lyophilized
preparation being combined with a sterile aqueous solution
prior to administration.
(Choi 17:22-40.)
28. Katinger teaches that, “[i]n some cases, an accompanying, oral
administration of liposomal SOD in the form of tablets, capsules, sugar-
coated tablets, powders, etc. may also have a supporting effect.” (Katinger
6:64—67.)
29. Tardi teaches
a liposome comprising: a negatively charged lipid having a
hydrophilic portion and a hydrophobic portion with a neutral
nonzwitterionic moiety attached to the hydrophilic portion of
the lipid. In particular embodiments, liposomes of this
invention are substantially free of cholesterol. The liposomes
will typically contain a biologically active agent. Liposomes of
the invention surprisingly exhibit enhanced circulation
longevity in the bloodstream.
The negatively charged lipid is typically a phospholipid
or a sphingophospholipid. . . .
... A preferred non-zwitterionic moiety is a short-chain
alcohol such as glycerol, or a cyclic alcohol, such as inositol, or
a polyalkylene oxide such as PEG.
In one embodiment, the liposomes comprise greater than
10 mol % of one or more of said aggregation preventing
lipids—i.e., the negatively charged lipids comprising a non­
zwitterionic moiety, as described above; and up to 90 mol % of
one or more vesicle-forming lipids, wherein the liposome
contains substantially no cholesterol.
. . . With regard to protection against damage by freezing, as
little as 1 mol % of the aggregation preventing lipid may be
present.
34
Appeal 2016-002058
Application 11/616,658
(Tardi 13—16; see also id. at Abstract (stating that “[ljiposomes that
contain at least 10 mol % of a negatively charged lipid coupled to a non-
zwitterionic moiety are stable in the blood”), 148 (stating that “[njegatively
charged lipids comprising non-zwitterionic moieties may be incorporated in
the liposome at 5 to 95 mol %, more preferably at 10 to 50 mol % and most
preferably at 15 to 30 mol %”), 1 55 (teaching that, “[i]n [an] embodiment,
the non-zwitterionic moiety may be a polymer to form a ‘hydrophilic
polymer-lipid conjugate” and further teaching that “[t]he lipid may be . . .
phospholipids, sphingolipids and ceramides” and “[a] preferred polymer is
polyethylene glycol (PEG)).)
30. Tardi teaches that “[t]he liposomes of [its] invention will be
useful in delivering drugs and will thus be formulated to contain a
biologically active agent” and that “[a] wide variety of agents may be
encapsulated in the liposomes of the present invention.” {Id. ^fl[ 71—72.)
31. Tardi teaches:
For storage, the liposomes of the invention may be frozen
or lyophilized, and may comprise cryoprotectants. The amount
of cryoprotectant used depends on the type of cryoprotectant
and the characteristics of the liposome to be protected. Persons
skilled in the art can readily test various cryoprotectant types
and concentrations to determine which cryoprotectant type and
concentration works best for a particular liposome preparation.
In general, sugar concentrations on the order of 100 mM and
above have been found necessary to achieve the highest level of
protection. In terms of moles of membrane phospholipid,
millimolar levels on the order of 100 mM correspond to
approximately 5 moles of sugar per mole of phospholipid.
In the event the liposomes of the invention are to be
frozen, it is preferred, but not required, that the liposomes be
substantially free of cholesterol and comprise hydrophilic
35
Appeal 2016-002058
Application 11/616,658
polymer lipid conjugates, particularly those greater than about
125 daltons as these liposomes are resistant to fusion and
leakage of agent subsequent to freezing. Thus, if the liposomes
are to be frozen, they will contain about 1-30 mol % of one or
more hydrophilic polymer-conjugated lipids and up to about 99
mol % of one or more vesicle-forming lipids, and substantially
no cholesterol. Preferably, the hydrophilic polymer-lipid
conjugate is a PEG lipid conjugate. The liposomes may also
contain cryoprotectants such as trehalose, maltose, sucrose,
glucose, lactose, dextran or aminoglycosides. Particularly
preferred is glucose.
The liposomes may be frozen to about -5° C., preferably
below about -10° C. and more preferably below about -20° C.
They may be lyophilized when frozen.
{Id. 17, 19, 20; see id. at Abstract (stating that “[ljiposomes containing at
least 1 mol % of [a negatively charged lipid coupled to a non-zwitterionic
moiety] may be frozen safely”), 110 (teaching that “[cjryoprotectants have
been added to liposome preparations in order to prevent the detrimental
effects due to freezing and freeze-drying (lyophilization)”), H 83, 88
(describing freezing and drying liposome preparations), 195 (teaching that
pharmaceutical compositions comprising the liposomes of Tardi’s invention
may be sterilized and “resulting aqueous solutions . . . lyophilized, the
lyophilized preparation being combined with a sterile aqueous solution prior
to administration”).)
32. Tardi teaches that
[i]t is preferable that liposome preparations exhibit extended
chemical and physical stability properties in order for these
compositions to be of practical use. This often requires the use
of frozen or freeze-dried (lyophilized) product formats in order
to avoid breakdown of labile drug and/or lipid components.
Without the use of cryoprotectants, liposomes are generally
prone to mechanical rupture, aggregation and fusion during the
thawing/rehydration process. . . .
36
Appeal 2016-002058
Application 11/616,658
. . . [Stabilizing lipids such as phosphatidylglycerol may
be employed to protect liposomes against the detrimental
effects of freezing without requiring the presence of
cryoprotectants.
(Id. 11118, 120.)
33. Tardi teaches that
[ijnclusion of cholesterol in liposomal membranes has been
shown to reduce release of drug after intravenous
administration .... Generally, cholesterol increases bilayer
thickness and fluidity while decreasing membrane permeability,
protein interactions, and lipoprotein destabilization of the
liposome. Conventional approaches to liposome formulation
dictate inclusion of substantial amounts (e.g., 30-45 mol %)
cholesterol or equivalent membrane rigidification agents (such
as other sterols) into liposomes.
(Id. 112.)
34. Tardi teaches that “[ljiposomes that contain ‘substantially no
cholesterol’ may contain an amount of cholesterol that is insufficient to
significantly alter the phase transition characteristics of the liposome
(typically less than 20 mol % cholesterol).” (Id. 147; see also id. at || 118—
120 (Example 5 entitled “Phosphatidylglycerol Liposomes Containing Low
Levels of Cholesterol Resist the Detrimental Effects of freezing” and
describing liposome preparations having 0, 5, 10, 15 and 20 mol %
cholesterol).)
Analysis
Claim 35
We agree with the Examiner that claim 35 is rendered obvious by the
combination of Skold, Yoshioka, Choi, Katinger, and Tardi and adopt the
Examiner’s findings of fact and reasoning regarding the scope and content of
37
Appeal 2016-002058
Application 11/616,658
the prior art as applied to claim 35. (Ans. 10—11, 21—24; FF1—34.) We
address Appellant’s arguments below.
Appellant argues that nothing in the cited art discloses or suggests “a
formulation with vesicles and particles, with bioactive agent associated with
both, . . . formulated [as a lyophilized dry form] for oral delivery.” (Appeal
Br. 26-27.)
Appellant first contends that Katinger is directed to a large enzyme
that is not susceptible to being systemically delivered in tablets, capsules or
the like and that Katinger is thus “speculative and non-enabling.” (Appeal
Br. 22.) Appellant further argues that any suggestion that Katinger’s tablets
are derived from lyophilization is “pure conjecture.” {Id. at 23.) Appellant
states that “[t]he only references to relevant terms in Katinger is two
references to ‘lyophilized,’ but these uses are as to lyophilized substances to
be added to the liposomes, not to the liposomes.” {Id. at 27.)
We are not persuaded. As an initial matter, the disclosures of
a prior art patent such as Katinger are presumed to be enabled, and the
applicant bears the burden of proving that the relevant disclosure is
not. Amgen, Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1355
(Fed. Cir. 2003). Appellant’s attorney argument that the enzyme in Katinger
is not susceptible to being systemically delivered in tablets, capsules or the
like does not meet this burden. Johnston v. IVAC Corp., 885 F.2d 1574,
1581 (Fed. Cir. 1989) (“Attorneys’ argument is no substitute for evidence.”).
As to Appellant’s argument that Katinger does not disclose that its tablets
are derived from lyophilization, we note that the Examiner does not rely on
Katinger for disclosures relating to lyophilization. Merck, 800 F.2d at 1097
(“Non-obviousness cannot be established by attacking references
38
Appeal 2016-002058
Application 11/616,658
individually where the rejection is based upon the teachings of a
combination of references.”).
Appellant next argues that “[t]he cited text of Choi never discloses or
suggests that the lyophilizate can be formulated by compression,
encapsulation or coating, as recited in Claim 3[5].”19 (Appeal Br 23.)
We are not persuaded. A reference must be considered for what it
fairly suggests as well as for what it expressly teaches, Baird, 16 F.3d at
383, and furthermore “must be read, not in isolation, but for what it fairly
teaches in combination with the prior art as a whole.” Merck, 800 F.2d at
1097. In this case, Tardi generally teaches that, because liposome
preparations preferably “exhibit extended chemical and physical stability
properties,” use of frozen or lyophilized product formats are often required.
(FF32.) Choi provides a specific example in which an aqueous liposomal
composition (albeit one for intravenous rather than oral administration) is
lyophilized and reconstituted prior to use. (FF27.) Katinger teaches that
liposomal preparations may be formulated usefully in the form of tablets and
capsules for oral administration. (FF28.)
Given the above, and give the Examiner’s reasonable finding that
“[tjablets and other dosages forms are well-known in the art, as are the
methods by which they can be prepared,” we find that it would be obvious
for a skilled artisan to formulate lyophilizate into tablets or capsules via
compression, encapsulation, or coating for eventual oral delivery. (Ans. 22.)
A skilled artisan would have reason to do so in order to impart extended
19 Although Appellant refers to claim 36 here, we understand Appellant to be
referring in fact to claim 35, because the dependent claim limitation in claim
36 is not a limitation relating to compression, encapsulation, or coating.
39
Appeal 2016-002058
Application 11/616,658
chemical and physical stability properties to a liposomal composition
comprising an active agent suitable for oral administration.
Appellant further argues that Choi, Katinger and Tardi all are “about
liposomes, not lipid vesicles AND lipid particles.” (Appeal Br. 23.)
Likewise, Appellant argues that “Katinger and Tardi only describe
lyophilizing vesicles, and does not disclose or suggest lyophilizing a mixture
of vesicles and particles,” and “[njothing in the cited art indicates a
reasonable expectation of success in freeze drying a composition containing
vesicles and particles as claimed.” {Id. at 25.)
We are not persuaded. As discussed above, Choi, which also
discloses lyophilizing an embodiment of its invention, teaches compositions
comprising “other lipid-based carriers” as well as liposomes. (FF22.) Skold
also teaches compositions comprising both lipid vesicles (i.e., liposomes) as
well as lipid particles. (FF5—11.) As previously discussed, “expectation of
success need only be reasonable, not absolute.” Pfizer, 480 F.3d at 1364.
Given that lyophilization of liposome compositions are well known in the
prior art (FF27, FF31, FF32), and the similarity in the components making
up lipid particles, we agree with the Examiner that a skilled artisan would
have a reasonable expectation of success in lyophilizing a composition
comprising both lipid vesicles such as liposomes as well as lipid particles, in
the absence of evidence to the contrary.
Finally, Appellant argues that, while “Choi states prophetically that
the liposomes can be provided in freeze-dried form,” “[t]his is negated by
the actual data in Tardi that shows that ordinary cholesterol-containing
liposomes (Cholesterol and phospholipid) are unstable to the first step
(freezing) of freeze-drying.” (Appeal Br. 27; see also Reply Br. 8.) In
40
Appeal 2016-002058
Application 11/616,658
particular, Appellant argues that Tardi teaches that “[i]f cholesterol is
present, the liposomes tremendously lose size integrity upon freezing ....
Thus, cholesterol-free is clearly preferred.” (Appeal Br.24.) Appellant also
argues that “the Tardi data shows stability to freezing, not to lyophilizationf
because “none of the examples provide data on stability after freeze drying.”
{Id. at 24-25.)
We are not persuaded. Tardi does not teach that the presence of any
amount of cholesterol renders liposomes unstable to freezing and/or freeze­
drying. In fact, Tardi teaches that “[ljiposomes that contain ‘substantially no
cholesterol’ may contain an amount of cholesterol that is insufficient to
significantly alter the phase transition characteristics of the liposome
(typically less than 20 mol % cholesterol)” and that phosphatidylglycerol
liposomes containing low levels of cholesterol (20% or less) resist the
detrimental effects of freezing. (FF34.)
Claim 35 recites an amount of cholesterol of 20—30 mol % or more
bilayer-stabilizing steroid such as cholesterol. Thus, the lower end of the
claimed cholesterol range essentially overlaps, or at least abuts the range of
what Tardi teaches as “substantially no cholesterol.” Peterson, 315 F.3d at
1329 (“A prima facie case of obviousness typically exists when the ranges
of a claimed composition overlap the ranges disclosed in the prior art.”); id.
(“[E]ven a slight overlap in range establishes a prima facie case of
obviousness.”); see also id. (“We have also held that a prima facie case of
obviousness exists when the claimed range and the prior art range do not
overlap but are close enough such that one skilled in the art would have
expected them to have the same properties”). We therefore disagree with
Appellant’s apparent contention that Tardi teaches away from the invention
41
Appeal 2016-002058
Application 11/616,658
of claim 35 and/or that Tardi obviates the reason to combine the cited prior
art to arrive at the claimed invention.
As to Appellant’s argument that “the Tardi data shows stability to
freezing, not to lyophilization,” because “none of the examples provide data
on stability after freeze drying” (Appeal Br. 24—25), we are likewise not
persuaded. As already discussed, a prior art reference is relevant for all that
it teaches to those of ordinary skill in the art, not merely what is exemplified.
Cf. Lemelson, 397 F.2d at 1009. In this case, Tardi teaches that freeze­
drying is a well-known method to extend chemical and physical stability
properties of liposome preparations (FF32) and further teaches that a skilled
artisan would be able to determine the cryoprotectant type and concentration
that would work best to protect a particular liposome preparation during the
freezing or freeze-drying process (FF31). Thus, we find that Tardi would
provide a skilled artisan a reason to lyophilize a liposomal preparation
comprising cryoprotectants.
Unexpected Results
Appellant makes three arguments that the subject matter of claim 35
exhibits unexpected results.
First, Appellant argues that because Tardi teaches that “[i]f cholesterol
is present, the liposomes tremendously lose size integrity upon freezing,”
the data presented in the Skold Supplemental Declaration “showing] that
[the claimed composition containing] cholesterol-loaded formulations are
particle size distribution stable after freeze-drying (but not after spray
drying)” demonstrates unexpected results. (Appeal Br. 24; see also Reply
Br. 8.)
42
Appeal 2016-002058
Application 11/616,658
We are not persuaded. As discussed above, Tardi does not suggest
that any amount of cholesterol present would lead to loss of size integrity
upon freezing. (FF34.) Appellant tested a formulation containing 0.6% by
weight cholesterol and trehalose, raffmose, or maltodextrin as
cryoprotectant, in contrast to formulations tested in Tardi comprising 45 mol
% cholesterol and glucose as cryoprotectant. (Skold ]Hf 24—25, Exhibits 5, 6;
Tardi 129-131 (Example 8).) Because Appellant has not shown that the
tested formulation has the same cryoprotectant or amounts of cholesterol as
a formulation tested in Tardi’s example(s), we are not persuaded that the
data presented by Appellant in fact shows unexpected results rather than,
e.g., an expected difference based on differing amounts of cholesterol in the
liposomes and a difference in the efficacy of the cryoprotectant.
Next, Appellant argues that that “the fact that particles and vesicles
reconstitute after drying as evidenced in the Skold [Supplemental]
Declaration, comprises unexpected results,” because “[njothing in the cited
art indicates a reasonable expectation of success in freeze drying a
composition containing vesicles and particles as claimed.” (Appeal Br. 25;
Reply Br. 9.) We are not persuaded. As already discussed above, we find
that a skilled artisan would have a reasonable expectation of success in
lyophilizing a composition comprising both lipid vesicles and particles.
Moreover, Appellant has provided only a conclusory statement that the
achieved results were unexpected without providing persuasive evidence of
what a skilled artisan would have expected upon lyophilizing a lipid particle.
Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1371 (Fed. Cir. 2007) (“[B]y
definition, any superior property must be unexpected to be considered as
evidence of non-obviousness. . . . Thus, in order to properly evaluate
43
Appeal 2016-002058
Application 11/616,658
whether a superior property was unexpected, the [fact-finder] should have
considered what properties were expected. . . . Here, Pfizer’s evidence must
fail because the record is devoid of any evidence of what the skilled artisan
would have expected.”) As with Appellant’s unexpected results data with
respect to claim 1 (Skold 125, Exhibit 6), moreover, we find that the data
here, which again relates to only a single composition, is not commensurate
with the scope of claim 35. In re Dill, 604 F.2d 1356, 1361 (CCPA 1979)
(“The evidence presented to rebut a prima facie case of obviousness must be
commensurate in scope with the claims to which it pertains.”).
Finally, Appellant argues that, since the lyophilized composition
reconstitutes to its previous form (i.e., the intermediate composition), the
same data that Appellant cited to show the alleged unexpected results with
respect to the subject matter of claim 1 also demonstrates unexpected results
with respect to the subject matter of claim 35. (Appeal Br. 25.) We are not
persuaded for the same reasons discussed with respect to the rejection of
claim 1.
Accordingly, we affirm the Examiner’s rejection of claim 35. Claims
74 and 75, which were not separately argued, fall with claim 35.
Claim 36
With respect from claim 36, which depends from claim 35, and
further recites that “the composition is packaged with a label with directions
for pulmonary administration,” Appellant argues that the claim is
additionally patentable for the same reasons as claims 23 and 24. (Appeal
Br. 26, 34.) We are not persuaded for the reasons already discussed.
44
Appeal 2016-002058
Application 11/616,658
Claim 64
With respect to claim 64, which depends from claim 35 and further
recites that the bioactive agent is a steroid hormone, Appellant further
contends that testosterone, the active agent used in the data Appellant relies
on to show unexpected results, clearly is a good representation of steroid
hormones.20 (Appeal Br. 26—27.) Appellant thus argues that, “even if the
Board does not accept the data for unexpected results for all of the claims, it
should accept it as to [claim 64].” {Id. at 28) We are not persuaded for the
same reasons already discussed above with respect to claim 60.
III.
Issue
The Examiner has rejected claims 61, 67, 69, 71, and 73 under pre-
AIA 35 U.S.C. § 103(a) as obvious over Skold, Yoshioka, Choi, Katinger,
and Scott. The Examiner has also rejected claims 65 and 76 under pre-AIA
35 U.S.C. § 103(a) as obvious over Skold, Yoshioka, Choi, Katinger, Tardi,
and Scott. Claims 61, 67, 69, and 71 depends directly or indirectly from
claim 1, and further recites that “the bioactive agent is testosterone.”
(Appeal Br. 35, 36 (Claims App.).) Claims 65 and 73 depend directly or
indirectly from claim 35, while claim 76 depends indirectly from claim 74,
and each claim similarly further recites that “the bioactive agent is
testosterone.” {Id. at 35, 36, 37.) The same issue is dispositive for both
rejections; we thus discuss them together.
20 Appellant also makes the same argument for claim 64 as for claim 35.
(Appeal Br. 26—27.) We are not persuaded by these arguments for the
reasons already discussed.
45
Appeal 2016-002058
Application 11/616,658
The Examiner finds that, while Skold discloses “steroid hormones,
estrogens and androgens as therapeutic agents that can be delivered,” none
of Skold, Yoshioka, Choi, and Katinger explicitly discloses testosterone.
(Ans. 9.) The Examiner finds that Scott discloses “therapeutic agents or
medicaments encapsulated in a charged liposome or micelle” and further
discloses that “[a]mong the therapeutic agents that can be encapsulated are
estrogen, testosterone and steroid hormones.” (Id.) The Examiner
concludes that a skilled artisan would have reason to use testosterone as the
active agent to be delivered in Skold’s formulation, with a reasonable
expectation of success, because
[Skold] generically disclosed steroid hormones and androgens
as therapeutic agents for delivery in the disclosed drug delivery
system and [Scott] discloses that testosterone and other steroids
can be delivered using lipid-based carrier drug delivery for
estrogens, steroid hormones and testosterone. The person of
ordinary skill in the art can readily select the appropriate
therapeutic agent from those that are taught as suitable by the
prior art for delivery using lipid-based carrier drug delivery
systems.
(Id.)
Appellant contends that Scott does not teach “fatty acid-dependent
particles as now claimed” or suggest “effectiveness in systemic delivery
through spray delivery.” (Appeal Br. 21.) Appellant contends that claim 65
is non-obvious for the same reason as claim 35. Appellant further contends
that the claimed subject matter exhibits unexpected results.
The issues with respect to this rejection are (1) whether a skilled
artisan would have a reason to use testosterone in a delivery device
suggested by the combination of Skold, Yoshioka, Choi, and Katinger, or the
delivery composition suggested by the combination of Skold, Yoshioka,
46
Appeal 2016-002058
Application 11/616,658
Choi, Katinger, and Tardi, and, if so, (2) whether Appellant has provided
evidence of unexpected results that, when considered together with the
evidence of obviousness, show the claims to be non-obvious.
Findings of Fact
35. Scott teaches “[a] charged liposome or micelle encapsulated
therapeutic agent or medicament for the treatment of an obstruction in blood
vessel.” (Scott Abstract.)
36. Scott teaches that “[t]he liposome-encapsulated therapeutic
agent... or micelle-encapsulated therapeutic agent. . ., can be selected
from the group consisting of. . . testosterone, steroid hormones, . . . and
combinations thereof.” {Id. 134.)
Analysis
We agree with the Examiner that claim 61 is rendered obvious by the
combination of Skold, Yoshioka, Choi, Katinger, and Scott and adopt the
Examiner’s findings of fact and reasoning regarding the scope and content of
the prior art as applied to claim 61. (Ans. 8—9, 20-21; FF1—26, 35, 36.) We
address Appellant’s arguments below.
Appellant argues that Scott does not teach “fatty acid-dependent
particles as now claimed” or “effectiveness in systemic delivery through
spray delivery.” (Appeal Br. 21.) We are not persuaded because the
Examiner relies on other cited prior art to suggest these limitations, as
discussed above.
Appellant further argues that the unexpected results data submitted by
Appellant, which relates to a composition comprising testosterone, renders
claims limited to testosterone as the bioactive agent patentable, even if the
47
Appeal 2016-002058
Application 11/616,658
Board finds that the data is not commensurate with the scope of the broader
claims. {Id. at 22.) We are not persuaded because, as discussed above, we
do not find Appellant’s unexpected results data to be sufficient to render the
claims non-obvious, when considered together with the evidence of
obviousness, even if the data were commensurate in scope with respect to
the bioactive agent.
Accordingly, we affirm the Examiner’s rejection of claim 61. Claims
67, 69, 71, and 73, which were not separately argued, fall with claim 61.
Appellant makes the same arguments for claims 65 and 76 as discussed
above with respect to claim 61. We are not persuaded for the same
reasons.21
SUMMARY
For the reasons above, we affirm the Examiner’s decision rejecting
claims 1, 23, 24, 35, 36, 49-51, 56—61, and 64—76.
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).
AFFIRMED
21 With respect to claim 65, Appellant also repeats some of the same
arguments discussed above with respect to claim 35. (Appeal Br. 28—29.)
We are not persuaded for the reasons already discussed above with respect
to claim 35.
48