Ex Parte Riley et al

Patent Trial and Appeal Board

Mar 23, 2017

13555472 (P.T.A.B. Mar. 23, 2017)

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.
13/555,472 07/23/2012 Thomas C. Riley 200407-405281 1540
83332 7590 03/23/2017
Jonathan P. O'Brien, Ph.D.
Honigman Miller Schwartz and Cohn LLP
350 East Michigan Avenue
Suite 300
KALAMAZOO, MI 49007
EXAMINER
HELM, CARALYNNE E
ART UNIT PAPER NUMBER
1615
MAIL DATE DELIVERY MODE
03/23/2017 PAPER
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.
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte THOMAS C. RILEY, R. SAUL LEVINSON,
ROBERT C. CUCA, and ELIO MARIANI
Appeal 2014-009435
Application 13/555,472
Technology Center 1600
Before LORA M. GREEN, JEFFREY N. FREDMAN, and
KRISTI L. R. SAWERT, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal1 under 35U.S.C. § 134 involving claims to a pharmaceutical
formulation to treat vaginal conditions. The Examiner rejected the claims as obvious.
We have jurisdiction under 35 U.S.C. § 6(b). We reverse.
1 Appellants identify the Real Party in Interest as DrugTech Corporation (see App. Br.
1).
Appeal 2014-009435
Application 13/555,472
Statement of the Case
Background
“Active agents having pharmaceutical qualities have been developed and
approved for use in the treatment of conditions and diseases of the vaginal cavity and
. . . include fungicides, antibiotics, spermicides” (Spec. 15). “The majority of gels,
foams, creams, suppositories and tablets presently used as vaginal delivery systems
can breakdown almost immediately following insertion into the vaginal cavity and
have minimal bioadherence to the vaginal walls” (Spec. 1 5).
“The present invention is directed to delivery systems, which stabilize surface
active therapeutic agents, or those therapeutic agents which obtain surface active
properties in a delivery system. These systems are suitable for use in the vaginal
cavity” (Spec. 12).
The Claims
Claims 1, 3, 6, 7, 20-24, 39-41, and 44-47 are on appeal. Claim 1 is
representative and reads as follows:
1. A pharmaceutical formulation to treat vaginal conditions in a
human patient comprising:
an effective amount of clindamycin phosphate; and
a modified release dosage form which provides modified release of
said clindamycin phosphate upon vaginal administration to said patient;
wherein said formulation, when containing a total dose of
clindamycin phosphate of about 25 pg to about 500 mg based on
clindamycin will produce a plasma concentration versus time curve
(ng/ml versus hours) having an area under the curve (AUC) of less than
about 600 ng/mL.hr; and
wherein said dosage form comprises:
a. an emulsion comprising an external lipoidal phase and an
internal non-lipoidal phase wherein said lipoidal phase is
continuous and said non-lipoidal phase comprises at least 70% by
volume of said emulsion;
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Application 13/555,472
b. one or more lecithins as primary stabilizing surfactants;
and
c. one or more auxiliary stabilizing surfactants.
The issues2
A. The Examiner rejected claims 1, 3, 20-24, and 39-41 under 35 U.S.C. § 103(a)
as obvious over Heide,3 Dunphy,4 Berthod,5 Cuca,6 and Tucker7 (Non-Final Act. 3—7).
B. The Examiner rejected claims 24, 44, and 45 under 35 U.S.C. § 103(a) as
obvious over Heide, Dunphy, Berthod, Cuca, Tucker, Chevalier,8 and Gidwani9 (Non-
Final Act. 7—9).
C. The Examiner rejected claim 6 under 35 U.S.C. § 103(a) as obvious over Heide,
Dunphy, Berthod, Cuca, Tucker, and Edwards10 (Non-Final Act. 9-10).
D. The Examiner rejected claim 7 under 35 U.S.C. § 103(a) as obvious over Heide,
Dunphy, Berthod, Cuca, Tucker, and Pereira11 (Non-Final Act. 10).
E. The Examiner rejected claim 46 under 35 U.S.C. § 103(a) as obvious over
Heide, Dunphy, Berthod, Cuca, Tucker, and Weete12 (Non-Final Act. 11).
2 The rejections are found in the Non-Final action mailed June 27, 2013.
3 Heide, P., DE 100 15 463 Al, publ. Oct. 18, 2001 (“Heide”).
4 Dunphy et al., US 5,085,856, issued Feb. 4, 1992 (“Dunphy”).
5 Berthod et al., US 4,446,051, issued May 1, 1984 (“Berthod”).
6 Cuca et al., US 5,554,380, issued Sept. 10, 1996 (“Cuca”).
7 S. B. Tucker et al., Comparison of Topical Clindamycin Phosphate, Benzoyl
Peroxide, and a Combination of the Two for the Treatment of Acne Vulgaris, 110
British J. Dermatology, 487^492 (1984) (“Tucker”).
8 Chevalier et al., US 6,284,281 Bl, issued Sept. 4, 2001 (“Chevalier”).
9 Gidwani et al., US 2003/0219465 Al, publ. Nov. 27, 2003 (“Gidwani”).
10 Edwards, L., US 4,803,066, issued Feb. 7, 1989 (“Edwards”).
11 Pereira et al., US 5,216,033, issued June 1, 1993 (“Pereira”).
12 Weete et al., US 4,943,389, issued July 24, 1990 (“Weete”).
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Application 13/555,472
F. The Examiner rejected claim 47 under 35 U.S.C. § 103(a) as obvious over
Heide, Dunphy, Berthod, Cuca, Tucker, Chevalier, Gidwani, and Weete (Non-Final
Act. 12).
Because the same issues, the same claims, and substantially the same prior art
disclosures are dispositive for all of the rejections, we will consider the rejections
together.
The Examiner finds:
Although Heide does not provide an explicit example of each
embodiment of their invention, it would have been obvious to one of
ordinary skill in the art at the time of the invention to follow their
teachings of lecithin containing hyper-hydrated water-in-oil emulsions
and prepare one with lecithin having 60 to 80% phosphatidylcholine as
the primary stabilizing surfactant and 0.5% of an active agent.... Given
that Heide’s compositions were known to have a water content of up to
80% and similar emulsions compositions were known to have a non-
lipoidal phase of about 75% by volume (e.g.[,j Cuca et al.), it would also
have been obvious to follow the teachings for hyper-hydrated water-in-
oil emulsions and prepare that of Heide with at least 75% by volume of
the non-lipoidal phase .... It further would have been obvious to select
clindamycin phosphate as the active agent in the topical composition
because 1) this active was known to be delivered topically to treat skin
conditions, 2) a delivery vehicle for this active would have benefited
from the reduced itching and dry feel conferred by the topical water-in-
oil composition of Heide and 3) the explicit contemplation of
clindamycin as an active agent in the composition of Heide. This
modification would have been obvious as the simple substitution of one
known element for [another] to yield a predictable result. Additionally, it
would also have been obvious for this artisan to select glycerol
monoisostearate at 3.5% as an auxiliary stabilizing surfactant or
coemulsifier to add along with lecithin to this composition to provide
added stability to the composition since it was known to be coupled with
lecithin in water-in-oil emulsions and known to be pharmaceutically
acceptable, thereby overcoming the limitations of past coemulsifiers in
such emulsions.
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Application 13/555,472
(Non-Final Act 5—6).
The issues with respect to these rejections are:
(i) Does the evidence of record support the Examiner’s conclusion that the prior
art renders the claims obvious?
(ii) If so, have Appellants presented evidence of secondary considerations, that
when weighed with the evidence of obviousness, is sufficient to support a conclusion
of non-obviousness?
Findings of Fact
1. Heide teaches
Methods for producing W/O emulsions with the help of the
soybean/lecithin emulsifier, wherein the water content is between 30%
and 80% without loss of the cream-like character of the W/O emulsion,
are described in [prior art]. The manufacturing technique described
therein is very costly and the stability of the creams obtained is not
satisfactory. In order to increase the stability, the addition of further
surface active emulsifiers, so-called co-emulsifiers, has become known.
However, such additions are not pharmaceutically safe.
(Heide 12).
2. Heide teaches
to provide a cream in the form of a hyperhydrated water-in-oil emulsion,
which can be produced easily, is constituted as simply as possible and
largely precludes side effects . . . composed of the following constituents,
namely: a) lecithin, containing phosphatidyl choline and phosphatidyl
ethanolamine, b) a short chain dihydric or trihydric alcohol, c) an oil d)
water and e) an active ingredient, wherein the cream is sterilized by
filtration.
(Heide H 4-5).
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Application 13/555,472
3. Heide teaches: “Water-soluble antibiotics do not penetrate the lipophilic,
outer layer of the skin very well. Packed in a W/O cream, these active ingredients can
easily pass through the skin barrier. Examples are . . . clindamycin” (Heide 120).
4. Heide teaches:
It has turned out to be particularly advantageous if the lecithin content
ranges from 5 to 20% by weight of the cream, the content of dihydric or
trihydric alcohol ranges from 10% to 20% by weight of the cream, the oil
content ranges from 30% to 50% by weight of the cream and the water
content ranges from 40% to 60% of the weight of the cream.
(Heide 122).
5. Dunphy teaches “the emulsion is a water-in-oil emulsion .... The
emulsifier system also comprises, in addition to the phospholipid, a second emulsifier
.... Examples of the second emulsifier include derivatives of glycerol” (Dunphy
2:16-65).
6. Berthod teaches the “emulsifier should be liquid at room temperature
(20° C.) and be cosmetically and pharmaceutically acceptable .... Examples of
suitable emulsifiers are . . . (glycerol monoisostearate)” (Berthod 3:54 to 4:4).
7. Cuca teaches “a water-in-oil emulsion system having at least two phases,
one phase comprises from about 25% to about 75% by volume of an internal
hydrophilic phase and the other phase comprises from about 25% to about 75% by
volume of an external hydrophobic phase” (Cuca 2:58—62).
8. Cuca teaches the “formulations of the invention may be used as is when
preblended with an active material or drug when being prepared. . . . Exemplary
nonlimiting examples include: . . . Anti-infective agents” (Cuca 8:22—54).
9. Cuca teaches “the emulsifiers are soluble in the hydrophobic (lipoidal) or
external phase. Suitable emulsifiers are those oil miscible surface active compounds
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Application 13/555,472
which are acceptable for use in foods, pharmaceuticals, and/or cosmetics” (Cuca
7:20-24).
10. Tucker teaches the “combination of therapy involving clindamycin
phosphate ... in the morning and benzoyl peroxide ... at night consistently
demonstrated the best overall efficacy when the acne severity index is applied”
(Tucker 491).
11. The Cuca Declaration13 states: “Many of the clindamycin formulations
made and tested were physically unstable and were deemed unacceptable for further
development” (Cuca Deck 1 6).
12. The Cuca Declaration states:
High internal phase ratio emulsions such as those of the present
application are generally difficult to stabilize, and those skilled in the art
would expect a charged molecule (such as a phospholipid) to have a
destabilizing effect on such a formulation. To the contrary, we found that
adding a phospholipid to the high internal phase ratio clindamycin
formulation of the present application in fact stabilized the formulation.
(CucaDecl. 12).
13. The Cuca Declaration tested a formulation with the composition
reproduced below:
. Cuca, dated Oct. 13, 2010.
7
13 Declaration of Robert C
Appeal 2014-009435
Application 13/555,472
Component Wt%
Water 37.819
Sorbitol 70% 39.288
EDTA, disodium, USP 0.05
Clindamycin phosphate 2.69
Propylene glycol 5
Gloria mineral oil, USP 8.032
Polyglyceroi'3 cleats 2.713
Hydrophobic silicon dioxide (R972) 1.013
Microcrystailine wax, w-835 0.452
Methyiparaben, NF 0.18
Propylparaben, NF 0.05
Glyceryl monoisostearate 2,713
Total - 100
(Cuca Decl. 14).
14. The Cuca Declaration states that the “specification of the present
application makes note of this unexpected finding, stating: ‘It has been unexpectedly
found that phospholipids in combination with surfactants from a system previously
destabilized with Clindamycin phosphate became physically stable.’” (Cuca Decl. 1
10 (quoting Paragraph [0028] of U.S. Patent Application Publication No.
2005/0095245)).” .
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Application 13/555,472
15. Exhibit A of the Cuca Declaration discloses unsuitable formulations and
is reproduced below:
EXHIBIT A
•* •* <* «.■» S'* s §g§|§g§|||j||yj^^
v^v
9’g5ycefTM csteas.« zm
«<5lteiidal ssfe«« iMc
mem'sysiaSItes wss AS2
m 127
prspy! ps.y#IW8 >02?
5 00.00
(Riley, Jr. 6:16—30).
14 Riley, Jr., T., US 5,266,329, issued Nov. 30, 1993 (“Riley, Jr.”).
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Application 13/555,472
17. Riley, Jr. teaches the “active agent may be any of those which are
approved for or used for the treatment, prophylaxis, cure or mitigation of any disease
of the vagina, urinary tract, cervix or other female reproductive organ or inducement
of conception” (Riley, Jr. 3:59—63), and that “this effect can be achieved with other
antibacterial agents and antifungal agents. Thus, the treatment of microbes can be
achieved in much shorter time or with substantially less drug” (Riley, Jr. 4:16—20).
Principles of Law
The Examiner has the initial burden of establishing a prima facie case
obviousness under 35 U.S.C. § 103. In re Oetiker, 977 F.2d 1443, 1445 (Fed. Cir.
1992). “The combination of familiar elements according to known methods is likely
to be obvious when it does no more than yield predictable results.” KSR Int 7 Co. v.
Teleflex Inc., 550 U.S. 398, 416 (2007).
Prima facie obviousness can be rebutted by presenting evidence of secondary
considerations and when such evidence is submitted, all of the evidence must be
considered anew. In re Piasecki, 745 F.2d 1468, 1472—1473 (Fed. Cir. 1984).
Secondary considerations include: long-felt but unsolved needs, failure of others,
unexpected results, commercial success, copying, licensing, and praise. In re Rouffet,
149 F.3d 1350, 1355 (Fed. Cir. 1998).
Analysis
We adopt the Examiner’s findings regarding the scope and content of the prior
art (Ans. 3—12) and agree with the conclusion that the pharmaceutical formulation of
claim 1 would have been prima facie obvious in view of the cited references.
Appellants present arguments disputing the prima facie case of obviousness. We do
not find it necessary to address these arguments because, as discussed below, we
conclude that the evidence of unexpected results, when considered with the prima
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Application 13/555,472
facie case of obviousness, has successfully overcome the prima facie case of
obviousness.
Appellants contend the “Cuca Declaration provided evidence of unexpected
results for the claimed formulation as compared to the formulation described in Riley”
(App. Br. 32). Appellants contend the
Declaration explained that when clindamycin was incorporated into a
previously stable water-in-oil emulsion composition similar to the
formulation exemplified by Riley, the composition quickly became
unstable and the oily and aqueous phases of the formulation separated. A
number of attempts were made to stabilize this physically unstable
clindamycin formulation, but most of these attempts failed
(App. Br. 32).
The Examiner responds:
Six elements are listed by the appellant.
1. Vaginal administration
2. Non-lipoidal phase comprising at least 70% by volume of the
formulation
3. One or more auxiliary stabilizing surfactants
4. Modified/low systemic effects
5. Selection of an antibacterial agent as active ingredient
6. Lecithin
. . . Riley et al. teach elements 2-3 and 5. When element 6 is absent and
element 5 is clindamycin phosphate, the declaration demonstrates that the
resulting emulsion is unstable. While disputed by the appellant, Heide
teaches elements 2 and 5-6. The declaration does not address or inform
the stability of such a composition such that the presence of element 3
when clindamycin phosphate is element 5 is unexpectedly critical. Since
Heide is the basis of the rejections under appeal, the declaration remains
insufficient to overcome the prima facie case of obviousness made in the
current rejections of record.
(Ans. 10-11).
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Application 13/555,472
We find that Appellants have the better position. “A comparison of the claimed
invention with the disclosure of each cited reference to determine the number of claim
limitations in common with each reference, bearing in mind the relative importance of
particular limitations, will usually yield the closest single prior art reference.” In re
Merchant, 575 F.2d 865, 869 (CCPA 1978).
We find that claim 1 requires, relevant to the claim limitations at issue,
clindamycin, an aqueous phase at least 70% by volume, lecithin, and auxiliary
stabilizing surfactants. We agree with the Examiner that for purposes of the
comparison, the intended use in the preamble does not impose any specific
requirements on claim 1.
Riley, Jr. teaches an exemplary formulation that has, approximately, 43% water
and 40% sorbitol, for a total “non-lipoidal phase” of 83%, as well as 2% active agent
(metronidazole), and 2.7% each of auxiliary stabilizing agents glyceryl isostearate and
polyglyceryl-4 oleate (FF 16; cf. instant claim 23 “wherein said auxiliary stabilizing
surfactants are selected from the group consisting of polyglycerol-3-oleate, glycerol
monoisostearate and mixtures thereof’).
Heide teaches a cream comprising an active agent with a large list of agents that
includes clindamycin, but provides no exemplification with clindamycin or any other
active agent (FF 3), an aqueous phase as high as 60% (FF 4), lecithin (FF 2), lacks any
teaching of the auxiliary stabilizing agents (see Ans. 11) and may even discourage,
slightly, the use of co-emulsifiers (see FF 1).Therefore, from a strict numerical
standpoint, Riley Jr. and Heide are equally close because Riley, Jr. has two elements
identical to claim 1, the aqueous phase concentration of at least 70% and the auxiliary
stabilizing agents and Heide teaches lecithin and lists clindamycin as an option for an
antibacterial active ingredient. However, we find that Riley, Jr. is closer prior art
because Riley Jr. also suggests the use of antibacterial agents (FF 17), and, as the
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Examiner found, clindamycin was an obvious antibacterial active ingredient (see Final
Rejection in US 10/944,416 mailed May 25, 2010).
Moreover, Riley Jr., provides an actual example suitable for testing purposes
that includes an active antibacterial agent, though clindamycin is not disclosed, the
aqueous phase, the auxiliary stabilizing agents (FF 16), lacking only lecithin, although
Heide provides no examples, requiring the ordinary artisan select clindamycin from a
lengthy list, optimize the aqueous phase concentrations (FF 3—4). In addition, the
artisan in Heide would be discouraged slightly from auxiliary stabilizing agents,
though inclusion of lecithin is disclosed (FF 1—2). Finally, we agree with Appellants
that requiring a comparison with clindamycin and lecithin, where Heide does not have
such an example, “would amount to requiring comparison of the results of the
invention with the results of the invention.” In re Chapman, 357 F.2d 418, 422
(CCPA 1966).
We also note that the comparative formulation tested in the Cuca Declaration
has, approximately, 38% water and 39% sorbitol, for a total “non-lipoidal phase” of
77%, as well as 2.7 % clindamycin, and the auxiliary stabilizing agent glyceryl
monoisostearate (FF 10). The Cuca Declaration provides sufficient evidence and
reasoning to establish that inclusion of lecithin in the formulation provides an
unexpected stability improvement in the composition (FF 11, 12, 14, 15) relative to
the formulation alone.
As we weigh this evidence of unexpected results focused on improved stability
of the specific active agent clindamycin in a specific aqueous amount in the water in
oil formulation with lecithin and auxiliary stabilizing agent with the prima facie case
of obviousness requiring selection of clindamycin from a list of active agents, a
different aqueous amount, lecithin and auxiliary stabilizing agents, we agree with
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Appellants that “the [Cuca] Declaration . . . provides evidence of unexpected results
sufficient to overcome any prima facie case of obviousness” (App. Br. 41).
Conclusion of Law
(i) The evidence of record supports the Examiner’s conclusion that the prior art
renders the claims prima facie obvious.
(ii) Appellants have presented evidence of secondary considerations, that when
weighed with the evidence of obviousness, is sufficient to support a final conclusion
of non-obviousness.
SUMMARY
In summary, we reverse the obviousness rejections.
REVERSED
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