Ex Parte Henke et al

Patent Trial and Appeal Board

Sep 9, 2016

13803008 (P.T.A.B. Sep. 9, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR
13/803,008 03/14/2013
28515 7590 09/13/2016
MICHAEL P, MORRIS
BOEHRINGER INGELHEIM USA CORPORATION
900 RIDGEBURY RD
P. 0. BOX 3686
RIDGEFIELD, CT 06877-0368
Stefan Henke
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
ATTORNEY DOCKET NO. CONFIRMATION NO.
01-1138-US-4 7940
EXAMINER
BORI, IBRAHIM D
ART UNIT PAPER NUMBER
1629
NOTIFICATION DATE DELIVERY MODE
09/13/2016 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):
USPTO.e-Office.rdg@boehringer-ingelheim.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
BEFORE THE PATENT TRIAL AND APPEAL BOARD
Ex parte STEP AN HENKE, BERND KRUSS,
BERNHARD HASSEL, HANS-JUERGEN KROPF,
MARTIN A. FOLGER, KLAUS DANECK,
and AXEL PROX
Appeal2015-004163
Application 13/803,008
Technology Center 1600
Before DONALD E. ADAMS, JEFFREY N. FREDMAN, and
TA WEN CHANG, Administrative Patent Judges.
FREDMAN, Administrative Patent Judge.
DECISION ON APPEAL
This is an appeal 1 under 35 U.S.C. § 134 involving claims to a kit
comprising meloxicam. The Examiner rejected the claims as obvious. We
have jurisdiction under 35 U.S.C. § 6(b). We affirm.
1 Appellants identify the Real Party in Interest as Boehringer
Ingelheim Vetmedica, Inc. (see App. Br. 3).
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Application 13/803,008
Statement of the Case
Background
"The present invention relates to highly concentrated stable
meloxicam solutions for oral and parenteral administration, particularly for
treating respiratory diseases in large farm animals." (Spec. i-f 2).
The Claims
Claims 18-27 are on appeal. 2 Claim 18 is representative and reads as
follows:
18. A kit comprising:
packaging material; and
an aqueous, cyclodextrin-free solution comprising a
pharmacologically acceptable meloxicam salt of an organic
or inorganic base and one or more suitable excipients
comprising EDT A or an alkali metal salt thereof, wherein
the concentration of dissolved meloxicam salt is 11-25
mg/mL;
wherein the solution is contained in the packaging
material, and EDT A or an alkali metal salt thereof is
provided in a sufficient amount within the solution such that
the solution has a long term shelf-life in the packaging
material of at least 9 months at a temperature of about 25 °C.
2 Claims 1-17 were withdrawn as non-elected (see App. Br. 5).
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The Issue
The Examiner rejected claims 18-27 under 35 U.S.C. § 103(a) as
obvious over the combination of Stei, 3 Gerard, 4 Hermann, 5 and Daubert6
(Final Act. 4--10).
The Examiner finds that Stei teaches "that sufficient physical stability
of meloxicam solutions are achieved when meloxicam salts are form in situ
by adding appropriate base combined with appropriate excipient. Stei
teaches using molar or slightly hypermolar amount of the base, and teaches
meglumine as the base for salt formation" (Final Act. 6).
The Examiner acknowledges that Stei "does not teach long term
stability of aqueous meloxicam solution and use of EDT A" (Final Act. 7).
The Examiner finds that Gerard "teaches that chelating agents such as
EDT A can be used in achieving stability of oxicams during storage period"
and that meloxicam is a type of oxicam (Final Act. 7). The Examiner finds
that Hermann teaches "the use of EDT A and its salts for stabilizing solutions
of pharmaceutically applicable compounds" (id.). The Examiner finds that
Daubert teaches "closures for containers, including vials and the like,
containing liquid pharmaceutical medicaments" (Final Act. 8).
3 Stei et al., Local Tissue Tolerability of Meloxicam, a New
NSAID; Indications for Parenteral, Dermal and Mucosa!
Administration, 35 BR. J. RHEUMATOLOGY 44--50 (1996) ("Stei").
4 Shwadrohn, Gerard, WO 93/01814 Al, published Feb. 4, 1993
("Gerard") (We rely upon the machine translation and number the
pages sequentially).
5 Hermann Ruckendorfer and Philippus Egger, WO 98/09654 Al,
published Mar. 12, 1998 ("Hermann") (We rely upon the machine
translation and number the pages sequentially).
6 Daubert et al., US 5,891,129, issued Apr. 6, 1999 ("Daubert").
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The Examiner finds it obvious "to use EDT A as an excipient in order
to achieve long term storage stability of the meloxicam solution. This is
because the use of EDT A and its salts for stabilizing solutions of
pharmaceutically applicable compounds are known" (Final Act. 9).
The issues with respect to this rejection are:
(i) Does the evidence support the Examiner's conclusion that Stei,
Gerard, Hermann, and Daubert render claim 18 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. Stei teaches "clinically relevant concentrations of 10-20
mg/ml" for meloxicam and that "solutions of sufficient physical stability for
preclinical studies were yielded when a salt was formed in situ by adding
molar or slightly hypermolar amounts of an appropriate base combined with
an appropriate excipient to prevent hydrolysis" (Stein 44, col. 2).
2. Stei teaches that: "For the final formulation of meloxicam (15
mg/1.5 ml) for parenteral administration, meglumine was selected as the
base for salt formation in situ. The excipients used to prevent hydrolysis
were glycofurol and pluronic F68." (Stei 44, col. 2).
3. Stei teaches "Eye-drops. No ocular changes indicative of poor
ocular tolerance were evident following 4 weeks of treatment with
meloxicam (50 µl, doses up to 0.3% meloxicam)" (Stei 47, col. 2).
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4. Gerard teaches "[e]ye drops containing anti-inflammatory drugs
to inhibit the rise of intraocular pressure ... [wherein] [a ]nti-inflammatory
agent[s] suitable for this purpose include the Meloxicam" (Gerard 5).
5. Gerard teaches:
It may be advantageous to add to the mix, a complexing agent
[] for better stability of the molecule when the active ingredient
is sensitive to the presence of trace metals may promote its
degradation. Be used for this purpose ...
ethylenediaminetetraacetic acid . . . . The role of the chelating
agent is also to promote the complexation of divalent ions
(calcium, magnesium), which have an unfavorable influence on
the evolution of the dosage form during the storage period.
(Gerard 4--5).
6. Hermann teaches the "use of EDT A and its salts for stabilizing
solutions of pharmaceutically applicable compounds are known" (Hermann
3).
7. Hermann teaches "stability data after 3 6 months of storage with
lomoxicam lyophilized formulations prepared according to the basic
formulations in Example 1 (without EDT A disodium) and Example 2 (with
disodium EDTA)" (Hermann 4).
8. Daubert teaches that "[m]any pharmaceutical products are
delivered to pharmacies in sealed containers such as glass or plastic vials,
glass or plastic bottles, and flexible bags" (Daubert 1:31-33).
Principles of Law
"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'! Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
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Analysis
We adopt the Examiner's findings of fact and reasoning regarding the
scope and content of the prior art (Ans. 4--10; FF 1-8) and agree that the
claims are rendered obvious by the combination of Stei, Gerard, Hermann,
and Daubert. We address Appellants' arguments below.
Appellants contend that "the stability test data provided both in the
present application and in the Folger Declaration clearly show an
unexpected result, that the addition of EDT A in sufficient amounts provides
long term stability to high concentration (e.g., 11 mg/mL or greater)
meloxicam solutions (since meloxicam solutions not having EDTA do not
yield long term stability)" (App. Br. 11 ).
The Folger Declaration7 teaches an experiment where
high concentration meloxicam solutions that do not
include EDT A have been determined to become unstable when
stored for time periods much shorter than 18 months. In
particular, stability tests were conducted for meloxicam
solutions that do not include EDT A ....
Two meloxicam solutions having the above composition
were stored for 18 months at 25°C and 60% r.h. and for 7
months at 60°C and 60% r.h., respectively. Upon analysis of
the solutions after the storage period, a precipitation of particles
was observed for both solutions. The stability tests further
indicated that, when adding EDT A to the same meloxicam
solutions, these solutions remained stable over the same time
periods (i.e., no observance of particles within the solutions
after the same time periods elapsed).
(Folger Dec. i-f 8).
7 Declaration of Dr. Martin Andreas Folger, dated April 26, 2013.
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We do not find this argument persuasive because Gerard and
Hermann evidence that EDT A is a known stabilizing agent that would have
been expected to increase stability of compositions (FF 5-7) and Gerard
specifically suggests combinations of EDTA and meloxicam (FF 4). Thus,
that EDT A functions to stabilize the composition represents an expected
result, not an unexpected result. See In re Skoner, 517 F.2d 947, 950 (CCPA
1975) ("Expected beneficial results are evidence of obviousness of a claimed
invention. Just as unexpected beneficial results are evidence of
unobviousness. ")
Additionally, the evidence in the Folger Declaration is not
commensurate in scope with claim 18, because claim 18 only requires
stability for 9 months at 25 °C, while the Folger Declaration tested either 18
months at 25 °C or 7 months at 60 °C and the Specification only tests
stability for up to 24 days (see Folger Dec. i-f 8; Spec. i-f 35). The unexpected
results must be "commensurate in scope with the degree of protection sought
by the claimed subject matter." In re Harris, 409 F.3d 1339, 1344 (Fed. Cir.
2005).
Appellants contend that "a meloxicam solution as taught by Stei does
not yield solubility for long term periods of at least 18 months and at 25 °C"
(App. Br. 13); that the "use of the chelating agent appears to be limited to
the context in which is it applied as described by Gerard, which is in a
different type of solution than that which is claimed by the present
invention" (App. Br. 14); that "the solutions taught by Gerard are for
oxicam concentrations that appear to be much less than 10 mg/ml. . . . The
teachings of Gerard would not fairly teach or suggest to one having ordinary
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skill in the art ways to stabilize high concentrations of meloxicam" (App. Br
15); and that "Hermann also appears to teach concentrations of oxicam (in
this case, lomoxicam) in solution that are much lower in concentration in
relation to the high concentration meloxicam solutions of the claimed
invention" (App. Br. 16).
We are not persuaded because these arguments focus on whether each
of the references anticipates the claims, not whether the combination of
references renders the claims obvious. "Non-obviousness cannot be
established by attacking references individually where the rejection is based
upon the teachings of a combination of references." In re Merck & Co., 800
F.2d 1091, 1097 (Fed. Cir. 1986). In determining obviousness, furthermore,
a reference "must be read, not in isolation, but for what it fairly teaches in
combination with the prior art as a whole." Id.
It is the combination of Stei's teaching of a clinically relevant
meloxicam solution of 10 to 20 mg/ml as well as the need for physical
stability (FF 1-3) combined with the teachings of Gerard and Hermann that
EDT A is a known stabilizing agent that would have been expected to
increase stability of meloxicam compositions (FF 4--7) that renders the
claims obvious, not any single reference alone.
Appellants contend that "[ t ]here is no indication in the teachings of
Stei of a concern for degradation of the active ingredient (meloxicam) in
solution. Furthermore, as previously noted, Stei already teaches that
'sufficient physical stability' is already achieved ... thus not requiring
anything further to achieve such stability" (App. Br. 15). Appellants further
contend that "no rational explanation has been provided in the final Office
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Action to support a conclusion that there existed at the time of the invention
an apparent reason to modify the meloxicam solution taught by Stei to
include EDTA" (App. Br. 17).
We find these arguments unpersuasive because Stei's teaching of
"sufficient physical stability for preclinical studies" (FF 1) directly indicates
that stability is a concern, and further suggests that this stability is only
"sufficient" for preclinical studies, not for commercial distribution.
Moreover, Gerard's teaching to combine anti-inflammatory agents such as
meloxicam with stabilizing agents such as EDT A (FF 4--5) provides
additional suggestion that stabilization of agents is of general interest.
DyStar explains that the reason to combine need not be found in the
prior art, but may be implicit when the "'improvement' is technology-
independent and the combination of references results in a product or
process that is more desirable, for example because it is stronger, cheaper,
cleaner, faster, lighter, smaller, more durable, or more efficient." DyStar
Textilfarben GmbH & Co. Deutschland KG v. CH Patrick Co., 464 F.3d
1356, 1368 (Fed. Cir. 2006).
The use of stabilizing agents in drug formulations is such a
technology independent improvement that results in a more durable drug
formulation, providing implicit reasons to combine Stei with Gerard and
Hermann, further supporting the Examiner's obviousness determination that
a "skilled artisan desiring for a meloxicam solution that would exhibit long
term storage stability, would have followed the path of Stei in view of
Gerard and Hermann in order to arrive at a meloxicam solution comprising
EDTA" (Ans. 7).
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Appellants contend that
this rationale improperly utilizes impermissible hindsight and
reliance upon the teachings of the present application in the
presumption that Stei "does not teach long term stability of
aqueous meloxicam solution". Clearly, the implication to one
having ordinary skill in the art at the time of the present
invention is that a meloxicam solution "having sufficient
physical stability" as taught by Stei would remain stable once it
is formed
(App. Br. 18).
We are not persuaded. While we are fully aware that hindsight bias
may plague determinations of obviousness, Graham v. John Deere Co., 383
U.S. 1, 36 (1966), we are also mindful that the Supreme Court has clearly
stated that the "combination of familiar elements according to known
methods is likely to be obvious when it does no more than yield predictable
results." KSR, 550 U.S. at 416. In the instant case, Gerard and Hermann
evidence that EDT A is a known stabilizing agent that would have been
expected to increase stability of compositions (FF 5-7) and Gerard
specifically suggests combinations of EDTA and meloxicam (FF 4). These
teachings, when combined with Stei's teaching of a meloxicam composition
where stability is a relevant consideration (FF 1 ), reasonably supports the
Examiner's conclusion that the person of ordinary skill would have found
the instant claims obvious.
Conclusion of Law
(i) The evidence of record supports the Examiner's conclusion that
the combination of Stei, Gerard, Hermann, and Daubert renders claim 18
obvious.
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(ii) Appellants have not presented evidence of secondary
considerations, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of non-obviousness.
SUMMARY
In summary, we affirm the rejection of claim 18 under 35 U.S.C.
§ 103(a) as obvious over the combination of Stei, Gerard, Hermann, and
Daubert. Claims 19--27 fall with claim 18.
TIME PERIOD
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
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