Jernej Grmas et al.

Patent Trials and Appeals Board

Aug 15, 2019

14366900 - (D) (P.T.A.B. Aug. 15, 2019)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
14/366,900 06/19/2014 Jernej Grmas X20570 6994
25885 7590 08/15/2019
ELI LILLY & COMPANY
PATENT DIVISION
P.O. BOX 6288
INDIANAPOLIS, IN 46206-6288
EXAMINER
GOTFREDSON, GAREN
ART UNIT PAPER NUMBER
1619
NOTIFICATION DATE DELIVERY MODE
08/15/2019 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):
patents@lilly.com
PTOL-90A (Rev. 04/07)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte JERNEJ GRMAS, ZDENKA JERALA-STRUKELJ,
and SEBASTJAN REVEN 1
____________

Appeal 2019-001117
Application 14/366,900
Technology Center 1600
____________

Before JEFFREY N. FREDMAN, DEBORAH KATZ, and JOHN G. NEW,
Administrative Patent Judges.

NEW, Administrative Patent Judge.

DECISION ON APPEAL

1 Appellants identify the real party-in-interest as Elanco Tiergesundheit AG.
App. Br. 1.

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SUMMARY
Appellants file this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Final Rejection of claims 1–4 and 9–12 as unpatentable under
35 U.S.C. § 103(a) over J. Häggström et al., Effect of Pimobendan or
Benazepril Hydrochloride on Survival Times in Dogs with Congestive Heart
Failure Caused by Naturally Occurring Myxomatous Mitral Valve Disease:
The QUEST Study, 22 J. VET. INTERN. MED. 1124–1135 (2008)
(“Häggström”); S. Bangalore et al., Fixed-Dose Combinations Improve
Medication Compliance: A Meta-Analysis, 120 AM. J. MED. 713–719 (2007)
(“Bangalore”); Dhaliwal et al. (US 2008/0268049 A1, October 30, 2008)
(“Dhaliwal”); M. Gana et al., Kinetics of the acidic and enzymatic hydrolysis
of benazepril HCl studied by LC, 27 J. PHARMA. BIOMEDICAL ANALYSIS
107–116 (2002) (“Gana”); and P.N. Remya et al., , Formulation and
Evaluation of Bilayered Tablets of Ibuprofen and Methocarbamol, 2 INT’L J.
PHARMTECH RES. 1250–1255 (2010) (“Remya”).
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

NATURE OF THE CLAIMED INVENTION
Appellants’ invention is directed to a fixed dose combination
combining benazepril and pimobendan. Spec. 1.

REPRESENTATIVE CLAIM
Claim 1 is representative of the claims on appeal and recites:
1. A fixed dose combination comprising benazepril
hydrochloride and pimobendan in a ratio of 2:1,
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in the form of a bilayer tablet

wherein said benazepril is in a benazepril layer in the form of
benazepril pellets and

wherein said pimobendan is in a pimobendan layer in the form
of a granulate, and

wherein said benazepril layer comprises 2.5, 5 or 10 mg
benazepril hydrochloride, and

wherein said pimobendan layer comprises 1.25, 2.5 or 5 mg
pimobendan.

ISSUES AND ANALYSIS
We agree with, and expressly adopt, the Examiner’s findings,
reasoning, and conclusion that the claims would have been obvious over the
prior art. We address below the arguments raised by Appellants.

Issue 1
Appellants argue that the Examiner erred in finding a motivation to
co-administer benazepril and pimobendan. App. Br. 2.

Analysis
The Examiner finds that Häggström teaches treating heart failure in
dogs by administering pimobendan or benazepril hydrochloride. Final Act.
3 (citing Häggström pp. 1124–1125). The Examiner finds that Häggström
teaches administering pimobendan as 1.25 or 2.5 mg capsules twice per day
for a total dose of 0.4–06 mg/kg/day, and benazepril as 5 mg tablets
administered once per day for a total dose of 0.25/0.5 mg/kg. Id. at 4 (citing
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Häggström 1126). The Examiner acknowledges that Häggström does not
teach administering benazepril and pimobendan together or as a bilayer
tablet. Id.
The Examiner finds it would have been prima facie obvious to modify
Häggström to combine a pimobendan composition and a benazepril
composition into a single composition as both are useful for the same
purpose, i.e., for the treatment of congestive heart failure in dogs. Ans. 4.
The Examiner finds that “Bangalore provides additional motivation to
combine the two actives in a single dosage form by showing that doing so
enhances patient compliance relative to administering the two actives in
separate compositions.” Ans. 4; see also Bangalore 713, 716.
Appellants contend that “there is no teaching in Haggstrom that
benazepril and pimobendan should be coadministered in any fashion, let
alone in a bilayer dosage form.” Appeal Br. 2. Appellants contend that
“Haggstrom states that ‘[f]urther studies are required to address the impact
of combined pimobendan and ACEI [acetylchinesterase inhibitor]
therapy….’” Id. (citing Häggström 1134). Appellants argue that “the
skilled artisan would have derived no motivation to co-administer
pimobendan and benazepril hydrochloride in the claimed fixed dose
combination with an expectation of success.” Id.
We are not persuaded. We agree that Häggström teaches the
superiority of pimobendan monotherapy over benazepril monotherapy.
Häggström 1124. However, the test for obviousness is what the prior art as
a whole would have suggested to those of ordinary skill in the art. In re
Keller, 642 F.2d 413, 425 (C.C.P.A. 1981). Häggström teaches “the use of
pimobendan in conjunction with or in place of an ACE
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[acetylcholinesterase] inhibitor has been associated with an improvement in
both clinical signs and quality of life, and some measures of outcomes.” Id.
at 1125 (emphasis added). Benazepril was a well-known ACE inhibitor.
See Gana 107. Therefore, Häggström suggests using pimobendan in
conjunction with an ACE inhibitor, e.g., benazepril. Häggström also teaches
that the “study fails to address the potential benefit of the combined therapy
of pimobendan and an ACEI such as benazepril” and, as noted by
Appellants, recommends: “[f]urther studies are required to address the
impact of combined pimobendan and ACEI therapy.” Häggström 1134.
Häggström’s recommendation, along with the known anti-hypertensive
fixed-dose combinations taught by Bangalore (p. 713), establishes a
motivation to combine pimobendan and benazepril into a fixed combination
product. See Allergan, Inc. v. Sandoz Inc., 726 F.3d 1286, 1292 (Fed. Cir.
2013) (“When viewed under the proper standard, the evidence of record
establishes a motivation to combine brimonidine and timolol into a fixed
combination product. Not only does DeSantis teach the fixed combination
of timolol with an alpha2-agonist, numerous other references teach the fixed
combination of other ophthalmic drugs”). Accordingly, we are not
persuaded that the Examiner erred in finding that a person of ordinary skill
in the art would have been motivated to combine pimobendan and benazepril
in a fixed-dose combination.

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Issue 2
Appellants argue that the Examiner erred in finding a motivation to
produce a benazepril and pimobendan bilayer dosage form. App. Br. 3.

Analysis
The Examiner finds that Dhaliwal teaches a bilayer tablet comprising
benazepril hydrochloride and a second active ingredient, e.g., amlodipine.
Final Act. 4 (citing Dhaliwal ¶¶ 9, 13). The Examiner finds that Dhaliwal
teaches the bilayer tablet may include a layer containing one active agent in
pellet form, and separate layer containing the second active agent as a
granulate. Id. (citing Dhaliwal ¶¶ 7, 65–72). The Examiner finds that
Remya teaches the purpose of a bilayer tablet is to separate physically or
chemically incompatible compounds. Id. (citing Remya 1250). The
Examiner finds that Gana teaches benazepril hydrochloride is an ester
prodrug subject to hydrolysis. Id. (citing Gana 107). The Examiner further
cites Bergman et al. (GB 2394660 A, May 5, 2004) (“Bergman”) for
teaching that ACE inhibitors, e.g., benazepril, are susceptible to degradation
due to cyclization, hydrolysis and oxidation. Final Act. 8 (citing Bergman
pp. 1–3). The Examiner finds that although “the skilled artisan may not
have known for certain that placing the benazepril in its own layer would
enhance its stability, such a modification would have been ‘obvious to try’
based upon the teachings of Dhaliwal, Ghana [sic], and Remya.” Ans. 7.
Appellants contend that Dhaliwal teaches “benazepril and amlodipine
are physically incompatible. Hence, if incorporated into a single dosage
form they must be kept physically separated.” App. Br. 3 (citing Dhaliwal
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¶ 7). Appellants contend the physical incompatibility is due to the instability
of amlodipine and not benazepril. Id. (citing Dhaliwal ¶ 1). Appellants
argue that “there would be no motivation on the basis of Dhaliwal to develop
the form into a bilayer tablet simply by virtue of benazepril’s presence.” Id.
Appellants contend that Remya “provides no information on co-
formulating pimobendan and benazepril, or their compatibility or
incompatibility in a solid dosage form.” App. Br. 3–4. Appellants contend
that the art relied on by the Examiner does not support the “broad
proposition that benazepril would benefit in isolation from all other
ingredients in a dosage form, nor do they suggest that a compound with
pimobendan’s features would promote benazepril degradation.” Reply Br.
3. Appellants contend that the Examiner’s position dismisses the reality of
drug product development and that the skilled artisan would not incur the
complications and costs of a bilayer tablet, absent motivation to do so. Id.
We are not persuaded. As we explained supra, the Examiner has
identified a design need to combine benazepril and pimobendan as a fixed
dose combination. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 418
(2007). There was a finite number of identified, predictable solutions for
combining benazepril with a second drug in a fixed dose combination as
taught by Dhaliwal. See id. The prior art was not vague in pointing toward
a general approach or area of exploration, but rather guided the formulator
precisely to the use of a bilayer tablet. See Bayer Schering Pharma AG v.
Barr Laboratories, Inc., 575 F.3d 1341, 1350 (Fed. Cir. 2009) (“[T]he prior
art . . . guided the formulator precisely to the use of either a normal pill or an
enteric-coated pill”). “[W]hen a patent claims a structure already known in
the prior art that is altered by the mere substitution of one element for
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another known in the field, the combination must do more than yield a
predictable result.” KSR, 550 U.S. at 416. The Examiner identified a
bilayer tablet in the prior art that is altered by the mere substitution of
pimobendan as the second active agent in combination with benazepril.
Accordingly, we agree with the Examiner’s conclusion that the claims are
prima facie obvious, and we address whether the combination yields more
than a predictable result below.

Issue 3
Appellants argue the improved stability of benazepril hydrochloride in
the fixed dosage combination is unexpected. App. Br. 6.

Analysis
Appellants contend that the results of Table 2 of the Specification
“demonstrate that bilayer tablets of pimobendan and benazepril exhibit
superior stability compared to monolayer tablets comprising the same. The
bilayer tablets are more stable with respect to increases of benazepril
hydrolytic degradation product Impurity C.” App. Br. 6 (citing Spec. 14,
Table 2). Appellants argue that the prior art does not teach the combination
of pimobendan and benazepril nor any incompatibility between the
compounds. Id. Appellants argue that, therefore, the skilled artisan could
not have predicated the resulting improved stability. Id.
The Examiner finds that “once benazepril’s instability problems were
known, it would have been obvious to try to prevent its degradation by
isolating it from all other ingredients in a bilayer configuration.” Ans. 7.
The Examiner finds the Bergman:
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[W]ould have suggested to the skilled artisan that formulating the
benazepril hydrochloride in its own layer as part of a bilayer
tablet would protect it from interaction with any other ingredient
that could potentially promote cyclization, hydrolysis, and/or
oxidation, and would reasonably have expected that enhanced
stability would occur as a result. Therefore, the skilled artisan
would not have found the enhanced stability of the claimed
composition to be unexpected.

Ans. 8.
We agree with Appellants that the bilayer tablet provides superior
stability of benazepril compared to a monolayer tablet as shown by Table 2
of the Specification. However, we do not agree that the resulting superior
stability was unexpected. See Bristol-Myers Squibb Co. v. Teva Pharms.
USA, Inc., 752 F.3d 967, 977 (Fed. Cir. 2014) (“To 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, and that the
difference would not have been expected by one of ordinary skill in the art at
the time of the invention”).
In order to evaluate whether a superior property was unexpected, we
consider what properties were expected. Pfizer, Inc. v. Apotex, Inc., 480
F.3d 1348, 1372 (Fed. Cir. 2007). The prior art identified by the Examiner
teaches that benazepril was known to degrade by several routes, and was
previously formulated as a bilayer tablet to avoid incompatibility with a
second active agent. Moreover, Remya teaches that bilayer tablets were a
known solution for separating physically or chemically incompatible
ingredients. Although we agree with Appellants that the Examiner has not
shown that benazepril was known to be incompatible with pimobendan, we
do not agree that it was unexpected for the bilayer tablet to have superior
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stability compared to the monolayer tablet. Rather, the mere substitution of
pimobendan into the preexisting benazepril bilayer tablet yields the
predictable result of a stable formulation.
Moreover, “[a]lthough secondary considerations must be taken into
account, they do not necessarily control the obviousness conclusion.”
Pfizer, 480 F.3d at 1372. Here, the Examiner has established a strong case
of obviousness so that Appellants’ alleged unexpectedly superior results are
ultimately insufficient when considered with the case for obviousness. See
id. Accordingly, we affirm the Examiner’s rejection of the claim as obvious.
Appellants do not argue the claims separately, relying on their
arguments for claim 1. We consequently affirm the Examiner’s rejection of
claims 1–4 and 9–12.

DECISION
The Examiner’s rejection of claims 1–4 and 9–12 under 35 U.S.C.
§ 103(a) is affirmed.
No time period for taking any subsequent action in connection with this
appeal may be extended under 37 C.F.R. § 1.136(a)(l)(iv).

AFFIRMED