DAEWOONG PHARMACEUTICAL CO., LTD.

Patent Trials and Appeals Board

Oct 15, 2020

2020001371 (P.T.A.B. Oct. 15, 2020)

UNITED STATES PATENT AND TRADEMARK OFFICE
UNITED STATES DEPARTMENT OF COMMERCE
United States Patent and Trademark Office
Address: COMMISSIONER FOR PATENTS
P.O. Box 1450
Alexandria, Virginia 22313-1450
www.uspto.gov
APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO.
14/388,115 09/25/2014 Hee-Chul Chang 068374-000029 1747
20230 7590 10/15/2020
Vorys, Sater, Seymour and Pease LLP
1909 K St., NW
9th Floor
WASHINGTON, DC 20006-1152
EXAMINER
TCHERKASSKAYA, OLGA V
ART UNIT PAPER NUMBER
1615
NOTIFICATION DATE DELIVERY MODE
10/15/2020 ELECTRONIC
Please find below and/or attached an Office communication concerning this application or proceeding.
The time period for reply, if any, is set in the attached communication.
Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the
following e-mail address(es):
patlaw@vorys.com
PTOL-90A (Rev. 04/07)
UNITED STATES PATENT AND TRADEMARK OFFICE
________________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
________________

Ex parte HEE-CHUL CHANG, BOK-KI KANG,
and JUN-KU KIM1
________________

Appeal 2020-001371
Application 14/388,115
Technology Center 1600
________________

Before ERIC B. GRIMES, JEFFREY N. FREDMAN, and JOHN G. NEW,
Administrative Patent Judges.

NEW, Administrative Patent Judge.

DECISION ON APPEAL

1 We use the word “Appellant” to refer to “applicant” as defined in
37 C.F.R. § 1.42. The Appellant identifies the real party in interest as
Daewoong Pharmaceutical Co., Ltd. Appeal Br. 3.
Appeal 2020-001371
Application 14/388,115
2
SUMMARY
Appellant files this appeal under 35 U.S.C. § 134(a) from the
Examiner’s Final Rejection of claims 33 and 36–42 as unpatentable under 35
U.S.C. § 103(a) as being obvious over the combination of Staab et al. (WO
2008/068217 A2, June 12, 2008) (“Staab”), Yada et al. (US 2010/0237530
A1, September 23, 2010) (“Yada ’530”), Yada et al. (US 2011/0038898 A1,
February 17, 2011) (“Yada ’898”), and Obara (US 6,380,381 B1, April 30,
2002) (“Obara”).2
We have jurisdiction under 35 U.S.C. § 6(b).
We AFFIRM.

NATURE OF THE CLAIMED INVENTION
Appellant’s claimed invention is directed to a pharmaceutical
composition having a single dosage form comprising a compartment
comprising olmesartan medoxomil; and a compartment comprising
rosuvastatin or its salt, wherein said compartments are formulated in a
separate form. Abstr.

REPRESENTATIVE CLAIM
Claim 33 is representative of the claims on appeal and recites:
33. A double-layer tablet comprising:

2 The Examiner also rejected claims 33–42 as unpatentable under 35 U.S.C.
§ 112, second paragraph, as indefinite. Final Act. 4. Claim 37 was also
rejected under 35 U.S.C. § 112, fourth paragraph, as being of improper
dependent form. Final Act. 8. These rejections were subsequently
withdrawn by the Examiner. Adv. Act. 2 (filed February 15, 2019).

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a first layer comprising olmesartan medoxomil as a single
active ingredient in an amount of 5 mg to 80 mg, and low-
substituted hydroxypropyl cellulose (L-HPC) as a disintegrant in
an amount of 19 wt.% to 21 wt.% based on the total weight of
the first layer, wherein the L-HPC contains 5 wt.% to 16 wt.% of
hydroxypropoxy[l] groups; and

a second layer comprising uncoated rosuvastatin or a salt
thereof as an active ingredient in an amount of 2 mg to 40 mg,
and a disintegrant selected from the group consisting of
crospovidone, L-HPC, croscarmellose sodium,
carboxymethylcellulose calcium and a mixture thereof, in an
amount of 2 wt.% to 20 wt.% based on the total weight of the
second layer, wherein the L-HPC contains 5 wt.% to 16 wt.% of
hydroxypropoxy[l] groups.

App. Br. 29.

ISSUES AND ANALYSES
We adopt the Examiner’s findings, reasoning, and conclusion that the
claims on appeal are prima facie obvious over the cited prior art. We
address the arguments raised by Appellant below.

Issue 1

Appellant argues that the Examiner erred because the prior art fails to
reveal any motivation for modifying the compositions taught by the prior art,
or any reason that would lead to the specific combination. App. Br. 10.

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Analysis
The Examiner finds that Staab teaches pharmaceutical compositions
comprising a HMG-CoA reductase inhibitor, e.g., rosuvastatin, in
combination with a renin angiotensin system inhibitor such as olmesartan.
Final Act. 9 (citing Staab 3–4, 6–7). The Examiner finds that Staab teaches
that these active ingredients can be located in different tablet layers that can
be compressed as tablet layers or may be filled in capsules as granules. Id.
(citing Staab Exs. 1–5). The Examiner finds that Staab teaches that the
layered tablets can be made in the form of tablets comprising a core of
HMG-CoA reductase inhibitor; or can be in form of bilayer tablet. Id.
(citing Staab 10, 13, 15).
The Examiner also finds that Staab teaches that the tablet layer
comprising the HMG-CoA reductase inhibitor may include 80 mg of that
active agent, and that the tablet layer comprising the renin angiotensin
system inhibitor may include 10–160 mg of the active compound. Final Act.
9 (citing Staab 11, 9). The Examiner finds that Staab teaches that the layers
may include a disintegrant, such as hydroxypropyl cellulose and other
cellulose derivatives, and/or crospovidone, in an amount of 1–20% of the
total weight of the layer. Id. at 10 (citing Staab 8, 12–13).
The Examiner further finds that Staab teaches that compositions
comprising the HMG-CoA reductase inhibitor (e.g., rosuvastatin) may also
include such diluents as dibasic calcium phosphate, lactose monohydrate,
and microcrystalline cellulose. Final Act. 10 (citing Staab 9–10).
The Examiner finds that Staab does not expressly teach compositions
including olmesartan medoxomil, or the use of low-substituted
hydroxypropyl cellulose. Final Act. 10. The Examiner finds, however, that
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Yada ’530 teaches formulations, including tablets, comprising olmesartan
medoxomil that can be used in combination with other active ingredients,
including rosuvastatin. Id. (citing Yada ’530 ¶¶ 8, 41, 39). The Examiner
finds that Yada ’530 further teaches that such formulations may include low-
substituted hydroxypropyl cellulose as a disintegrant that allows controlling
and/or improving the dissolution properties. Id. (citing Yada ’530 ¶ 30).
The Examiner finds that Yada ’530 provides an example of a formulation
comprising olmesartan medoxomil, and low-substituted hydroxypropyl
cellulose (“L-HPC”) in an amount of 12.5 wt%. Id. (citing Yada ’530
Example A-1, ¶ 54).
The Examiner also finds that Yada ’898 teaches formulations
comprising olmesartan medoxomil that provide controlled dissolution
properties and allows minimizing interactions between the olmesartan and a
second therapeutically active agent. Final Act. 10 (citing Yada ’898 Title,
Abstr., ¶¶ 14–15). To this point, the Examiner finds, Yada ’898 expressly
teaches the use of such disintegrants as L-HPC, croscarmellose sodium,
crospovidone, and carboxymethylcellulose calcium. Final Act. 10–11
(citing Yada ’898 ¶ 41). The Examiner finds that Yada ’898 provides
examples of formulations comprising olmesartan medoxomil and L-HPC) in
an amount of about 20 wt%. Id. at 11 (citing Yada ’898 Table 3).
Finally, the Examiner finds that Obara teaches L-HPCs having a
hydroxypropoxyl content of 5–16 wt% can be used in oral solid
pharmaceutical preparations for controlling the disintegration time of such
preparations, providing good granulation characteristics and tablet
properties. Final Act. 11 (citing Obara Abstr., col. 1, ll. 33–60, Table 1).
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The Examiner finds that Obara explicitly teaches the use of L-HPC in an
amount of 5-50% by weight. Id. (citing Obara col. 4, ll. 1–5).
The Examiner therefore concludes that it would have been obvious to
a person of ordinary skill in the art was made to use an inhibitor of the renin-
angiotensin system as olmesartan medoxomil and L-HPC as a disintegrant,
as taught by Yada ’530, Yada ’898, and Obara, in the layered tablets taught
by Staab. Final Act. 11. The Examiner reasons that a skilled artisan would
have been motivated to combine the teachings of the references, because the
artisan would have expected beneficial results, because the cited prior art
teaches that compositions including olmesartan medoxomil provide
controlled dissolution properties and allow minimizing interactions between
olmesartan medoxomil and a second therapeutically active agent, i.e.,
rosuvastatin. Id.
Appellant argues that Staab teaches a pharmaceutical composition
having a cholesterol-lowering agent in combination with an inhibitor of the
renin angiotensin system (RAS). App. Br. 11 (citing, e.g., Staab Abstr.).
Appellant asserts that these teachings of Staab constitute an extremely broad
disclosure, and cover a virtually unlimited number of drug combinations, not
to mention many possible types of formulations, excipients, combinations
thereof, and relative amounts. Id. Appellant points to certain embodiments
of Staab, in which the cholesterol-lowering agent may be a HMG-CoA
reductase inhibitor, such as a statin, for example, as specified in independent
claim 33. Id. However, Appellant asserts that Staab teaches that “[t]he
terms HMG-CoA reductase inhibitor and statin are referred to in the
description and the claims in a broad sense to include not only HMG-CoA
reductase inhibitors or statins per se but also their salts, solvates, derivatives,
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prodrugs, enantiomers, racemic mixtures, or polymorphs.” Id. (quoting
Staab 4; see also id. (“Additionally various available salts, solvates,
derivatives, prodrugs, enantiomers, racemic mixtures, or polymorphs of the
various HMG-CoA reductase inhibitors mentioned above may be used”)).
Furthermore, argues Appellant, Staab defines an inhibitor of the renin
angiotensin system (“RAS”) extremely broadly. App. Br. 11. In support of
this contention, Appellant points to Staab’s teaching that:
An “inhibitor of the renin-angiotensin system (RAS)” means any
compound which in itself or upon administration blocks the
negative effects of angiotensin II on the vasculature either by
reducing the synthesis of angiotensin II or blocking its effect at
the receptor. It includes pharmaceutically acceptable derivatives
or salts of said compounds. Inhibitors of the renin-angiotensin
system (RAS) known from the prior art include angiotensin
converting enzyme (ACE) inhibitors, angiotensin II antagonists,
also known as angiotensin receptor blockers (ARBs), renin
inhibitors, and vasopeptidase inhibitors (VPIs).

Id. at 11–12 (quoting Staab 7).
Appellant therefore contends that Staab teaches an extremely large
number of possible combinations, and provides no support for the
Examiner’s position that a skilled artisan would have made the specific
combination of olmesartan and rosuvastatin recited in the claims. App. Br.
12. By way of example, Staab teaches that the “preferred HMG-CoA
reductase inhibitor is simvastatin,” and the Examples of Staab relate to
agents such as simvastatin, telmisartan, or ramipril, but there is no teaching
to select either olmesartan medoxomil or rosuvastatin. Id.
Appellant also asserts that nothing in the other references cures this
alleged deficiency. Id. Specifically, Appellant contends that although Yada
’530 and Yada ’898 references may employ L-HPC in certain olmesartan
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medoxomil formulations, neither reference teaches or suggests the
combination with rosuvastatin at all, much less in a specific double-layer
tablet or with the specific amounts of L-HPC claimed. Id. at 14. Appellant
argues that Yada ’530 teaches that increased dissolution is due to the effects
of compression applied to the formulation. Id. (citing Yada ’530, e.g., ¶¶ 9,
10–15). Therefore, Appellant argues, a person of ordinary skill would not
have been directed to the use of L-HPC, much less the specific amount
recited in currently pending claim 33. Id. at 14-15.
Appellant points to the First Declaration of Hee-Chul Chang, filed
July 5, 2016 (the “First Chang Declaration”), one of the inventors of the
application on appeal. App. Br. 15. Appellant contends that, according to
Dr. Chang, the rate of dissolution of the prior art formulation, when
formulated as part of a bilayer tablet, was much lower than when compared
to a tablet according to Example A-1 of Yada ’530, which contained only
one active agent. Id. Therefore, Appellant argues, simply combining the L-
HPC from the formulations of Yada ’530 with Staab would not have led to a
successful formulation. Id.
Similarly, Appellant argues, Yada ’898 teaches that a calcium-
containing additive should be used for addressing the drug interaction of
olmesartan medoxomil with amlodipine contained in the same compartment
with hydrochlorothiazide. App. Br. 15. Appellant asserts that a person of
ordinary skill would not have had any reason to believe that the drug
interactions relating to an entirely different combination of drugs (having
different chemical structures and properties) would be applicable to the
claimed combination. Id. Furthermore, argues Appellant, at best Yada ’898
would have directed a skilled artisan to use a calcium-containing additive.
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Id. Appellant contends that, although L-HPC is used in some of the
examples, Yada ’898 does not direct a person of ordinary skill to select L-
HPC for the formulations of Staab, much less in the specific amounts recited
in claim 33. Id. Indeed, argues Appellant, Yada ’898 suggests Formula 7
(which uses 20% of L-HPC) has an unfavorable dissolution rate of
olmesartan medoxomil, and describes formulations having carmellose
calcium as disintegrant as providing favorable dissolution of olmesartan
medoxomil. Id. at 15–16. Appellant argues that Yada ’898 thus teaches
away from using L-HPC and instead would have directed the skilled artisan
to use carmellose calcium as the disintegrant. Id. at 16.
Appellant also argues that no reason is given by the Examiner with
respect to why a person of ordinary skill would have selected the specific
double-layer tablet having a first layer comprising olmesartan medoxomil
and a second layer comprising uncoated rosuvastatin, much less the
including the disintegrants that are recited in the claims, or the specific
amounts claimed. App. Br. 12.
Appellant argues further that drug development is a highly
unpredictable field, and it is not possible to predict, with any certainty,
which combinations or formulations will be successful. App. Br. 12.
Appellant asserts that there is nothing in the references that would have
directed a skilled artisan to specific combinations of drugs, much less
specific excipients or the relative amounts. Id. Furthermore, argues
Appellant, even if a skilled artisan had attempted to combine the references,
the prior art does not teach that there would have been a drug interaction
when the two active ingredients are formulated in combination in a same
layer or different layers, much less how to address such drug interaction. Id.
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Appellant argues that it would not have been “obvious to try” to
combine the teachings of the cited references to arrive at the claimed
invention. App. Br. 13 (citing Final Act. 15). Appellant argues that this is
because such an attempt at combination would have amounted to an
impermissible effort to “vary all parameters or try each of numerous possible
choices until one possibly arrived at a successful result, where the prior art
gave either no indication of which parameters were critical or no direction as
to which of many possible choices is likely to be successful.” Id. (quoting In
re Kubin, 561 F.3d 1351, 1359 (Fed. Cir. 2009)).
We are not persuaded by Appellant’s arguments. Staab is directed to
“a pharmaceutical composition comprising a coated HMG-CoA reductase
inhibitor…, an inhibitor of the renin angiotensin system, and optionally
further pharmaceutically acceptable excipients.” Staab 3. Staab also teaches
that “the present invention provides processes for the preparation of a
pharmaceutical composition wherein the inhibitor of the renin angiotensin
system and the HMG-CoA reductase inhibitor are comprised in different
tablet layers….” Id. at 13.
More specifically, Staab teaches: “According to the present invention
the various statins (HMG-CoA reductase inhibitors) that can be used
comprise lovastatin, simvastatin, pravastatin, mevastatin, fluvastatin,
cerivastatin, pitavastatin, rosuvastatin and atorvastatin. The preferred
HMG-CoA reductase inhibitor is simvastatin” (emphasis added) and further
notes that “various available salts, solvates, derivatives, prodrugs,
enantiomers, racemic mixtures, or polymorphs of the various HMG-CoA
reductase inhibitors mentioned above may be used.” Id. at 4. Staab thus
expressly includes rosuvastatin as one of the relatively limited number of
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named HMG-CoA reductase inhibitors that can be used in its invention.
Although Staab teaches that simvastatin is the preferred HMG-CoA
reductase inhibitor, rosuvastatin is named as a useable constituent, and “all
disclosures of the prior art, including unpreferred embodiments, must be
considered.” Merck & Co., Inc. v. Biocraft Labs., Inc., 874 F.2d 804, 807
(Fed. Cir. 1989) (quoting In re Lamberti, 545 F.2d 747, 750 (C.C.P.A.
1976)).
Furthermore, Staab teaches that:
In a preferred embodiment of the present invention there is
provided a dosage unit or tablet layer preferably comprising from
5 mg to 80 mg of simvastatin or any suitable HMG-CoA
reductase inhibitor and preferably a dosage amount selected
from 10 mg, 20 mg and 40 mg of simvastatin. Further the total
weight of the single dosage unit of statin is identical for all
strengths such as 150-250 mg.

Staab 11 (emphasis added). Staab thus teaches the use of a concentration of
5–80 mg of a suitable HMG-CoA inhibitor (including rosuvastatin), which
largely overlaps the range of “2mg to 40 mg” of “rosuvastatin or a salt
thereof” recited in claim 33.
Staab also teaches the use of:
An “inhibitor of the renin-angiotensin system (RAS)” means any
compound which in itself or upon administration blocks the
negative effects of angiotensin II on the vasculature either by
reducing the synthesis of angiotensin II or blocking its effect at
the receptor. It includes pharmaceutically acceptable derivatives
or salts of said compounds.… Examples of angiotensin II
antagonists which can be used in a fixed dose combination with
statins are candesartan, candesartan cilexetil, eprosartan,
irbesartan, losartan, olmesartan, telmisartan and valsartan.

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Staab 7 (emphasis added). Staab also teaches the use of olmesartan as an
inhibitor of the renin-angiotensin system. Although Staab does not
expressly teach “olmesartan medoxomil” as an active agent, as recited in
claim 33, “olmesartan” and “olmesartan medoxomil” are used
interchangeably by those of skill in the art, and refer to the same drug, with
“olmesartan” being the brand name, as manufactured by Daiichi Sankyo,
Inc. See The Marshall Protocol Knowledge Base, Olmesartan (Benicar),
available at: https://mpkb.org/home/mp/olmesartan (last visited September
25, 2020).
With respect to the concentration of RAS inhibitor employed, Staab
teaches using “10–160 mg, and preferably 20–80 mg or 40–80 mg
telmisartan, a comparable RAS inhibitor.” Furthermore, Yada ’530 teaches
that “[a]lthough its [i.e., olmesartan medoxomil’s] dosage amount varies
depending on the symptoms, age and the like, an adult human is generally
administered orally with 5 to 40 mg, once a day. Preferably, a tablet
containing 5 mg, 10 mg, 20 mg or 40 mg is administered orally once a day.”
Yada ’530 ¶ 51. Similarly, Yada ’898 teaches that “[o]lmesartan medoxomil
is marketed as OLMETEC (registered trademark) tablets or Benicar(R), and
these contain 5 mg, 10 mg, 20 mg, or 40 mg of olmesartan medoxomil as
active ingredient.” Yada 898 ¶ 5. All of these teachings are encompassed
by “olmesartan medoxomil … in an amount of 5 mg to 80 mg,” as recited in
claim 33.
With respect to the disintegrants in the HMG-CoA reductase inhibitor
layer, claim 33 recites: “a disintegrant selected from the group consisting of
crospovidone, L-HPC, croscarmellose sodium, carboxymethylcellulose
calcium and a mixture thereof, in an amount of 2 wt.% to 20 wt.% based on
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the total weight of the second layer, wherein the L-HPC contains 5 wt.% to
16 wt.% of hydroxypropoxy[l] groups.” Staab teaches that the HMG-CoA
reductase inhibitor layer is made by:
(a1) coating an HMG-CoA reductase inhibitor with a solution of
polymer and subsequently adding antioxidant and suitable
excipients to form a premix; or

(a2) coating an HMG-CoA reductase inhibitor with a solution of
polymer and antioxidant and subsequently adding suitable
excipients to form a premix; or

(a3) coating a mixture of HMG-CoA reductase inhibitor and
antioxidant with a solution of polymer and subsequently adding
suitable excipients to form a premix.

Staab 13–14. Staab teaches that suitable excipients of the HMC-CoA
reductase inhibitor layer may include: “a diluent, binder, disintegrant,
lubricant/glidant, chelating agent and coloring agent.” Staab 12.
Specifically, Staab teaches that:
Suitable disintegrants may include one or more of but not limited
to hydroxypropyl cellulose, carboxymethylcellulose, calcium
carboxymethylcellulose, sodium carboxymethylcellulose,
croscarmellose sodium, starch crystalline cellulose, sodium
starch glycolate, hydroxypropyl starch, partly pregelatinized
starch, crospovidone and equivalents thereof. Suitably the
disintegrants may be present in a quantity ranging from 1 to 20%
w/w relative to the total weight of the statin layer, preferably 5 to
20% w/w. The preferred disintegrant is Croscarmellose sodium.

Staab 13 (emphases added for species corresponding to those recited in
claim 33); see also id. Examples 2, 3. Claim 33 also recites weight
percentages of disintegrant in an amount of 2 wt.% to 20 wt.%, which is
within the 1–20% by weight concentrations taught by Staab.
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With respect to the RAS inhibitor layer, claim 33 requires: “low-
substituted hydroxypropyl cellulose (L-HPC) as a disintegrant in an amount
of 19 wt.% to 21 wt.% based on the total weight of the first layer.” Staab
teaches that, in addition to the active agent, “other excipients and adjuvants
from binders, carriers, fillers, lubricants, flow control agents, crystallization
retarders, solubilizers, coloring agents, pH control agents, surfactants and
emulsifiers” may be included. Staab 8 (see also claim 19). However, Staab
is otherwise silent as to what may constitute these excipients.
Yada ’530 is directed to “an olmesartan medoxomil-containing drug
product having an improved dissolution property.” Yada ’530 ¶ 8. Yada
’530 also teaches that “in the present invention, other active ingredients may
be included if necessary. As for such active ingredients, there can be
mentioned for example,… HMG-CoA reductase inhibitors such as
Pravastatin, Simvastatin, Atorvastatin, Rosuvastatin, Cerivastatin,
Pitavastatin and Fluvastatin.” Id. ¶ 39.
Specifically, Yada ’530 teaches that, in its compositions: “As for the
‘disintegrants’ used, cellulose derivatives such as low-substituted
hydroxypropyl cellulose [i.e., L-HPC], carboxymethyl cellulose, calcium
carboxymethyl cellulose or internally crosslinked sodium carboxymethyl
cellulose; crosslinked polyvinylpyrrolidone; or chemically modified
starches/celluloses such as carboxymethyl starch or sodium carboxymethyl
starch can be mentioned.” Yada ’530 ¶ 30 (emphasis added). Furthermore,
Example A-1 of Yada ’530 demonstrates, in Table A, a 20 mg dosage of
olmesartan medoxomil combined with, inter alia, 20 mg of L-HPC as a
disintegrant. Id. ¶ 54. The total mass of the formulation of Table A is 160
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mg, which yields a concentration of L-HPC of 12.5 wt%, which is somewhat
less than the range recited in claim 33.
Yada also teaches combination drugs with olmesartan medoxomil and
amlodipine as active agents. Yada ’898 Abstr. Yada ’898 also teaches that,
in its compositions “[e]xamples of ‘disintegrants’ that may be used include
cellulose derivatives such as low-substituted hydroxypropyl cellulose [i.e., L-
HPC], carboxymethyl cellulose, carboxymethyl cellulose calcium, or
croscarmellose sodium; crospovidone; or chemically modified starches or
celluloses such as carboxymethyl starch or carboxymethyl starch sodium.”
Id. ¶ 41 (emphasis added). Formulation 7 of Yada ’898’s Table 3
demonstrates a composition of olmesartan medoxomil (40 mg) and
amlodipine with L-HPC at 20 wt% (84 mg out of 420 mg).
In summary, both Yada ’530 and Yada ’898 teach that L-HPC is a
suitable disintegrant for combination therapies including olmesartan
medoxomil and (in the case of Yada ’530) rosuvastatin, an HMG-CoA
reductase inhibitor, as claimed. The wt% values for L-HPC in the
exemplary formulation of Yada ’898 (20 wt%) is within the concentration
range of “19 wt.% to 21 wt.%” recited in claim 33. Moreover, because the
relative concentration of a disintegrant is a result-effective variable,
determining the rate of disintegration of the composition, we find that a
skilled artisan would be able to optimize the concentration of L-HPC within
the ranges recited by the combined references and claim 33.
With respect to the study reported by the First Chang Declaration, the
Declaration describes a study comparing the dissolution rates of:
Tablet A, containing the ingredients of Formulation A [of
Example A-1 of Yada ’530], but in an increased amount to
correspond to the formulation of Example 1 in the present
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application for comparison purposes. The other one is Tablet B,
containing the formulation of Tablet A as the compartment [i.e.,
the layer] for olmesartan medoxomil in the formulation of
Example 1 in the present application. Tablet A was prepared
according to the method described in Example A-1 of Yada et al.
Tablet B was prepared to a bilayer tablet according to the method
of Example 1 in the present application but with no coating[,] for
comparison purposes.

First Chang Decl. ¶ 5. The relative formulations of Tablet A and B is
reproduced below:
Tablet A
Formulation A Tablet A
Olmesartan medoxomil 20 mg 40 mg
Lactose 106 mg 212 mg
L-HPC 20 mg 40 mg
HPC-L 3 mg 6 mg
Avicel 10 mg 20 mg
Magnesium stearate 1 mg 2 mg

Tablet B

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Id. ¶ 6. The First Chang Declaration compares the dissolution rates of
Tablets A and B as depicted below:

Id. ¶ 7. The First Chang Declaration states that these values demonstrate
that the dissolution rate of Tablet B is significantly lower than the
dissolution rate of Tablet A, indicating that olmesartan medoxomil and
rosuvastatin, when combined into a single formulation, show a drug
interaction or interference in dissolution. Id. ¶ 8.
We are not persuaded of the relevance of this demonstration. As an
initial matter, Yada ’530 expressly teaches formulations combining
olmesartan medoxomil and rosuvastatin, and not merely olmesartan
medoxomil as the sole active agent. See Yada ¶ 39. Furthermore, Staab
teaches a layered combination tablet formulation of olmesartan and
rosuvastatin, with crospovidone and croscarmellose sodium as disintegrants
in the latter layer. Both Yada references teach that L-HPC is a suitable
disintegrant for olmesartan medoxomil and Yada ’898 teaches use of a
concentration of L-HPC within the range recited in claim 33. The First
Chang Declaration’s conclusion that “olmesartan medoxomil and
rosuvastatin, when combined into a single formulation, show a drug
interaction or interference in dissolution” when compared to a formulation
containing only olmesartan medoxomil, has little relevance when compared
to the combined teachings of the cited prior art references, which teach all
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the elements of Tablet B in the experiment described in the First Chang
Declaration.
Summarizing, we find that the combined references teach or suggest
all of the limitations of the claims and that the experiments described in the
First Chang Declaration are not relevant in showing that claim 33 is
nonobvious over the cited prior art.

Issue 2
Appellant argues that the Examiner erred because a person of ordinary
skill in the art would have had no reasonable expectation of success in
combining the references. App. Br. 17.

Analysis
Appellant argues that, because biological and pharmacokinetic
properties are unpredictable, it would not have been possible for a person of
ordinary skill in the art to reasonably expect that simply combining a
formulation of Staab with one of the many components in the compositions
from the secondary references would have been successful. App. Br. 18.
Appellant contends that none of the cited references teach the behavior of
both drugs in a single composition. Id.
Appellant points to the Second Declaration of Dr. Chang, filed
September 10, 2018 (the “Second Chang Declaration”) as explaining that, in
developing the claimed double-layer tablets, the inventors overcame two
previously unknown technical problems involving this specific drug
combination. App. Br. 18. These problems were (1) absorption of
rosuvastatin in the gastrointestinal membrane was inhibited due to the delay
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in dissolution caused by drug-drug interaction between rosuvastatin and
olmesartan medoxomil; and (2) the dissolution profile of olmesartan
medoxomil, which is pharmaceutically equivalent to the reference
(OLMETEC™), was unexpectedly found biologically non-equivalent to the
reference tablet, when administered to a patient. Id. (citing Second Chang
Decl. ¶¶ 5–6). According to Appellant, the inventors invested much time,
due to these issues, in the research and development of a formulation that
would meet the standards for bioequivalence, while providing the
olmesartan medoxomil and rosuvastatin in a double-layered tablet
formulation. Id.
We do not find this argument persuasive. As an initial matter, Staab
teaches a layered formulation that possesses all of the structural limitations
of independent claim 33, except for the use of L-HPC as a disintegrant in the
olmesartan medoxomil layer at the claimed concentration range. As we
have explained, the Yada references teach this limitation.
More importantly, the reasons for the difficulty in arriving at the
claimed composition argued by Appellant, are functional reasons related to
the olmesartan-rosuvastatin drug interactions and dissolution rates. Neither
of these functional properties are recited in claim 33, which is purely
structural in its limitations. As such, Appellant’s arguments are not
commensurate with the scope of the claims, and are not persuasive.

Issue 3
Appellant argues that the Examiner erred in ignoring evidence that the
references teach away, and of unexpected results. App. Br. 20.

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Analysis
Appellant contends that, according to conventional standards, when
developing a formulation that could be regarded as pharmaceutically
equivalent to the reference formulation (i.e., OLMETEC™ tablet), the
skilled artisan would have been aware that “two requirements should be
satisfied in order to meet the pharmaceutical equivalence criteria of the
applicable [Korean] Pharmaceutical Affairs Law.” Id. at 20–21 (quoting
Spec. ¶ 76, alteration in original). Specifically, Appellant asserts that:
[W]here the dissolution rate of a reference formulation (i.e.,
Olmetec™ tablet) in water for the defined time (i.e., 6 hours) is
below 85%, the following two requirements should be satisfied
in order to meet the pharmaceutical equivalence criteria of the
applicable [Korean] Pharmaceutical Affairs Law: the first
requirement that the dissolution rate of the test formulation for 6
hours is located between the dissolution rate of the reference
formulation (i.e., Olmetec™ tablet) ± l5% (i.e., 36.13 to
66.13%); and the second requirement that the dissolution rate
thereof for 5 minutes (the nearest time to the time for attaining to
about ½ (i.e., 25.5%) of the dissolution rate of the reference
formulation for 6 hours) is located between the dissolution rate
of the reference formulation ± l5% (i.e., 6.30 to 36.30%).

Id. at 21 (quoting Spec. ¶ 76).
Appellant argues that, when formulations meeting these conventional
requirements were tested, they did not provide pharmaceutical equivalence
to the reference formulation (i.e., OLMETEC™ tablet). Id. (citing Spec.
¶¶ 81–82). According to Appellant, the inventors unexpectedly found that
the specific tablet claimed causes the tablet to have a dissolution rate over
15% higher than the reference listed tablet, making it pharmaceutically
inequivalent and thereby expected to be not bio-equivalent. Id.
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We are not persuaded. “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.” Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc., 752
F.3d 967, 977 (Fed. Circ. 2014). OLMETEC™, the so-called reference
drug, contains only a salt of olmesartan medoxomil as its active agent,
whereas the claimed composition is a layered tablet containing olmesartan
medoxomil and rosuvastatin as active agents in the respective layers.
The closest prior art in the present case is either Yada ’898 or Staab.
Staab teaches a layered tablet composition containing olmesartan and
rosuvastatin in separate layers. Yada ’898 teaches a two drug combination
(olmesartan medoxomil and amlodipine besylate) in which the L-HPC
content is 20 wt%, which is within the 19–21 wt% range recited in claim 33.
Absent any evidence that the claimed composition exhibits unexpected
properties compared to those of the layered tablet compositions of Staab, we
do not find the Second Chang Declaration probative of non-obviousness.
Furthermore, even standing upon its own merits, we do not find the
data presented in the Second Chang Declaration to be probative of
nonobviousness. Table 13 of the Second Chang Declaration is reproduced
below:
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Although we acknowledge Dr. Chang’s point that Example 4-1, with
5 wt% L-HPC was found to be pharmaceutically equivalent to the
OLMETECTM reference tablet, we also note that even slightly greater
concentrations of L-HPC, e.g., 7.5 wt%, well outside the claimed range of
19–21%, also show results that are pharmaceutically non-equivalent, and
comparable to that of the claimed range. In sum, we find the differences
between the claimed range and weight percentage values outside of the
range to be differences in degree, rather than kind, as is required to
demonstrate unexpected results. See Iron Grip Barbell Co. v. USA Sports,
Inc., 392 F.3d 1317, 1322 (Fed. Cir. 2004) (holding that unexpected results
that are probative of nonobviousness are those that are “different in kind and
not merely in degree from the results of the prior art”).

Issue 4
Appellant argues that the Examiner erred in failing to properly
consider the First and Second Chang Declarations. App. Br. 23. We
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disagree. As we have explained, both the First and Second Chang
Declaration fail to demonstrate that the properties of the claimed
composition are unexpected in comparison with the combined teachings of
the cited prior art references, particularly Yada ’898 and Staab.
We consequently affirm the Examiner’s rejection of the claim 33.
Furthermore, because Appellant argues all of the claims together, we
similarly affirm the Examiner’s rejection of claims 36–42.

CONCLUSION
The Examiner’s rejection of claims 33 and 36–42 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)(1).

AFFIRMED
Claims
Rejected
35
U.S.C. §
Reference(s)/Basis Affirmed Reversed
33, 36–42 103(a) Staab, Yada’503,
Yada ’898, Obara

33, 36–42