Ex Parte Folli et al

Board of Patent Appeals and Interferences

May 21, 2010

10868227 (B.P.A.I. May. 21, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte FRANCO FOLLI,
PAOLO MANFREDI, and GILBERT GONZALES
__________

Appeal 2010-000183
Application 10/868,227
Technology Center 1600
__________

Decided: May 24, 2010
__________

Before DONALD E. ADAMS, LORA M. GREEN, and
JEFFREY N. FREDMAN, Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION ON APPEAL
This is a decision on appeal under 35 U.S.C. § 134 from the
Examiner’s rejection of claims 1, 3-5, 9, 25, 27-29, 33, 46, and 47.1 We
have jurisdiction under 35 U.S.C. § 6(b).

1 Claims 6, 7, 10, 11, 13-24, 30, 31, 34, 35, and 37-45 stand withdrawn from
consideration. (App. Br. 2.)

Appeal 2010-000183
Application 10/868,227

STATEMENT OF THE CASE
The claims are directed to a composition and a method of using the
composition for treating obesity. Claims 1, 25, 46 and 472 are representative
of the claims on appeal, and read as follows:

1. A composition for treatment of obesity comprising metformin; a lipid
lowering agent; and a blood pressure reducing agent
wherein said blood pressure lowering agent is selected from the group
consisting of renin angiotensin system inhibitors, beta-blockers, diuretics,
calcium channel antagonists, and combinations thereof; and
wherein said blood lipid lowering agent is selected from the group
consisting of hydroxymethylg[l]utaryl coenzyme A reductase inhibitors, bile
acid sequestrants, probucol and fibric acid agents.

25. A method of treating an individual diagnosed with obesity comprising
administering to said individual a single dose medicine said medicine
including metformin; a lipid lowering agent; and a blood pressure reducing
agent
wherein said blood lipid lowering agent is selected from the group
consisting of hydroxymethylg[l]utaryl coenzyme A reductase inhibitors, bile
acid sequestrants, probucol and fibric acid agents; and
wherein said blood pressure lowering agent is a renin angiotensin
system inhibitor selected from the group consisting of angiotensin
converting enzyme inhibitors, angiotensin II receptor antagonists, renin
inhibitors, and combinations thereof.

46. A composition for treatment of obesity comprising lisinopril,
simvastatin and metformin.

47. A method of treating an individual diagnosed with obesity comprising
administering to said individual a single dose medicine said single dose
medicine comprising lisinopril, simvastatin and metformin.

2 Claims 46 and 47 were chosen as representative as they represent the
elected species. (Ans. 5.)
2
Appeal 2010-000183
Application 10/868,227

We affirm.

ISSUES
Does the preponderance of evidence of record support the Examiner’s
conclusion that the combination of Gaebe, Zimmet, and Hunninghake, as
combined with Abbott or Sevak render the claimed composition and method
of using the composition in the treatment of obesity obvious?
If yes, have Appellants provided evidence of unexpected results,
which when weighed with the evidence of obviousness, is sufficient to
support a conclusion of nonobviousness?

FINDINGS OF FACT
FF1 The Specification notes that “[o]besity, the Metabolic Syndrome (also
referred to as Syndrome X), and Type II Diabetes Mellitus, are very much
interrelated.” (Spec. 1.) The Specification notes further 80% of the people
suffering from Type II Diabetes are obese. (Id.)
FF2 The Specification teaches that compliance of patients with diabetes
taking multiple pills is a “critical problem” and thus “reducing the number of
pills, or, in other words, combining drugs into a single dosage will greatly
improve compliance.” (Id. at 4.)
FF3 In the experimental study presented in the Specification, mice were
given saline, a placebo, 0.015 ml of formula I, or 0.03 ml of formula I. (Id.
at 16.) Formula 1 contains metformin, aspirin, simvastatin, lisinopril, folic
acid, vitamin B6 and vitamin B12 in specified amounts. (Id. at 13.)
3
Appeal 2010-000183
Application 10/868,227

FF4 The Specification notes that there were no signs of liver or kidney
toxicity, and the weight for the mice given formula 1 were lower than those
mice given saline or the placebo (Id. at 17.)
FF5 The Examiner rejects claims 1, 3-5, 9, 25, 27-29, 33, 46, and 47 under
35 U.S.C. § 103(a) as being rendered obvious by the combination of Gaebe,3
Zimmet,4 and Hunninghake,5 as combined with Abbott6 or Sevak.7 (Ans.
5.) As Appellants do not argue the claims separately, we focus our analysis
on claim 1 as representative of the composition claims, and claim 25 as
representative of the method claims.
FF6 We adopt the Examiner’s findings as to each of the Gaebe, Zimmet,
Hunninghake, Abbott and Sevak references as our own. (See id. at 5-10.)
We also make the following findings.
FF7 Gaede teaches that there are multiple modifiable risk factors for
complications in patients with type II diabetes, including hyperglycemia,

3 Gaede et al., Multifactorial Intervention and Cardiovascular Disease in
Patients with Type 2 Diabetes, 348 THE NEW ENGLAND JOURNAL OF
MEDICINE 383-393 (2003).
4 Paul Zimmet and Greg Collier, Clinical Efficacy of Metformin against
Insulin Resistance Parameters Sinking the Iceberg, 58 DRUGS 21-28 (1999).
5 Hunninghake et al., Comparative Effects of Simvastatin and Atorvastatin in
Hypercholesterolemic Patients with Characteristics of Metabolic Syndrome,
25 CLINICAL THERAPEUTICS 1670-86 (2003).
6 Abbott et al. Treatment of the diabetic patient: focus on cardiovascular
and renal risk reduction, 139 PROGRESS IN BRAIN RESEARCH 289-98 (2002);
Abstract.
7 Ashish R. Sevak and Ramesh K. Goyal, Effects of Chronic Treatment with
Lisinopril on Cardiovascular Complications in Streptozotocin Diabetic and
DOCA Hypertensive Rats, 34 PHARMACOLOGICAL RESEARCH 201-209
(1996); Abstract.
4
Appeal 2010-000183
Application 10/868,227

hypertension, and dyslipidemia. (Gaede 384.) Based on that, Gaede teaches
that guidelines such as those from the American Diabetes Association
recommend an intensified, multifactorial treatment approach. (Id.)
FF8 Gaede teaches that obese patients were given metformin, all patients
were prescribed an angiotensin-enzyme inhibitor or an angiotensin II
receptor antagonist. (Id. at 385.) Also, if patients were hypertensive, Gaede
teaches that thiazides, calcium-channel blockers, and beta blockers were
added as needed. (Id.) Gaede teaches that fibrates could be added to treat
hypertriglyceridemia. (Id.)
FF9 According to Gaede, long term, intensified intervention involving
multiple risk factors reduced the risk of cardiovascular events among
patients with type II diabetes and microalbuminuria. (Id. at 389.) Gaede
notes that serious adverse events were few. (Id. at 391.)
FF10 Thus, Gaede teaches the use of one or more of oral hypoglycemic
agents, such as metformin, antihypertensive treatment, and lipid-lowing
treatment, such as statins and fibrate, in the treatment of patients with type II
diabetes. (See, e.g., id. at 387, Table 2.)
FF11 Zimmet teaches that type II diabetes “is part of a cluster of
cardiovascular risk factors known as the metabolic syndrome.” (Zimmet,
Abstract.) Thus, treatment requires not only agents that lower blood glucose
levels, as well as “a therapy with both antihyperglycaemic effects and
beneficial effects on dyslipidaemia, hypertension, obesity,
hyperinsulinaemia and insulin resistance is likely to be most useful.” (Id.)
FF12 Zimmet teaches with respect to metformin, that metformin “has been
shown to lower blood glucose and triglyceride levels in plasma without
5
Appeal 2010-000183
Application 10/868,227

causing hypoglycaemia, to assist with weight reduction and to reduce
hyperinsulinaemia and insulin resistance.” (Id. at 24.)
FF13 Hunninghake teaches that both simvastatin and atorvastatin can be
used in hypercholestemic patients with metabolic syndrome, and that the
patients metabolic syndrome status was effectively modified by both drugs.
(Hunninghake, Abstract.)
FF14 Both Abbott and Sevak teach the use of lisinopril in the treatment of
hypertension in subjects with diabetes, with Sevak teaching that lisinopril
“may be considered as one of the drugs of choice in treatment of
hypertension when it is associated with diabetes mellitus.” (Sevak, page 2 of
2).

PRINCIPLES OF LAW
In KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 415 (2007), the
Supreme Court rejected a rigid application of a teaching-suggestion-
motivation test in the obviousness determination. The Court emphasized
that “the [obviousness] analysis need not seek out precise teachings directed
to the specific subject matter of the challenged claim, for a court can take
account of the inferences and creative steps that a person of ordinary skill in
the art would employ.” Id. at 418; see also id. at 421 (“A person of ordinary
skill is also a person of ordinary creativity, not an automaton.”). “The
combination of familiar elements according to known methods is likely to be
obvious when it does no more than yield predictable results.” Id. at 416. “If
a person of ordinary skill can implement a predictable variation, § 103 likely
bars its patentability.” Id. at 417.
6
Appeal 2010-000183
Application 10/868,227

The burden of demonstrating unexpected results rests on the party
asserting them, and “it is not enough to show that results are obtained which
differ from those obtained in the prior art; that difference must be shown to
be an unexpected difference.” In re Klosak, 455 F.2d 1077, 1080 (CCPA
1972). “[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 re Baxter Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991).

ANALYSIS
Appellants assert that while the references relied upon by the
Examiner describe all of the components of the composition of claim 1, they
“fail to disclose the combined composition as one pill (a polypill).” (App.
Br.8 6.) According to Appellants, such a polypill has many advantages, such
as increased patient compliance, and may be widely prescribed to patients
who are obese, prediabetic. (Id.) Appellants assert further that the “pill
treats hypoglycemia but does not induce hypoglycemia in patients not
already hyproglycemic.” (Id.) Appellants assert that the pill requires
metformin, which was chosen because “it is the only available drug that
increases insulin sensitivity (i.e. the ability of insulin to stimulate glucose
metabolism) without causing hypoglycemia.” (Id. at 7.) Appellants assert
that its use composition results in “a highly effective composition that can be
safely prescribed to a large population of patients.” (Id. at 7-8.)

8 All references to the Appeal Brief are to the “Revised Brief on Appeal,”
dated January 15, 2009.
7
Appeal 2010-000183
Application 10/868,227

Appellants argue that none of the references “teach treating obesity
per se with a single composition.” (Id. at 8.) Appellants assert that Gaede
actually teaches away from the claimed invention, as it does not teach a
polypill, and is drawn to a clinical trial. (Id. at 9.) Thus, Appellants assert,
all the patients were already diagnosed as having type II diabetes, and the
patient population is extremely selective, which contraindicates that the
selected components would be suitable for the treatment of obesity in a wide
population. (Id.) Appellants thus argue that the combination is based on
impermissible hindsight, as the prior art does not discuss compliance. (Id. at
12.)
Appellants’ arguments have been considered, but are not convincing.
While none of the references teaches combining metformin; a lipid lowering
agent; and a blood pressure reducing agent into a single composition, Gaede
teaches intensive treatment of type II diabetes, which includes treatment
with one or more of oral hypoglycemic agents, such as metformin,
antihypertensive treatment, and lipid-lowing treatment, such as statins and
fibrate. Gaede specifically teaches the use of metformin as the oral
hypoglycemic agent, and Zimmet further provides reasons as to why the
ordinary artisan would have selected metformin. Hunninghake provides a
reason as to why the ordinary artisan would have chosen simvastatin as the
lipid-lowering agent, and both Abbott and Sevak would direct the ordinary
artisan to the use of lisinopril for the treatment of hypertension. As noted by
Gaede, guidelines such as those from the American Diabetes Association
recommend an intensified, multifactorial treatment approach, as well as
teaching that long term, intensified intervention involving multiple risk
8
Appeal 2010-000183
Application 10/868,227

factors reduced the risk of cardiovascular events among patients with type II
diabetes and microalbuminuria. Thus, based on those teachings, we agree
with the Examiner that it would have been obvious to the ordinary artisan to
combine all three agents into a single composition because the ordinary
artisan would understand that a patient is more likely to take a single
composition, such as a pill, than three separate medications. While the prior
art does not specifically discuss compliance, the issue of patient compliance
would be understood by the ordinary artisan as a patient can not be helped
by a medication that is not taken. Thus, the combination of Gaebe, Zimmet,
and Hunninghake, as combined with Abbott or Sevak renders the
composition of claim 1 obvious.
We note that Appellants did not specifically argue the claims
separately. But, as Appellants argue that none of the references teach
treating obesity with a single composition, we notes that Gaede, Zimmet,
Hunninghake, and Abbott, as well as the instant Specification, all recognize
that type II diabetes and obesity are closely related. Moreover, Zimmet
specifically teaches that metformin is known to assist with weight reduction.
Thus, administering the composition to a diabetic or prediabetic patient who
is also obese would also result in treating the obesity.
According to Appellants, “[a] foundation question in this appeal is
whether the results of this invention are unexpected.” (App. Br. 11.)
Appellants argue they have “made the surprising discovery that treating
obesity with one pill that may be administered prior to the development of
the additional risk factors for diabetes and cardiovascular disease is
surprisingly more effective than administering the drugs individually
9
Appeal 2010-000183
Application 10/868,227

because this particular combination is safe for use in a very large patient
population and increases drug compliance.” (Id. at 6-7.) Appellants argue
that the data presented in the Specification “demonstrates that the present
invention is not only effective in treating obesity, but also safe,” and that
there is no suggestion in the references relied upon by the Examiner “that
this combination would be safe and effective for the treatment of obese
patients.” (Id. at 10-11.)
Appellants argue further that the “Examiner’s rejection is based
entirely on studies related to diabetes and metabolic syndrome.” (Reply Br.
2.) Appellants assert that “the rejection fails to appreciate the unexpected
advantage of being able to safely treat obesity whether or not the patient is a
known diabetic.” (Id. at 3.)
As to Appellants assertion of unexpected results, the Specification
only compares the composition of formula 1 to a placebo. Thus, Appellants
have not compared the claimed composition to the closest prior art. As
Gaede teaches that established guidelines recommend a multifactorial
approach, the closet prior art would appear to be administering the three
claimed active agents as separate compositions. Moreover, as all three
medications are known in the art to be useful in diabetic patients, and Gaede
specifically teaches using a combination of at least two of the medications,
we agree with the Examiner (Ans. 12-13) that it would not have been
unexpected to the ordinary artisan that the claimed composition would be
safe. In addition, given Zimmet’s teaching that metformin is known to assist
in weight reduction; it would also not be unexpected to the ordinary artisan
that the composition would be effective in the treatment of obesity.
10
Appeal 2010-000183
Application 10/868,227

CONCLUSIONS OF LAW
We conclude that the preponderance of evidence of record supports
the Examiner’s conclusion that the combination of Gaebe, Zimmet, and
Hunninghake, as combined with Abbott or Sevak render the claimed
composition and method of using the composition in the treatment of obesity
obvious. We conclude further that Appellants have not provided evidence of
unexpected results, that when weighed with the evidence of obviousness, is
sufficient to support a conclusion of nonobviousness.
We thus affirm the rejection of claims 1, 3-5, 9, 25, 27-29, 33, 46, and
47 under 35 U.S.C. § 103(a) as being rendered obvious by the combination
of Gaebe, Zimmet, and Hunninghake, as combined with Abbott or Sevak.

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)(1)(iv)(2006).

AFFIRMED

cdc

WOOD, HERRON & EVANS, LLP
2700 CAREW TOWER
441 VINE STREET
CINCINNATI OH 45202

11