Ex Parte Gregory et al

Board of Patent Appeals and Interferences

Jun 22, 2009

10360208 (B.P.A.I. Jun. 22, 2009)

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.
10/360,208 02/06/2003 Jefferson J. Gregory PAT-0011-US-NP 5449
57999 7590 06/22/2009
KING PHARMACEUTICALS, INC.
400 CROSSING BOULEVARD
BRIDGEWATER, NJ 08807
EXAMINER
CHANNAVAJJALA, LAKSHMI SARADA
ART UNIT PAPER NUMBER
1611
MAIL DATE DELIVERY MODE
06/22/2009 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 BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte JEFFERSON J. GREGORY,
ROBERT G. BRUNS, DEAN R. CIROTTA,
THOMAS K. ROGERS III, and CHARLES L. PAMPLIN III
__________

Appeal 2008-005266
Application 10/360,208
Technology Center 1600
__________

Decided:1 June 22, 2009
__________

Before DONALD E. ADAMS, DEMETRA J. MILLS, and
LORA M. GREEN, 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 final rejection of claims 1, 8-10, 16-18, and 21. We have
jurisdiction under 35 U.S.C. § 6(b).

1 The two-month time period for filing an appeal or commencing a civil
action, as recited in 37 C.F.R. § 1.304, begins to run from the decided date
shown on this page of the decision. The time period does not run from the
Mail Date (paper delivery) or Notification Date (electronic delivery).
Appeal 2008-005266
Application 10/360,208

2
STATEMENT OF THE CASE
The claims are directed to an oral trimethobenzamide formulation that
may be used to treat and control nausea and/or vomiting. Claim 1 is
representative of the claims on appeal, and reads as follows:
1. An oral trimethobenzamide composition for treating and controlling
nausea and/or vomiting comprising 300mg trimethobenzamide
hydrochloride and a suitable pharmaceutical excipient, wherein said oral
trimethylbenzamide composition is at least about as effective as a 200mg
intramuscular (I.M.) trimethobenzamide HCL injectable formulation in
treating and controlling nausea and/or vomiting.
The Examiner relies on the following references:
Howard C. Ansel et al., “Pharmaceutical Dosage Forms and Drug Delivery
Systems”, 7th ed. 125, (1999).

Trimethobenzamide Hydrochloride Injection and Capsules, Federal Register
Notice, 44(6): 2017 (1979).

We affirm.

ISSUES
The Examiner concludes that claims 1, 8-10, 16-18, and 21 would
have been obvious over the combination of the FDA Federal Register notice
issued in 1979 and Ansel.
Appellants contend that the ordinary artisan reading the FDA directive
would have reformulated their 100 mg and 250 mg capsules to 200 mg and
400 mg, respectively, and thus the FDA directive teaches away from a 300
Appeal 2008-005266
Application 10/360,208

3
mg oral formulation. Appellants contend further that the patentability of
claim 1 is supported by objective evidence of non-obviousness.
Thus, the issues on appeal are:
Have Appellants demonstrated that the Examiner erred in concluding
that the claims on appeal are rendered obvious by the combination of the
FDA Federal register notice issued in 1979 and Ansel;
And have Appellants demonstrated that, even if a prima facie case has
been established, that the Examiner erred in not considering objective
evidence of non-obviousness?

FINDINGS OF FACT
FF1 “Trimethobenzamide hydrochloride is a prescription drug that has
been available in the market since the 1960s.” (Spec. 2.) “Even though
trimethobenzamide hydrochloride has been widely available for many years,
the only routes and dosage forms that have been approved by the FDA are:
100 mg and 250 mg capsules; 100 mg and 200 mg suppositories; and 100
mg/ml in 2-ml ampules and prefilled syringes and in 20-ml vials as
injectables. The injectable form is intended for intramuscular administration
only; it is not recommended for intravenous use.” (Id. at 3.)
FF2 In 1979, the FDA published a notice stating that trimethobenzamide
capsules containing 100 mg or 250 mg of the drug were “not approximately
bioequivalent to a 200-milligram intramuscular dose and do not achieve
levels necessary to effectively treat or control nausea and vomiting.” (Id. at
5.) Thus, the FDA stated that 100 mg and 250 mg capsules must be
reformulated into 200 mg and 400 mg capsules “to achieve approximate
Appeal 2008-005266
Application 10/360,208

4
bioequivalence to a 200-milligram intramuscular dose.” (Id.) The
Specification discloses that “[n]otwithstanding this FDA notice, which was
published more than 23 years ago, there is no oral trimethobenzamide dose
available today which is approximately bioequivalent to a 200-milligram
intramuscular dose or which achieves plasma levels effective to control
nausea and vomiting.” (Id.)
FF3 According to the Specification, “[q]uite amazingly, it has been
discovered that an oral dose of about 300 mg of trimethobenzamide is
uniquely approximately bioequivalent to a 200 mg intramuscular (I.M.)
trimethobenzamide HCl injectable formulation, whereas an oral dose of
about 400 milligrams of trimethobenzamide is not.” (Id. at 6.)
FF4 The Specification teaches further that “it has been discovered, quite
unexpectedly, that the bioequivalency (PK) parameters of an oral dose of
about 400 mg of trimethobenzamide are uniquely approximately at least
about 20% greater than the corresponding bioequivalency (PK) parameters
for a 200 mg intramuscular (I.M.) trimethobenzamide HCl injectable
formulation.” (Id. at 6-7.)
FF5 The Examiner rejects claims 1, 8-10, 16-18, and 21 under 35 U.S.C.
§ 103(a) as being obvious over the combination of FDA Federal register
notice issued in 1979 (Applicants’ admission in the Specification) and Ansel
(Ans. 3). As Appellants do not argue the claims separately, we focus our
analysis on claim 1, and claims 8-10, 16-18, and 21 stand or fall with that
claim. 37 C.F.R. § 41.37(c)(1)(vii).
FF6 According to the Examiner:
Applicants admit on pages 5-6 of the instant specification that a
FDA advised public that trimethobenzamide capsules
Appeal 2008-005266
Application 10/360,208

5
comprising 100 mg and 250 mg drug should be reformulated to
200 and 400 mg respectively because the bioavailability of the
100 and 250 mg dosages are not approximately equivalent to
the 200 mg IM injection formulations containing the drug.
Thus, by applicants’ own admission the need to improve the
oral dosage formulations of trimethobenzamide has been
recognized.

(Ans. 3.)
FF7 The notice issued by the FDA “reclassifies trimethobenzamide and
hydrochloride injection and capsules to effective for certain indications and
to lacking substantial evidence of effectiveness for their other less-than-
effective indications,” and “states that to obtain effective plasma levels for
these drug products, a dosage of 200 milligrams intramuscularly or 400
milligrams orally is required, and that as part of the marketing conditions for
the capsule dosage form, the capsules, now containing 100 milligrams or
250 milligrams must be reformulated to 200 milligrams or 400 milligrams
respectively.” 44 Fed. Reg. 2017 (1979).
FF8 The notice further states that:
The relative bioavailability or extent of absorption of the
capsule in the two studies was 50-62 percent of that of the
intramuscular injection. As the oral route of administration
produced blood levels which were approximately half of the
levels produced by the intramuscular route, the oral route
should be approximately two times the intramuscular dose.

Id. at 2019.
FF9 Thus, the following statement was added to the Action section:
ORAL AND PARENTAL TRIMETHOBENZAMIDE ARE
NOT BIOEQUIVALENT, AN ORAL DOSE OF 400
MILLIGRAMS OF TRIMETHOBENZAMIDE YIELDS
Appeal 2008-005266
Application 10/360,208

6
PLASMA LEVELS APPROXIMATELY EQUAL TO A 200-
MILLIGRAM INTRAMUSCULAR DOSE. The systemic
bioavailability of orally administered trimethobenzamide is
about 60 percent of the bioavailability of intramuscularly
administered drug, possibly because of slow absorption and
rapid liver metabolism (first pass effect). This difference is
manifested as diminished peak blood levels and a diminished
area under the plasma concentration curve following oral, as
compared to parenteral administration.

Id.
FF10 Ansel is cited by the Examiner for its discussion of various routes of
drug administration, and that “drugs administered orally are destroyed or
inactivated in the GI tract or are poorly absorbed to provide a satisfactory
response and that the parental administration requires smaller doses of
drugs.” (Ans. 3.)
FF11 The Examiner concludes:
Thus, it is evident from the teachings of Ansel as well as the
FDA notice that the injection formulations require smaller
doses than oral route of administration. Therefore, it would
have been obvious for one of an ordinary skill in the art at the
time of the instant invention was made to optimize the amounts
of trimethobenzamide in an oral formulations, based on the
suggestion of FDA that the 100 and 250 mg doses to be
increased to 200 and 400 mg respectively because it is well
established (from the teachings of Ansel) that the parenteral
formulations require smaller doses than the corresponding oral
formulations and that in order to achieve the same
bioavailability (with oral and parenteral), one requires higher
dosages of drug in an oral formulation. Accordingly, one of an
ordinary skill in the art would have been motivated to optimize
the amounts of oral trimethobenzamide (higher than 250) with
an expectation to achieve the optimum bioavailability desired.

Appeal 2008-005266
Application 10/360,208

7
(Id. at 3-4.)
FF12 Appellants have not supplemented the record with any evidence of
non-obviousness beyond what is in the FDA notice.

PRINCIPLES OF LAW
The question of obviousness is resolved on the basis of underlying
factual determinations including: (1) the scope and content of the prior art;
(2) the level of ordinary skill in the art; (3) the differences between the
claimed invention and the prior art; and (4) secondary considerations of
nonobviousness, if any. Graham v. John Deere Co., 383 U.S. 1, 17 (1966).
In KSR Int’l 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. Thus, an “[e]xpress suggestion to substitute one
equivalent for another need not be present to render such substitution
obvious.” In re Fout, 675 F.2d 297, 301 (CCPA 1982).
Further,

[i]f a person of ordinary skill can implement a predictable
variation, § 103 likely bars its patentability. For the same
reason, if a technique has been used to improve one device, and
a person of ordinary skill in the art would recognize that it
would improve similar devices in the same way, using the
technique is obvious unless its actual application is beyond his
or her skill.
Appeal 2008-005266
Application 10/360,208

8

KSR., 550 U.S. at 418. It is proper to “take account of the inferences and
creative steps that a person of ordinary skill in the art would employ.” Id.
See also id. at 421 (“A person of ordinary skill is also a person of ordinary
creativity, not an automaton.”).
“In cases involving ranges . . . even a slight overlap in range
establishes a prima facie case of obviousness.” In re Peterson, 315 F.3d
1325, 1329 (Fed. Cir. 2003). In addition, as noted by the Peterson, “[t]he
normal desire of scientists or artisans to improve upon what is already
generally known provides the motivation to determine where in a disclosed
set of percentage ranges is the optimum combination of percentages.” Id.
1330.
The prima facie case of obviousness can be rebutted “by establishing
‘that the [claimed] range is critical, generally by showing that the claimed
range achieves unexpected results relative to the prior art range.’” Id.
(alteration in original). Such a showing must be commensurate in scope
with the claims. Id. In addition, mere improvement in properties is not
always sufficient to demonstrate unexpected results. In re Soni, 54 F.3d
746, 751 (Fed. Cir. 1995).
The other way in which the prima facie case may be rebutted is by
demonstrating that the “prior art teaches away from the claimed invention in
any material respect.” Peterson, 315 F.3d at 331. See also In re Geisler,
116 F.3d 1465, 1469 (Fed, Cir. 1997) (citing in re Malagari, 499 F.2d 1297,
1303 (CCPA 1974)).
Moreover, “[w]hen prima facie obviousness is established and
evidence is submitted in rebuttal, the decision-maker must start over.” In re
Appeal 2008-005266
Application 10/360,208

9
Rinehart, 531 F.2d 1048, 1052 (CCPA 1976); In re Hedges, 783 F.2d 1038,
1039 (Fed. Cir. 1986) (“If a prima facie case is made in the first instance,
and if the applicant comes forward with reasonable rebuttal, whether
buttressed by experiment, prior art references, or argument, the entire merits
of the matter are to be reweighed”). Thus, all of the evidence must be
considered under the Graham factors in reaching the obviousness
determination.
In speaking about the relationship of patent law and FDA law, the
Federal Circuit has noted:
On the basis of animal studies, and controlled testing in a
limited number of humans (referred to as Phase I testing), the
Food and Drug Administration may authorize Phase II clinical
studies. See 21 U.S.C. § 355(i)(1); 5 C.F.R. § 312.23 (a)(5),
(a)(8) (1994). Authorization for a Phase II study means that the
drug may be administered to a larger number of humans, but
still under strictly supervised conditions. The purpose of a
Phase II study is to determine primarily the safety of the drug
when administered to a larger human population, as well as its
potential efficacy under different dosage regimens. See 21
C.F.R. § 312.21(b). FDA approval, however, is not a
prerequisite for finding a compound useful within the meaning
of the patent laws. . . . . Usefulness in patent law, and in
particular the context of pharmaceutical inventions, necessarily
includes the expectation of further research and development.
The stage at which an invention in this field becomes useful is
well before it is ready to be administered to humans. Were we
to require Phase II testing in order to prove utility, the
associated costs would prevent many companies from obtaining
patent protection on promising new inventions, thereby
eliminating an incentive to pursue, through research and
development, potential cures in many crucial areas such as the
treatment of cancer.

Appeal 2008-005266
Application 10/360,208

10
In re Brana, 51 F.3d. 1560, 1568 (Fed. Cir. 1995) (citations omitted).
Although the above statements were made in the context of utility and
enablement, the clear inference is that FDA determinations are not
controlling on patentability, which would include the obviousness
determination.

ANALYSIS
Appellants argue that the “FDA recognized a need for an oral
formulation of trimethobenzamide hydrochloride that would yield plasma
levels approximately equivalent to a 200 mg IM injection,” and the FDA
required that existing oral capsules be reformulated into either 200 mg or
400 mg capsules, and that the 400 mg capsule would be equivalent to the
200 mg IM injection (App. Br. 6). Thus, Appellants assert, the ordinary
artisan reading the FDA directive would have reformulated their 100 mg and
250 mg capsules to 200 mg and 400 mg, respectively, not 300 mg as claimed
(id.). Ansel, Appellants assert, is unrelated to the claims on appeal, as it
“merely makes a general statement that one may employ smaller dosages of
a drug when administered parentally as opposed to orally.” (Id.)
Appellants argue further, “the prior art taught only the use of a 400
mg oral formulation to be equivalent to the 200 mg IM injection.” (Id. at 7.)
Appellants argue further that the “prior art does not suggest a range for oral
administration,” and “does not suggest a formula for one to determine an
equivalent oral dosage strength from an IM injection strength.” (Id.)
According to Appellants, “[w]ithout any direction in the prior art, it would
Appeal 2008-005266
Application 10/360,208

11
not be obvious to one skilled in the art how to determine what oral dosage
strength of a particular drug would be equivalent to an injectable.” (Id. at 8.)
Appellants note that the Examiner concludes “that ‘ . . . a skilled
artisan would have readily calculated the equivalent dosages of oral
trimethobenzamide to that of intramusculsar injection . . .,’” which
Appellants contend “is absurd.” (Id. at 9.) Appellants assert that:
The Examiner fails to note that someone in the art did
calculate what it believed to be the oral dose of
trimethobenzamide that would be equivalent to the 200 mg IM
dose. It was calculated by the U.S. Food and Drug
Administration and it was wrong.

(Id.)
Appellants argue further that there is objective evidence of non-
obviousness (App. Br. 8). According to Appellants:
In this case the prior art showed there was an unmet
medical need for an oral dosage strength of trimethobenzamide
hydrochloride that would be equivalent to a 200 mg IM
injection. The prior art taught that the oral dosage would be
400 mg.
Applicants were the first to show that it is a 300 mg oral
dosage that provides optimal control of nausea and vomiting.
The success of Applicants invention is evidenced by the FDA
approval of its 300 mg product and the commercial acceptance
of the invention.

(App. Br. 8.)
Appellants’ arguments have been carefully considered, but are not
convincing. First, as to Appellants’ argument that the prior art does not
teach a range, Appellants acknowledge that oral formulation comprising 100
mg, 200 mg, 250 mg, and 400 mg have been approved by the FDA in the
Appeal 2008-005266
Application 10/360,208

12
past. Thus, we agree with the Examiner that a range of trimethobenzamide
is known to be useful for the treatment of nausea, wherein the range extends
from 100 mg to 400 mg. Although that range is not explicitly taught by the
FDA notice, one of ordinary skill in the pharmaceutical arts would recognize
it as such. The ordinary artisan in the pharmaceutical art, which is a heavily
regulated industry, would understand that only certain dosage amounts in a
range that would have been obvious under the patent laws would eventually
be approved for clinical use by the FDA. The ordinary artisan understands
that the showing required to demonstrate that a compound intended for
clinical use is patentable under the patent statute is not as strict as the
showing required by the FDA for approval for in vivo clinical use. See, e.g.,
Brana, 51 F.3d. at 1568 (“FDA approval, however, is not a prerequisite for
finding a compound useful within the meaning of the patent laws.”).
As we agree with the Examiner that the art establishes a range, and as
claim 1 is drawn to an amount in that range, the subject matter of claim 1 is
prima facie obvious under Peterson. We thus determine if Appellants have
rebutted that prima facie case by determining if Appellants have established
that the prior art teaches away from the claimed amount in any material
respect, or have established that the claimed amount is critical.
As noted by Appellants, the FDA in 1979, 24 years before Appellants’
filing date, reclassified trimethobenzamide capsules, and stated that “to
obtain effective plasma levels for these drug products, a dosage of 200
milligrams intramuscularly or 400 milligrams orally is required, and that as
part of the marketing conditions for the capsule dosage form, the capsules,
Appeal 2008-005266
Application 10/360,208

13
now containing 100 milligrams or 250 milligrams must be reformulated to
200 milligrams or 400 milligrams respectively.” (FF7.)
The notice stated, however, that the “relative bioavailability or extent
of absorption of the capsule in the two studies was 50-62 percent of that of
the intramuscular injection,” and thus the FDA acknowledged that there was
some variability in the data (FF8). Moreover, while noting that an oral dose
of 400 mg yields plasma levels approximately equal to that of a 200 mg
intramuscular dose, as noted by the Examiner (Ans. 6), the FDA also stated
that the “systemic bioavailability of orally administered trimethobenzamide
is about 60 percent of the bioavailability of intramuscularly administered
drug.” (FF9.) Thus, 60% of a 400 mg dose would be approximately
equivalent to a 240 mg IM dose, and 60% of the claimed 300 mg dose would
be approximately equivalent to a 180 mg IM dose, which is “about as
effective” as a 200 mg IM dose.
Thus, given the variability reported by the FDA, that is, the fact that
the FDA notice stated that the “relative bioavailability or extent of
absorption of the capsule in the two studies was 50-62 percent of that of the
intramuscular injection,” and given that the FDA notice states that the
systemic bioavailability of orally administered trimethobenzamide is about
60 percent of the bioavailability of intramuscularly administered drug, the
ordinary artisan would have been motivated to reconsider the
pharmacodynamics of trimethobenzamide in order to find other dosage
amounts that may be at least about as effective as a 200mg intramuscular
(I.M.) trimethobenzamide. That finding is further supported by the fact that
24 years had passed since the FDA directive, and given that the background
Appeal 2008-005266
Application 10/360,208

14
knowledge in the art and the technology available in the pharmaceutical
industry had substantially increased in those 24 years, the ordinary artisan
would have been further motivated to take another look at the
pharmacodynamics of trimethobenzamide, a drug that has already been
approved by the FDA for clinical use. As it is the “normal desire of
scientists or artisans to improve upon what is already generally known
provides the motivation to determine where in a disclosed set of percentage
ranges is the optimum combination of percentages,” Peterson, we conclude
that the prior art does not teach away from the composition of claim 1 in a
material way. See In re Aller, 220 F.2d 454, (CCPA 1955) (noting that
“where the general conditions of a claim are disclosed in the prior art, it is
not inventive to discover the optimum or workable ranges by routine
experimentation); see also KSR, 550 U.S. at 421 (“When there is a design
need or market pressure to solve a problem and there are a finite number of
identified, predictable solutions, a person of ordinary skill has good reason
to pursue the known options within his or her technical grasp. If this leads
to the anticipated technical success, it is likely the product not of innovation
but of ordinary skill and common sense.”).
We also conclude that Appellants have not established that the
claimed amount is critical. As noted above, the FDA noted there was
variability in the data, and also noted that the systemic bioavailability of
orally administered trimethobenzamide is about 60 percent of the
bioavailability of intramuscularly administered drug. As 60% of a 300 mg
oral dose would be approximately equivalent to a 180 mg IM dose, we
conclude that the ordinary artisan would not find it unexpected that a 300 mg
Appeal 2008-005266
Application 10/360,208

15
oral dose would be “a least about as effective” as a 200 mg IM dose as is
required by Appellants’ claim 1.
While Appellants assert that the criticality of the amount is established
by the FDA approval of its 300 mg product, FDA determinations are not
controlling on patentability determinations, which would include the
obviousness determination. In addition, while Appellants assert that there is
commercial acceptance of the invention, Appellants have provided no
evidence on the record that would support commercial success, or even
commercial acceptance.

CONCLUSION(S) OF LAW
We conclude that:
Appellants have not demonstrated that the Examiner erred in
concluding that the claims on appeal are rendered obvious by the
combination of the FDA Federal register notice issued in 1979 and Ansel;
and
Appellants have not demonstrated that, even if a prima facie case has
been established, the Examiner erred in not considering objective evidence
of non-obviousness.
We thus affirm the rejection of claims 1, 8-10, 16-18, and 21 under 35
U.S.C. § 103(a) as being obvious over the combination of FDA Federal
Register Notice and Ansel.

Appeal 2008-005266
Application 10/360,208

16
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).

AFFIRMED
lp
KING PHARMACEUTICALS, INC.
400 CROSSING BOULEVARD
BRIDGEWATER NJ 08807