Ex Parte Semple et al

Patent Trial and Appeal Board

Aug 13, 2013

10535345 (P.T.A.B. Aug. 13, 2013)

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

Ex parte GRAEME SEMPLE, THOMAS SCHRADER,
PHILIP J. SKINNER, STEVEN L. COLLETTI, TAWFIK GHARBAOUI,
JASON E. IMBRIGLIO, JAE-KYU JUNG, RUI LIANG,
SUBHAREKHA RAGHAVAN, DARBY SCHMIDT,
and JAMES R. TATA,
____________

Appeal 2011-012978
Application 10/535,345
Technology Center 1600
____________

Before JEFFREY N. FREDMAN, ULRIKE W. JENKS, and
JOHN G. NEW, Administrative Patent Judges.

JENKS, Administrative Patent Judge

DECISION ON APPEAL
This is an appeal1 under 35 U.S.C. § 134 involving claims directed to
3-(1H-tetrazol-5-yl)-2,4,5,6-tetrahydrocyclopentapyrazole and methods of
using the compound. The Patent Examiner has rejected the claims as

1 Appellants state that the real party in interest is Arena Pharmaceuticals,
Inc. and Merck & Co., Inc. (App. Br. 1.)
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lacking enablement. We have jurisdiction under 35 U.S.C. § 6(b). We
affirm-in-part.

STATEMENT OF THE CASE
The Specification provides that “[n]icotinic acid inhibits the
production and release of free fatty acids from adipose tissue, likely via an
inhibition of adenylyl cyclase, a decrease in intracellular cAMP levels, and a
concomitant decrease in hormone sensitive lipase activity” (Spec. 2, ll. 13-
15). Nicotinic acid therapies are therefore limited because of adverse side
effects (Spec. 2, ll. 21-23). The Specification is directed to tetrazole
derivatives that exhibit useful properties as antagonists for the nicotinic acid
receptor, RUP25 (Spec. 1, ll. 7-8).
Claims 65-67 are on appeal, and can be found in the Claims Appendix
of the Appeal Brief (App. Br. 23). Claims 65 and 67 read as follows:
65. A compound, which is 3-(1H-tetrazol-5-yl)-2,4,5,6-
tetrahydrocyclopentapyrazole, or a pharmaceutically acceptable
salt, solvate or hydrate thereof.
67. A method of lowering free fatty acids in an individual
comprising administering to said individual a therapeutically-
effective amount of 3-(1H-tetrazol-5-yl)-2,4,5,6-tetrahydro-
cyclopentapyrazole, or a pharmaceutically acceptable salt,
solvate or hydrate thereof.
The following grounds of rejection are before us for review:
The Examiner has rejected claims 65-67 under 35 U.S.C. § 112 first
paragraph as being non-enabled with respect to the “solvate” and “hydrate”
of the tetrazole derivative (Ans. 11).
The Examiner has rejected claims 67 under 35 U.S.C. § 112 first
paragraph as being non-enabled with respect to the recited method (Ans. 5).
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The Issue: Enablement of Solvates and Hydrates
The Examiner takes the position that “the specification fails to teach
the preparation of solvates and hydrates.” (Ans. 11.) “There is no evidence
that solvates or hydrates of the instantly claimed compounds exist.” (Id. at
12.) “[T]he breadth of the claims includes the tens of thousands of forms
encompassed by the terms salts, solvates and hydrates.” (Id. at 13.)
Appellants contend that “at the time of filing, there were routine
methods for preparing hydrates and solvates, as well as empirical methods
for determining whether a pharmaceutical compound may form a solvate or
hydrate.” (App. Br. 13-14.) Appellants further contend that “the water or
solvent molecules are not bonded through covalent or ionic bonds to other
elements of the molecule. . . . [there is] little reason to suspect that the
solvates and hydrates would somehow not have pharmacological activity of
the unsolvated compound, since it will become unsolvated compound in
vivo.” (Id. at 17.)
The issue is: Does the production of solvates or hydrates of 3-(1H-
tetrazol-5-yl)-2,4,5,6-tetrahydrocyclopentapyrazole require undue
experimentation?
The first paragraph of 35 U.S.C. § 112 requires, inter
alia, that the specification of a patent enable any person skilled
in the art to which it pertains to make and use the claimed
invention. Although the statute does not say so, enablement
requires that the specification teach those in the art to make and
use the invention without “undue experimentation.” In re
Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). That some
experimentation may be required is not fatal; the issue is
whether the amount of experimentation required is “undue.”
In re Vaeck, 947 F.2d 488, 495 (Fed. Cir. 1991) (emphasis in original).
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We find that Appellants have the better position. As acknowledged
by the Examiner, the present Specification provides descriptive support for
salts of 3-(1H-tetrazol-5-yl)-2,4,5,6-tetrahydrocyclopentapyrazole (Ans. 11).
We agree with the Examiner that the Specification does not disclose
examples of solvates or hydrates. Nevertheless, solvates or hydrates are the
same compound in different physical form and are routinely produced in the
chemical arts as evidenced by Guillory.2
The art at the time of the invention was such that production of
hydrates and solvates was within the grasp of the ordinary artisan in the field
of pharmaceutical formulations. Hydrates are formed “[w]hen water is
incorporated into the crystal lattice of the compound in stoichiometric
proportions.” (Guillory 202.) “Hydrates can be prepared by recrystallization
from water or from mixed aqueous solvents. They can also result, in some
instances, from exposure of crystal solvates (such as methanolates or
ethanolates) to an atmosphere containing water vapor.” (Guillory 203.)
Solvates on the other hand are formed by using solvents during
“recrystallization, it is observed that the isolated crystals include solvent
molecules, either entrapped within empty spaces in the lattice or interacting
via hydrogen bonding or van der Waals force with molecules constituting
the crystal lattice.” (Guillory 205.) In addition, the art provides that 95% of
the known solvate structure incorporate one of 15 solvents, with water
topping the list as the most abundant solvent (Guillory 206). Thus, the art at
the time of filing the present invention provides guidance in directing the

2 J. Keith Guillory, Generation of Polymorphs, Hydrates, Solvates, and
Amorphous Solids, POLYMORPHISM IN PHARMACEUTICAL SOLIDS, edited
Harry G Britain 183-226 (1999).
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ordinary artisan in choosing a solvent from a short list of the most frequently
incorporated solvents for the formation of hydrate and solvate crystal
structures.
The Examiner provides no evidence to support the position that
solvates of the claimed compounds could not be made by routine
experimentation. The Examiner merely points to the lack of solvate or
hydrate examples in the Specification and speculates that the claimed
hydrates and solvates may not exist (Ans. 12). As to the Wands factor
analysis and the lack of working examples, although “working examples are
desirable in complex technologies … examples are not required to satisfy
section 112, first paragraph.” In re Strahilevitz, 668 F.2d 1229, 1232
(CCPA 1982) (emphasis in original). See also In re Stephens, 529 F.2d
1343, 1344 (CCPA 1976). Even if there are some inoperable embodiments
that fall within the scope of the claim, inoperable embodiments only became
an issue when they are so numerous that it would become undue to find
actual working structures. The Examiner has not provided sufficient
evidence that this would apply to the present claims. After all, solvates,
hydrates, and salts of a compound are the same compound, in different
physical form.
The Examiner takes the position that the claims are not commensurate
in scope with the disclosure citing Application of Fisher, 57 C.C.P.A 1099
(1970) in support (Ans. 18). The claims in Fisher differ from the presently
recited claims in that the Fisher claims require achieving a particular level of
potency for the claimed hormone. As acknowledged by the Examiner, the
present Specification provides descriptive support for salts of 3-(1H-tetrazol-
5-yl)-2,4,5,6-tetrahydrocyclopentapyrazole (Ans. 11). Contrary to the
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claims in Fisher, the present claims do not require achieving particular
potencies with respect to the claimed solvates and hydrates of 3-(1H-
tetrazol-5-yl)-2,4,5,6-tetrahydro-cyclopentapyrazole. We are not persuaded
that the claimed hydrates and solvates are not commensurate in scope given
that the claims do not require that the composition achieves a particular level
of potency when administered.
The Examiner also takes the position that the breadth of the present
claims is such that it could include compositions that may be unsuitable for
pharmacological use (Ans. 15), however, it is not the function of the claims
to exclude inoperative substances. In re Dinh-Nguyen, 492 F.2d 856, 859
(CCPA 1974).
In light of the fact that the salts of the of 3-(1H-tetrazol-5-yl)-2,4,5,6-
tetrahydrocyclopentapyrazole are disclosed in the Specification, we find that
the Examiner has not met the burden of showing that the production of
solvates and hydrates requires undue experimentation. We reverse the
enablement rejection with respect to hydrates and solvates.

The Issue: Scope of Enablement for the Limitation of “Lowering Free Fatty
Acids”
The Examiner takes the position that Appellants are not enabled for
the full scope of the claim, specifically, “[t]he enablement issue is with the
term ‘lowering free fatty acids.’” (Ans. 24.) “Lowering free fatty acids
describes a multitude of different disorders in addition to dyslipidemia.”
(Id.) The Examiner asserts “that individuals are complex and vary greatly
and that one compound could not possibly have the same mechanism of
action, i.e. lowering free fatty acids, in 100% of all individuals even where
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the patient population is known, i.e. patients requiring treatment from
dyslipidemia.” (Id. at 9.)
The issue is: Has the Examiner provided sufficient evidence or
reasoning to substantiate the rejection for lack of enablement?
The enablement requirement ensures that the public knowledge
is enriched by the patent specification to a degree at least
commensurate with the scope of the claims. The scope of the
claims must be less than or equal to the scope of the
enablement. The scope of enablement, in turn, is that which is
disclosed in the specification plus the scope of what would be
known to one of ordinary skill in the art without undue
experimentation.
National Recovery Technols. Inc. v. Magnetic Separation Sys., Inc., 166
F.3d 1190, 1195-1196 (Fed. Cir. 1999). “[T]he PTO bears an initial burden
of setting forth a reasonable explanation as to why it believes that the scope
of protection provided by that claim is not adequately enabled by the
description of the invention provided in the specification of the application.”
In re Wright, 999 F.2d 1557, 1561-62 (Fed. Cir. 1993).
Appellants contend that “the method is directed to treatment of a very
specific type of dyslipidemia-high levels of free fatty acids.” (App. Br. 7.)
Appellants contend that “[m]easurement of free fatty acid levels after
administration of MK-0354 [the claimed compound] is a simple blood test
measurement” citing Semple3 in support (id. at 4). Appellants contend that
niacin was known to have fatty acid lowering activity (id. at 5), and that
niacin was known to bind to the GPR109A receptor (id.).

3 Semple et al., 1-Alkyl-benzotriazole-5-carboxylic Acids Are Highly
Selective Agonist of the Human Orphan G-Protein-Coupled Receptor
GPR109b, 49 J. MED. CHEM. 1227-1230 (2006).
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We agree with the Examiner’s finding that the Specification does not
provide any “biological data at all with regard to the instantly claimed
compound” (Ans. 21). The Specification provides only generic examples,
even if disclosed in the past tense, describing assay protocols for measuring
the receptor binding for RUP25 (Spec. 55-57). Again, the method of
measuring the inhibition of free fatty acids in rats is described without
providing any data points (Spec. p. 57, ll. 19-31).
Appellants’ arguments substantially rely upon post filing date
references of Semple and Lai to establish the role of 3-(1H-tetrazol-5-yl)-
2,4,5,6-tetrahydrocyclopentapyrazole (MK-0354) as a compound that binds
to and agonizes the GPR109A receptors as well as results directed to
lowering free fatty acids in an individual. Generally, references that are
published “after the filing date of appellant's application . . . are not,
therefore, evidence of subject matter known to ‘any person skilled in the art’
as required by 35 U.S.C. § 112, paragraph 1.” In re Gunn, 537 F.2d 1123,
1128 (CCPA 1976).
Appellants rely on Semple to show that claimed compound provides
the fatty acid lowering activity as measured following the procedures
disclosed in Examples 3, 4, and 6D of the Specification. Appellants contend
that:
the claimed compound had an EC50 value of 1.65 in a whole
cell cAMP assay at hGPR109a (i.e., as measured by the assay
of Example 3 of the specification); an EC50 value of 2.3 in a
hGPR109a GTPγS assay (i.e., as measured by the assay of
Example 4 of the specification); and Ki of 505 nM as compared
with a Ki of 50 nM for nicotinic acid as measured in a 3H
nicotinic acid binding assay (i.e., as measured by the assay of
Example 6D of the specification).
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(Reply Br. 8.) Appellants cite In re Brana, 51 F.3d 1560, 1567 (Fed. Cir.
1995) for the position that post filing date data may be used to support
statements in the Specification (id. at 9).
The Examiner takes the position that “[t]he Semple and Lai references
discuss the instantly claimed compound, however, the instant claim language
fails to limit the scope of the claim to the data found in Semple and Lai.”
(Ans. 21.) In the Final Rejection the Examiner concluded that:
The Phase I and II clinical trial data has been considered
fully, but is not found persuasive for a method of lowering free
fatty acid alone. The Semple and Lai references studied
lowering free fatty acids. The references showed that 3-(1H-
tetrazol- 5-yl)-2,4,5,6-tetrahydrocyclopentapyrazole was found
to lower plasma free fatty acids by activation of GPR109a,
which would result in similar “HDL-c elevating lowering effect
observed with nicotinic acid” in patients with specific disorders.
See Semple page 5104, column 2 and Lai page 376, column 2.
The studies linked lowering free fatty acids with a particular
disorder, such as dyslipidemia, but not the treatment of high-
density lipoprotein cholesterol, low-density lipoprotein
cholesterol, or triglycerides. . . . Based on the studies of
Stemple [sic] and Lai it appear that the lowering of free fatty
acids has been connected to disorders such as dyslipidemia,
high-density lipoprotein cholesterol, low density lipoprotein
cholesterol, or triglycerides and that 3-(1H-tetrazol-5-yl)-
2,4,5,6- tetrahydrocyclopentapyrazole has shown promise in the
lowering of free fatty acids connected to dyslipidemia, but not
high-density lipoprotein cholesterol, low-density lipoprotein
cholesterol, or triglycerides. Therefore, it is asserted that
lowering free fatty acids should be associated with a particular
disorder and patient population to be treated.
(Final Office Action June 1, 2010, pg. 4-5.)
The Examiner finds that patient populations vary “and that a
compound that works in one patient population may not work in another. . . .
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A healthy male individual is very different from an individual suffering from
type 2 diabetes or some other metabolic disorder” (Ans. 22), this finding is
supported by Lai. Lai provides that “[t]reatment with MK-0354 2500 mg for
4 weeks did not produce clinically meaningful changes in HDL-C, LDL-C,
or TG in dyslipidemic patients.” (Lai 380.) The claimed compound, MK-
0354, does not behave identically to niacin, therefore, what was known
about niacin in the art at the time of filing the present application cannot be
extrapolated to apply to the claimed compound. Lai further concedes that:
it is not understood why longterm treatment with MK-0354
failed to produce an altered global lipid profile similar to niacin.
It should be noted that the FFA-lowering response of MK-0354
was not evaluated in the Phase II study; thus it is possible that
tachyphylaxis occurred during the extended 4-week treatment
period. . . . [T]hese results may imply that mechanisms other
than GPR109A-mediated FFA suppression contribute to the
global lipid effects of niacin, and that MK-0354 is unable to
promote these effects.
(Lai 382.) Lai supports the Examiner’s position that treatment in a patient
population is unpredictable. Even when considering the post filing date
references cited by Appellants, we find that the Examiner has set forth a
reasonable explanation as to why the claimed composition is not enabled for
the full scope of “lowering free fatty acid” in any patient population as
claimed. Providing a starting point in the Specification for further research
in an unpredictable field does not provide enablement for the full scope of
the claims, as measure at the filing date. Wyeth and Cordis Corporation v.
Abbott Laboratories, ---F.3d ---, 2013 WL 3198008 (Fed. Cir. 2013).
We are therefore not persuaded by Appellants’ contention that the
Specification provides a nexus between the claimed compound and its
ability to lower free fatty acids in all possible patient populations as claimed.
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The evidence of record supports the Examiner’s conclusion that claim 67
fails to comply with the enablement requirement.

SUMMARY
We reverse the Examiner rejection of claims 65-67 under 35 U.S.C.
§ 112 first paragraph as being non-enabled with respect to the terms
“solvate” and “hydrate.”
We affirm the Examiner’s rejection of claim 67 under 35 U.S.C. § 112
first paragraph as being non-enabled with respect to the full scope of the
recited method.

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-IN-PART

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