Ex Parte Liu et al

Board of Patent Appeals and Interferences

Sep 15, 2010

10820647 (B.P.A.I. Sep. 15, 2010)

UNITED STATES PATENT AND TRADEMARK OFFICE
__________

BEFORE THE BOARD OF PATENT APPEALS
AND INTERFERENCES
__________

Ex parte KEVIN LIU and CUNXIANG ZHAO

Appeal 2009-015302
Application 10/820,647
Technology Center 1600
__________

Before TONI R. SCHEINER, LORA M. GREEN, and
FRANCISCO C. PRATS, Administrative Patent Judges.

SCHEINER, Administrative Patent Judge.

DECISION ON APPEAL1
This is an appeal under 35 U.S.C. § 134 from the final rejection of
claims 1-13, 18-36, 41-49, 51-57, and 59-69, directed to a pharmaceutical
compound and methods of using it. The claims have been rejected as
lacking enablement. 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, or for filing a request for rehearing,
as recited in 37 C.F.R. § 41.52, begins to run from the “MAIL DATE”
(paper delivery mode) or the “NOTIFICATION DATE” (electronic delivery
mode) shown on the PTOL-90A cover letter attached to this decision.

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STATEMENT OF THE CASE
“[T]he present invention relates to aryl compounds and methods for
treating various diseases by modulation of nuclear receptor mediated
processes . . . in particular processes mediated by peroxisome proliferator
activated receptors (PPARs)” (Spec. 1).
Representative claim 1 is directed to an aryl compound having the
structure of Formula I:

wherein [Ar1, Ar2, R1, R2, R3, B, and R4 are as detailed on page 25 of
Appellant’s Brief on Appeal, in the Claims Appendix],
“or a pharmaceutically acceptable N-oxide, pharmaceutically
acceptable prodrug, pharmaceutically active metabolite, pharmaceutically
acceptable salt, pharmaceutically acceptable ester, pharmaceutically
acceptable amide, or pharmaceutically acceptable solvate thereof.”
Representative claim 51 reads: “A method of modulating a
peroxisome proliferator-activated receptor (PPAR) function comprising
contacting said PPAR with a compound of Claim 1 and monitoring a change
in cell phenotype, cell proliferation, activity of said PPAR, or binding of said
PPAR with a natural binding partner.”
Representative claim 59 reads: “A method of treating a PPAR-
modulated disease or condition comprising identifying a patient in need
thereof, and administering a therapeutically effective amount of a compound
of Claim 1 to the patient.”
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Finally, representative claim 60 reads: “A method of treating a
metabolic disorder or condition comprising identifying a patient in need
thereof, and administering a therapeutically effective amount of a compound
of Claim 1 to the patient.”
The Examiner rejected the claims as follows:2
(A) Claims 1-13, 18-36, 41-49, 51-56, 59-64, and 66-69 under the
first paragraph of 35 U.S.C. § 112 “because the specification, while being
enabling for a compound of Formula I or a pharmaceutically acceptable N-
oxide or salt thereof, does not reasonably provide enablement for a
pharmaceutically acceptable prodrug, metabolite, ester, amide or solvate
thereof” (Ans. 4); and
(B) claims 51-57 and 59-65 under 35 U.S.C. § 112, first paragraph,
“because the specification, while being enabling for a method for treatment
of diabetes, does not reasonably provide enablement” for the various
methods recited in these claims (id. at 10).
We reverse.

ENABLEMENT REJECTION A
Findings of Fact
1. The Examiner rejected claims 1-13, 18-36, 41-49, 51-56, 59-64,
and 66-69 “because the specification, while being enabling for a compound
of Formula I or . . . [an] N-oxide or salt thereof does not reasonably provide
enablement for a pharmaceutically acceptable prodrug, metabolite, ester,
amide or solvate thereof” (Ans. 4).

2 Claims 50 and 70 have been allowed (Final Rej., October 4, 2007). Claims
14-16, 37-40, and 58 have been cancelled (App. Br. 3).
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2. The Specification teaches that an amide is “a chemical moiety
with formula -C(O)NHR or -NHC(O)R, where R is optionally substituted”
and “[a]ny amine, hydroxy, or carboxyl side chain on the compounds of the
present invention can be amidified” (Spec. 13).
3. “The procedures and specific groups to be used to . . . make[ ]
such amides are known to those of skill in the art and can readily be found in
reference sources such as Greene and Wuts, Protective Groups in Organic
Synthesis, 3rd Ed., . . . 1999, which is incorporated herein by reference”
(Spec. 13).
4. The Specification defines a prodrug as “an agent that is
converted into the parent drug in vivo” (Spec. 27).
An example . . . would be a compound of the present invention
which is administered as an ester (the “prodrug”) to facilitate
transmittal across a cell membrane where water solubility is
detrimental to mobility but which then is metabolically
hydrolyzed to the carboxylic acid, the active entity, once inside
the cell where water-solubility is beneficial. A further example
of a prodrug might be a short peptide (polyaminoacid) bonded
to an acid group where the peptide is metabolized to reveal the
active moiety.
(Id.)
5. The Specification teaches that “the compounds of the present
invention can exist in unsolvated as well as solvated forms with
pharmaceutically acceptable solvents such as water, ethanol, and the like”
(Spec. 19).
6. West,3 a reference cited by the Examiner, teaches that

3 ANTHONY R. WEST, SOLID STATE CHEMISTRY AND ITS APPLICATIONS 358,
365 (1988).
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The factors that govern whether or not solid solutions
[i.e., hydrates and solvates], especially the more complex ones,
form are understood only qualitatively. For a given system, it is
not usually possible to predict whether solid ‘solutions’ will
form or, if they do form, what is their compositional extent.
Instead, this has to be determined experimentally.
(West 365.)
7. Vippagunta,4 another reference cited by the Examiner, teaches:
Predicting the formation of solvates or hydrates of a
compound and the number of molecules of water or solvent
incorporated into the crystal lattice of a compound is complex
and difficult. Each solid compound responds uniquely to the
possible formation of solvates or hydrates and hence
generalizations cannot be made for a series of related
compounds. Certain molecular shapes and features favor the
formation of crystals without solvent; these compounds tend to
be stabilized by efficient packing of molecules in the crystal
lattice, whereas other crystal forms are more stable in the
presence of water and/or solvents. There may be too many
possibilities so that no computer programs are currently
available for predicting the crystal structures of hydrates and
solvates.
(Vippagunta 18.)
Discussion
The Examiner acknowledges that “[t]he term ‘prodrug’ [is] generally
known to represent ‘a physiologically functional derivative, for example, an
ester or an amide, which upon administration to a mammal is capable of
providing (directly or indirectly) a compound of the invention or an active
metabolite thereof’” (Ans. 4-5). In addition, the Examiner acknowledges

4 Sudha R. Vippagunta et al., Crystalline solids, 48 ADVANCED DRUG
DELIVERY REVIEWS 3-26 (2001).
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that “many strategies for making prodrugs” were known in the art at the time
of the invention (id. at 6).
However, the Examiner concludes that the Specification is not
enabling for prodrugs or pharmaceutically active metabolites of the
compound of Formula I because “[t]he term ‘prodrug and/or ‘metabolite’ is
directed to esters and amides of compounds of Formula I” (id. at 5), but the
“substituent groups in Formula I already include . . . acids, esters, amides,
etc.” (id.), and “[t]he specification does not provide what other ‘compounds’
. . . are intended to be the above refer[enc]ed ‘prodrugs’ and ‘metabolites’”
(id.). In other words, because the Specification doesn’t provide examples of
other amide or ester derivatives of the compound of Formula I capable of
functioning as prodrugs or pharmaceutically active metabolites, the
Examiner concludes “[i]n a clinical trial setting, it would require undue
experimentation to determine whether a particular compound meets the
criteria of a ‘prodrug’” or metabolite (id. at 6).
In addition, the Examiner concludes that “[t]he quantity of
experimentation needed [to make solvates of the compound of Formula I]
would be an undue burden on [one] skilled in the chemical art” (id. at 10)
because “[t]he state of the art is that [it] is not predictable whether solvates
will form or what their composition will be” (id. at 7). The Examiner notes
that “some of the exemplified compounds within the claimed genus were in
contact with solvent . . . [but] have not formed solvate” (id. at 6), thus,
“[t]here is no evidence that solvates of these compounds actually exist” (id.
at 9).

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Nevertheless,
[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 . . . [a] claim is not adequately enabled by the
description of the invention provided in the specification . . .
this includes . . . providing sufficient reasons for doubting any
assertions in the specification as to the scope of enablement. If
the PTO meets this burden, the burden then shifts to the
applicant to provide suitable proofs indicating that the
specification is indeed enabling.
In re Wright, 999 F.2d 1557, 1561-1562 (Fed. Cir. 1993).
In other words, “Section 112 does not require that a specification
convince persons skilled in the art that the assertions therein are correct.” In
re Armbruster, 512 F.2d 676, 678 (CCPA 1975). Instead, “it is incumbent
upon the Patent Office . . . to explain why it doubts the truth or accuracy of
any statement in a supporting disclosure and to back up assertions of its own
with acceptable evidence or reasoning which is inconsistent with the
contested statement.” In re Marzocchi, 439 F.2d 220, 224 (CCPA 1971).
Thus, the threshold issue raised by this rejection is not whether
Appellants have established that their Specification is enabling for making
prodrugs, pharmaceutically active metabolites, esters, amides or solvates of
the compound of Formula I. Rather, the issue is whether the Examiner has
met his initial burden of providing a reasonable explanation as to why it
isn’t.
The Examiner’s explanation as to why it would have required undue
experimentation for one skilled in the art to make and/or use prodrugs,
metabolites, esters, amides or solvates of the compound of Formula I is
insufficient to satisfy that initial burden.
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The determination of what constitutes undue experimentation in
a given case requires the application of a standard of
reasonableness, having due regard for the nature of the
invention and the state of the art . . . . The test is not merely
quantitative, since a considerable amount of experimentation is
permissible, if it is merely routine, or if the specification in
question provides a reasonable amount of guidance with respect
to the direction in which the experimentation should proceed to
enable the determination of how to practice a desired
embodiment of the invention claimed.
Ex parte Forman, 230 USPQ 546, 547 (BPAI 1986). “The key word is
‘undue,’ not ‘experimentation.’” In re Angstadt, 537 F.2d 498, 504 (CCPA
1976).
Essentially, we agree with Appellants that the Examiner has
overemphasized the importance of working examples (App. Br. 10), and
given “too little credit to the abilities of a person having ordinary skill in the
art” (id. at 11).
Even accepting that the experimentation required to produce prodrugs
and metabolites based on the compound of Formula I would be tedious and
time-consuming, the Examiner has not established that it would have been
anything other than routine and empirical for one of skill in the art.
In addition, while the West and Vippagunta references show that it is
difficult to predict whether a given compound will form a solvate or hydrate,
or what its composition will be, the references also provide evidence that
solvates and hydrates are routinely produced and characterized empirically
(FF 6, 7). As for the Examiner’s concern that some of the compounds of the
invention were in contact with solvents, but didn’t form solvates (Ans. 6),
Appellants point out that the examples in the Specification used “a drying
agent . . . to remove trace amounts of water as part of the purification
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process following a number of the chemical steps involved in the syntheses
of exemplary compounds” (App. Br. 14), thus, “conditions . . . were
unfavorable for solvate formation and therefore not indicative of the
nonexistence of solvates” (id. at 14-15).
Conclusion
The Examiner has failed to provide a reasonable explanation as to
why pharmaceutically acceptable prodrugs, metabolites, esters, amides or
solvates of Formula I are not adequately enabled by the description of the
invention provided in the Specification.

ENABLEMENT REJECTION B
Findings of Fact
8. The Examiner concedes that the Specification is enabling for a
method of treating diabetes, but maintains the rejection of claims 51-57 and
59-65 because
[T]he specification . . . does not reasonably provide enablement
for a method of modulating a peroxisome proliferator[]-
activated receptor (PPAR) function; a method of inhibiting the
formation of adipocytes in a mammal; a method of treating a
disease generally; a method of treating a PPAR-modulated
disease or condition or a metabolic disorder generally.
(Ans. 10.)
9. According to the Specification:
Biological processes modulated by PPAR . . . include, for
example, plasma lipid transport and fatty acid catabolism,
regulation of insulin sensitivity and blood glucose levels, which
are involved in hypoglycemia/hyperinsulinemia . . . ,
macrophage differentiation which lead to the formation of
atherosclerotic plaques, inflammatory response, carcinogenesis,
hyperplasia, and adipocyte formation.
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(Spec. 1-2.)
10. The Specification teaches that “[s]ubtypes of PPAR include
PPAR-alpha, PPAR-delta (also known as . . . PPAR-beta . . .) and two
isoforms of PPAR-gamma” (Spec. 2). All of the isoforms “have been shown
to be important molecular targets for treatment of metabolic and other
diseases” (id. at 3), and “[c]ompounds that activate or otherwise interact
with one or more of the PPARs have been implicated in the regulation of
triglyceride and cholesterol levels in animal models” (id. at 1).
11. According to the Specification, activators of PPAR-gamma
“have been clinically shown to enhance insulin-action, to reduce serum
glucose and to have small but significant effects on reducing serum
triglyceride levels in patients with Type 2 diabetes” (Spec. 2); and “have
been implicated in the treatment of polycystic ovary syndrome” (id. at 24).
12. “Pharmacological PPAR-alpha activators . . . are used
particularly for the treatment of hypertriglyceridemia, hyperlipidemia and
obesity” and “may be useful in treating atherosclerotic diseases” (Spec. 24-
25).
13. “PPAR-delta . . . has been shown to be a valuable molecular
target for treatment of dyslipedimia [sic] and other diseases” (Spec. 2).
14. The Specification teaches that
[T]he disease to be treated by the methods of the present
invention is selected from the group consisting of obesity,
diabetes, hyperinsulinemia, metabolic syndrome X, polycystic
ovary syndrome, climacteric, disorders associated with
oxidative stress, inflammatory response to tissue injury,
pathogenesis of emphysema, ischemia-associated organ injury,
doxorubicin-induced cardiac injury, drug-induced
hepatotoxicity, atherosclerosis, and hypertoxic lung injury.
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(Spec. 25.)
15. According to the Specification:
The term “modulate” refers to the ability of a compound
of the invention to alter the function of a PPAR. A modulator
may activate the activity of a PPAR, may activate or inhibit the
activity of a PPAR depending on the concentration of the
compound exposed to the PPAR, or may inhibit the activity of a
PPAR. The term “modulate” also refers to altering the function
of a PPAR by increasing or decreasing the probability that a
complex forms between a PPAR and a natural binding partner.
(Spec. 20-21.)
16. The Specification teaches that “[c]ompounds may be screened
for functional potency in transient transfection assays in CV-1 cells for their
ability to activate the PPAR [α, γ, and δ] subtypes” (Spec. 22). Eighteen
“compounds were evaluated in a cell-based [transfection] assay to determine
their human PPAR [α, γ, and δ] activity” (Spec. 48). The results, displayed
in the Table on pages 49-51 of the Specification, show that most of the
compounds tested were able to activate two or more PPAR subtypes under
experimental conditions, while a few compounds were unable to activate any
subtype at all.
17. Fayer,5 a reference cited by the Examiner, teaches that there is a
“[l]ack of correlation between in vitro inhibition of CYP3A-mediated
metabolism by [RG 12525] a PPAR-gamma agonist and its effect on the
clinical pharmacokinetics of midazolam, an in vivo probe of CYP3A

5 JL Fayer et al., Lack of correlation between in vitro inhibition of CYP3A-
mediated metabolism by a PPAR-gamma agonist and its effect on the
clinical pharmacokinetics of midazolam, an in vivo probe of CYP3A activity,
41 J. CLIN. PHARMACOL. 305-316 (2001) (Abstract only).

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activity,” probably due to “the high degree of RG 12525 protein binding”
(Fayer, Abstract). Fayer emphasizes “the need to recognize factors other
than plasma drug concentrations and potency of in vitro enzyme inhibition
when extrapolating in vitro data to predict in vivo drug-drug interactions”
(id.).
Discussion
The threshold issue raised by this rejection is whether the Examiner
has met his initial burden of providing a reasonable explanation as to why
the Specification isn’t enabling for using the compounds of Formula I to
modulate a PPAR function, treat a PPAR-modulated disease or condition,
inhibit the formation of adipocytes, treat a metabolic disorder, or treat a
variety of specifically identified diseases.
With respect to claims 51 and 52, directed to “modulating a PPAR
function,” the Examiner argues that modulating “generally encompasses
blocking, activating, partial blocking and partial activating. However, the
compounds were not shown to have all these properties . . . [and] it is
revolutionary for a compound to be effective as a blocker, activator and
partial blocker/activator” (Ans. 11).
However, the Examiner’s interpretation of the term “modulating”
doesn’t comport with the Specification’s definition of the term (FF15). We
agree with Appellants that “nowhere in the specification is it suggested that
any of the claimed compounds have the ability to block, activate partially
block and partially activate a PPAR function at the same time” (App. Br.
18).
With respect to the remaining claims, the Examiner finds that “one
having ordinary skill in the art would have to undergo an undue amount of
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experimentation to use the claimed compounds as PPAR regulators” (Ans.
11), because PPAR activity “is highly structure specific and unpredictable as
can be seen from the range of the results obtained for the tested compounds”
(id. at 10-11).
However, the “range of results” obtained for the 18 compounds tested
simply reflects the fact that most of the compounds were able to activate two
or more PPAR subtypes, while a few were unable to activate any subtype at
all (FF16). The Specification teaches, and the Examiner does not dispute,
that all of the isoforms “have been shown to be important molecular targets
for treatment of metabolic and other diseases” (Spec. 3; FF10) - so it’s not
clear why structure specificity would be a problem, especially as the
Specification discloses an assay for determining subtype specificity.
The Examiner also argues that “there is no evidence on record which
demonstrates that the in-vitro screening tests relied upon are recognized in
the art as being reasonably predictive of success in any of the contemplated
areas of regulating PPAR” (Ans. 11). The Examiner cites Fayer as evidence
that “such correlation or lack thereof is important to predict drug-drug
interactions” (id.), but doesn’t elaborate further.
Again, it is the Examiner’s initial burden to “to explain why it doubts
the truth or accuracy of any statement in a supporting disclosure and to back
up assertions of its own with acceptable evidence or reasoning which is
inconsistent with the contested statement.” Marzocchi, 439 F.2d at 224.
The Examiner has not done so.
Finally, the Examiner acknowledges that the Specification “provides a
select list of disorders such as diabetes, hyperinsulinemia, atherosclerosis,
etc.” (Ans. 12) to be treated with the compounds of Formula I, but argues
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that “[c]laims are drawn to a method for treatment of ‘a PPAR-modulated
disease or condition’ . . . include[ ] disorders that are known to exist and
those that may be discovered in the future and therefore, [are] extremely
broad” (id.).
Nevertheless, it is well settled that the purpose of the Specification is
not to “enable technology that arises after the date of application. The law
does not expect an applicant to disclose knowledge invented or developed
after the filing date. Such disclosure would be impossible.” Chiron Corp. v.
Genentech, Inc., 363 F.3d 1247, 1254 (Fed. Cir. 2004).
Conclusions
The Examiner has failed to meet the initial burden of providing a
reasonable explanation as to why the Specification isn’t enabling for using
the compounds of Formula I to modulate a PPAR function, treat a PPAR-
modulated disease or condition, inhibit the formation of adipocytes, treat a
metabolic disorder, or treat a variety of specifically identified diseases.
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SUMMARY
(A) The rejection of claims 1-13, 18-36, 41-49, 51-56, 59-64, and 66-
69 under the enablement provision of 35 U.S.C. § 112, first paragraph, is
reversed.
(B) The rejection of claims 51-57 and 59-65 under the enablement
provision of 35 U.S.C. § 112, first paragraph, is reversed.

REVERSED

cdc

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