Neptune Generics LLCv.AUSPEX Pharmaceuticals, Inc.

Patent Trial and Appeal Board

Dec 9, 2015

11565451 (P.T.A.B. Dec. 9, 2015)

Trials@uspto.gov Paper No. 25
571.272.7822 Entered: December 9, 2015

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

NEPTUNE GENERICS, LLC.,
Petitioner,

v.

AUSPEX PHARMACEUTICALS, INC.,
Patent Owner.
____________

Case IPR2015-01313
Patent 7,456,317 B2
____________

Before LORA M. GREEN, DEBORAH KATZ, and
JACQUELINE WRIGHT BONILLA, Administrative Patent Judges.

GREEN, Administrative Patent Judge.

DECISION
Denying Institution of Inter Partes Review
37 C.F.R. § 42.108

IPR2015-01313
Patent 7,456,317 B2

2
INTRODUCTION I.
Neptune Generics, LLC (“Petitioner”) filed a Petition requesting an
inter partes review of claims 1–10 of U.S. Patent No. 7,465,317 B2 (Ex.
1001, “the ’317 patent”). Paper 1 (“Pet.”). Auspex Pharmaceuticals, Inc.
(“Patent Owner”) filed a Preliminary Response to the Petition. Paper 13
(“Prelim. Resp.”).
An inter partes review may not be instituted “unless . . . there is a
reasonable likelihood that the petitioner would prevail with respect to at least
1 of the claims challenged in the petition.” 35 U.S.C. § 314. Upon
considering the Petition and the Preliminary Response, we determine that
Petitioner has not shown a reasonable likelihood that it would prevail in
showing the unpatentability of claims 1–10. Accordingly, we decline to
institute an inter partes review of the challenged claims.
A. Related Proceedings
Petitioner states that it “is unaware of any other matters related to the
’317 patent.” Pet. 6; see also Paper 7 (stating that there “is no related
litigation pending,” and “no related inter partes or other administrative
review proceedings pending”).
B. The ’317 Patent (Ex. 1001)
The ’317 patent issued on November 25, 2008, with Thomas G. Gant
and Sepehr Sarshar as the listed inventors. Ex. 1001. The claims of the ’317
patent are drawn to a deuterated form of venlafaxine (“VF”), an inhibitor of
monoamine neurotransmitters. Id. at 69:30–70:38, 1:20–34.
The ’317 patent teaches that the human body expresses several
enzymes that aid in breaking down or solubilizing nutrients and chemicals
that have been absorbed into the blood, producing novel intermediates or
IPR2015-01313
Patent 7,456,317 B2

3
metabolites. Id. at 1:37–42. Those enzymes include cytochrome P-450
enzymes (also referred to as “CYPs”), esterases, proteases, reductases, and
others. Id. at 1:39–41. As taught by the ’317 patent:
Some of the most common metabolic reactions of
pharmaceutical compounds involve the oxidation of a carbon-
hydrogen (C–H) bond to either a carbon-oxygen (C–O) or
carbon-carbon (C–C) π-bond. The resultant metabolites may be
stable or unstable under physiological conditions, and can have
substantially different pharmacokinetic, pharmacodynamic,
acute and long-term toxicity profiles relative to the parent
compounds. For most drugs, such oxidations are generally
rapid and ultimately lead to administration of multiple or high
daily doses. There is therefore an obvious and immediate need
for improvements of such drugs.
Id. at 1:43–53.
The ’317 patent teaches that the chemical bond between a carbon and
deuterium (an isotope of hydrogen) is stronger than the bond between a
carbon and hydrogen. Id. at 2:45–53. Thus, if breaking a carbon-hydrogen
bond is a rate limiting step in a reaction, substituting the hydrogen with
deuterium will decrease the reaction rate, slowing the reaction down. Id.
That phenomenon is known as the deuterium kinetic isotope effect, and can
range from a value of 1, with no isotope effect, to over 50, in which the
substitution of deuterium with hydrogen makes the reaction proceed 50
times more slowly. Id. at 2:54–58.
According to the ’317 patent, “[d]euteration of pharmaceuticals to
improve pharmokinetics (PK), pharmacodynamics (PD), and toxicity
profiles, has been demonstrated previously with some classes of drugs.” Id.
at 3:47–49. The ’317 patent teaches that the method, however, may not be
applicable to all classes of pharmaceuticals due to the phenomenon of
metabolic switching, which can lead to different proportions of known
IPR2015-01313
Patent 7,456,317 B2

4
metabolites, as well as the production of new metabolites, which may impart
more or less toxicity. Id. at 3:52–65.
During prosecution of the ’317 patent, in the statement of the reasons
for allowance, the Examiner noted:
The prior art neither teaches, nor suggests the limitations
of Applicant’s claims . . . . Nor would it have been obvious to
modify the prior art’s venlafaxine to arrive at the instantly
claimed invention. There is no teaching in the prior art that
correlates improvements in the pharmacological properties of
venlafaxine with the instantly claimed D-9 deuterated
derivatives of venlafaxine. In addition, venlafaxine has 27
positions that can be deuterated, along with 134,217,727
potential deuterated analogs of venlafaxine. Because of the
large number of possible deuterated analogs of venlafaxine, it
would not be “obvious to try” to synthesize the instantly
claimed D-9 deuterated derivative of venlafaxine.
Ex. 2032, 3.
C. Illustrative Claim
Petitioner challenges claims 1–10 of the ’317 patent. Claim 1 is the
only independent claim, is illustrative, and is reproduced below, with the
symbol “D” in the structural formula indicating a deuterium:
1. A compound having the structural formula:

or a pharmaceutically acceptable salt, solvate, or prodrug
thereof.

IPR2015-01313
Patent 7,456,317 B2

5
C. The Asserted Grounds of Unpatentability
Petitioner challenges the patentability of claims 1–10 of the
’317 patent on the following grounds (Pet. 7–8):
References Basis Claims Challenged
Fogelman1 and Miwa2 § 103(a) 1
Fogelman, Miwa , and
Platteeuw3
§ 103(a) 2 and 8
Fogelman, Miwa , Platteeuw,
and Jerussi4
§ 103(a) 3–7, 9, and 10

ANALYSIS II.
A. Claim Construction
In an inter partes review, claim terms in an unexpired patent are
interpreted according to their broadest reasonable construction in light of the
specification of the patent in which they appear. 37 C.F.R. § 42.100(b); In
re Cuozzo Speed Techs., LLC, 793 F.3d 1268, 1276–79 (Fed. Cir. 2015);
Office Patent Trial Practice Guide, 77 Fed. Reg. 48,756, 48,766
(Aug. 14, 2012). Claim terms also are given their ordinary and customary
meaning, as would be understood by one of ordinary skill in the art in the
context of the entire disclosure. In re Translogic Tech., Inc., 504 F.3d 1249,

1 Fogelman et al. (“Fogelman”), O- and N-demethylation of Venlafaxine In
Vitro by Human Liver Microsomes and by Microsomes from cDNA-
Transfected Cells: Effet of Metabolic Inhibitors and SSRI Antidepressants,
20 NEUROPSYCHOPHARMACOLOGY 480–490 (1999) (Ex. 1003).
2 GERALD T. MIWA AND ANTHONY Y. H. LU (“MIWA”), Kinetic Isotope
Effects and ‘Metabolic Switching’ in Cytochrome P450-Catalyzed
Reactions, 7 BIOESSAYS 215–19 (1987) (Ex. 1004).
3 Platteeuw et al. (“Platteeuw), US 2003/0190351 AI, published Oct. 9, 2003
(Ex. 1005).
4 Jerussi et al., (“Jerussi”), US 6,197,828 B1, issued Mar. 6, 2001(Ex. 1006).
IPR2015-01313
Patent 7,456,317 B2

6
1257 (Fed. Cir. 2007). Only terms which are in controversy need to be
construed, and then only to the extent necessary to resolve the controversy.
Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir.
1999). We determine that explicit construction of any specific claim term is
not necessary to determine whether to institute a trial in this case.
B. Obviousness of Claim 1 Over the Combination of
Fogelman (Ex. 1003) and Miwa (Ex. 1004)
Petitioner asserts that claim 1 is rendered obvious by the combination
of Fogelman and Miwa. Pet. 22–30.
i. Overview of Fogelman (Ex. 1003)
Fogelman studied the transformation of VF into its two major
metabolites—O-desmethylvenlafaxine (“ODV”) and N-
desmethylvenlafaxine (“NDV”). Ex. 1003, Abstract. Fogelman teaches that
VF is transformed in the liver to ODV, NDV, and N,O-
didesmethylvenlafaxine (“N,O-DV”). Id. at 481. According to Fogelman,
“ODV has a receptor affinity profile similar to its parent compound VF,
while the latter two metabolites have little if any affinity for the . . . receptor
sites.” Id.

IPR2015-01313
Patent 7,456,317 B2

7
Table 4 of Fogelman is reproduced below.

Id. at 486. Table 4 provides details of the formation of ODV and NDV by
microsomes containing human cytochromes expressed by cDNA-transfected
human lymphoblastoid cells. Id.
Fogelman found that “[u]sing the Vmax//Km ratio as a quantity to
estimate intrinsic clearance, approximately 90% of total intrinsic clearance
was accounted for by the O-demethylation pathway.” Id. at 483.
ii. Overview of Miwa (Ex. 1004)
Miwa is a review of kinetic isotope effect and “metabolic switching”
in cytochrome P-450-catalyzed reactions. Ex. 1004, Summary. Miwa
teaches that the carbon-deuterium bond is stronger than the carbon-hydrogen
bond, and thus many reactions that involve cleavage of that bond are
IPR2015-01313
Patent 7,456,317 B2

8
retarded by deuterium substitution, a phenomenon known as kinetic isotope
effect. Id. at 215. Miwa teaches:
In most enzymic reactions involving a C-H bond
cleavage step, the reduction in product formation for the
deuterated substrate is accompanied by a concomitant decrease
in substrate metabolism. The tight complimentary binding
between the substrate and the enzyme active site places severe
restrictions on alternative orientations of the substrate, thus
limiting metabolism to only a single site. In contrast, an
unexpected change in regional selectivity was observed when
the products of cytochrome P-450-catalyzed reactions were
carefully determined. . . . [T]he term ‘metabolic switching’
[has been coined] to describe this change in selectivity during
the metabolism of deuterated substrates. In this essay,
‘metabolic switching’ is defined more generally and refers to
the increase in substrate flux through alternative pathways,
catalyzed by either cytochrome P-450 or alternate enzymes,
when the primary pathway for metabolism is reduced by a
hydrogen isotope or other substituents.
Id. (reference omitted).
Thus, Miwa teaches that for some drugs, isotope substitution (i.e.,
from hydrogen to deuterium) may reduce the rate of drug metabolism, and,
therefore, may reduce the rate of clearance of the drug from the body. Id. at
218. Miwa teaches further, however, that for other drugs, isotope
substitution may not give rise to significant isotope effects in metabolism or
clearance, which may be due to the lack of contribution of C-H bond in the
overall metabolism of the drug, or because of metabolic switching, which
results in the potentiation of other metabolic pathways. Id. When metabolic
switching occurs, the pharmacological and toxicological consequences
depend on the new metabolic pathway, which may either enhance or inhibit
the production of toxic metabolites. Id.
IPR2015-01313
Patent 7,456,317 B2

9
ii. Analysis
Petitioner asserts that claim 1 is unpatentable as being rendered
obvious by the combination of Fogelman and Miwa. Pet. 22–30. Petitioner
relies on the Declaration of Dr. William Braunlin (Ex. 1002) to support its
obviousness challenge. Patent Owner disagrees. Prelim. Resp. 20–36.
Petitioner relies on Fogelman for teaching that the transformation of
VF to ODV is the major pathway for clearance of VF. Pet. 24 (citing Ex.
1002 ¶ 15). Petitioner relies also on Fogelman for teaching the major
metabolites of VF, the specific P-450 enzymes responsible for the
production of the O-demethylation and N-demethylation metabolism
products of VF, as well as the extent of which P-450 enzyme is responsible
for the production of those products. Id. at 23–24.
Petitioner relies on Miwa for demonstrating that the use of strategic
deuteration of the active sites of pharmaceutically active compounds to alter
their preferred metabolic route and rate of clearance was known. Id. at 24.
Miwa is also relied upon for its teaching that the possibility of metabolic
switching was known, as well as the factors that may influence its
occurrence. Id. (citing Ex. 1002 ¶ 16).
Petitioner relies on Dr. Braunlin for his statement that an important
aspect of the effectiveness of a particular drug “is how long it remains in the
body before being metabolized and cleared from the body.” Id. at 28
(quoting Ex. 1002 ¶ 19). Fogelman teaches that the major pathway of
clearance for VF is through the ODV pathway, and that approximately 90%
of total intrinsic clearance is through that pathway. Id. at 29 (citing Ex. 1002
¶ 19). Thus, Petitioner contends that “one of ordinary skill in the art would
have been motivated to deuterate the drug venlafaxine at the sites acted upon
IPR2015-01313
Patent 7,456,317 B2

10
by cytochrome P-450 enzymes in order to reduce the rate of venlafaxine
metabolism, reduce the clearance of venlafaxine from the body and improve
the duration of action and peak plasma levels of venlafaxine.” Id. at 29–30
(quoting Ex. 1002 ¶ 19).
As for a reasonable expectation of success, Petitioner relies on the
Declaration of Dr. Braunlin for the explanation that VF has only two
cytochrome P-450 enzyme active sites that would be expected to be
successful for deuteration, the carboxymethyl oxygen and the two methyl
groups on the nitrogen. Id. at 30 (citing Ex. 1002 ¶ 20). Thus, Petitioner
contends that “a person of ordinary skill in the art would have had a
reasonable expectation of success in determining the sites for deuteration
that are recited in claim 1 of the ’317 patent.” Id. (citing Ex. 1002 ¶¶ 19–
20).
Patent Owner responds that it is not possible to predict whether any
given kinetic isotope effect will provide a beneficial change in metabolism
without extensive testing. Prelim. Resp. 22 (citing Ex. 2021, 5 404–406).
Specifically, Patent Owner argues that a primary deuterium kinetic isotope
effect “will only be observed if the breaking of the carbon-hydrogen bond is
the rate-limiting step.” Id. at 23 (reference omitted) (citing Ex. 2020,6 102).
According to Patent Owner, the evidence of record demonstrates that the
ordinary artisan would not have known, nor been able to predict, the
rate-limiting step of P-450 mediated metabolic oxidation of VF. Id.

5 Scott L. Harbeson and Roger D. Tung (“Harbeson”), Deuterium in Drug
Discovery and Development, 46 ANNUAL REPORTS IN MEDICINAL
CHEMISTRY 403–417 (John E. Macor, Ed., 2011).
6 Fisher et al. (“Fisher”), The Complexities Inherent in Attempts to Decrease
Drug Clearance by Blocking Sites of CYP-Mediated Metabolism, 9
CURRENT OPINION IN DRUG DISCOVERY & DEVELOPMENT 101–109 (2006).
IPR2015-01313
Patent 7,456,317 B2

11
Patent Owner cites to evidence that shows that even if the breaking of
the carbon-hydrogen bond is the rate-limiting step of P-450 mediated
metabolic oxidation of VF, the evidence of record demonstrates further that
the ordinary artisan would not have been able to predict the magnitude of the
deuterium substitution effect. Id. at 24 (citing Ex. 2021, 104). If the effect
is too low, there may be no impact on the metabolism of the drug, and if it is
too high, metabolic switching may occur. Id. (citing Ex. 2020, 102–104).
Patent Owner cites to evidence that the ordinary artisan would not have been
able to predict the metabolites that would be formed by metabolic switching,
nor the impact of those metabolites. Id. at 26 (citing Ex. 1004, 218).
Thus, Patent Owner contends that the ordinary artisan would not have
had a reasonable expectation of success of deuterating VF to achieve a
molecule with improved duration of action and peak plasma levels. Id. at
27. In fact, according to Patent Owner, Miwa—relied upon by Petitioner—
teaches that “isotope substitution may not give rise to significant isotope
effects in metabolism or clearance.” Id. (quoting Ex. 1004, 218).
As noted above, Petitioner relies on Fogelman for teaching that the
major pathway for clearance of VF is oxidation to its major metabolite,
ODV. Id. at 28. In that pathway, the methoxy group is converted to a
hydroxyl, and thus, according to Petitioner, it would have been obvious to
replace the -OH3 group with an -OD3 group to replace the rate of clearance
of VF. Id. Patent Owner argues, however, that “the exact opposite effect
occurred for two deuterated forms of paroxetine in which methylene
hydrogens adjacent to an oxygen were substituted with deuterium.” Id.
(citing Ex. 2021, 413–414). Patent Owner points out that deuterium
IPR2015-01313
Patent 7,456,317 B2

12
substitution of paroxetine, which is also a serotonin reuptake inhibitor,
resulted in an increase in metabolism, not a decrease. Id. at 28–29.
Patent Owner argues further that the compound of claim 1 is not just
the substitution of an -OH3 group with an -OD3 group, but also replaces the
hydrogen with deuterium on two N-methyl groups, making for a total of nine
replacements, leaving the other hydrogens on the compound unreplaced. Id.
at 29. The deuteration of alkyl groups in an N-alkylated compound, Patent
Owner contends, is also not predictable. Id. at 30. According to Patent
Owner, when phentermine was tested, which has a N-di-(tri-deuteromethyl)
group similar to VF, no deuterium kinetic isotope effect was observed. Id.
(citing Ex. 2019,7 22–23).
And even if decreased metabolism is observed, Patent Owner argues,
there may be no net benefit in vivo. Id. Patent Owner cites studies of
tramadol, which is also a serotonin reuptake inhibitor, and which, Patent
Owner argues, shares many structural features with VF, and is also
metabolized via O- and N-demethylation. Id. at 31. Patent Owner argues
that although some of the deuterated versions of tramadol that were
prepared, including a d9-tramadol, “exhibited reduced in vitro metabolism,
none of the prepared deuterated versions were superior to tramadol in terms
of potency or duration of effect; clearance was not reduced and half-life was
not increased.” Id. (citing Ex. 2026,8 692–693). According to Patent
Owner, the “deuterated venlafaxine claimed in the ’317 patent, however, has

7 Allan B. Foster (“Foster”), Deuterium Isotope Effects in the Metabolism of
Drugs and Xenobiotics: Implications for Drug Design, 14 ADVANCES IN
DRUG RESEARCH 1–40 (1985).
8 Shao et al. (“Shao”), Derivatives of Tramadol for Increased Duration of
Effect, 16 BIOORGANIC & MEDICINAL CHEMISTRY LETTERS 691–94 (2006).
IPR2015-01313
Patent 7,456,317 B2

13
superior pharmacokinetic properties compared to venlafaxine, including
increased half-life, reduced Cmax, and reduced inter-patient variability.” Id.
(citing Ex. 20189).
Patent Owner contends also that “Petitioner provides no credible
motivation . . . to modify venlafaxine by deuteration.” Id. at 31. Petitioner,
Patent Owner asserts, relies on the unsupported assertion of its expert that
the ordinary artisan would have been motivate to deuterated the sites acted
upon by cytochrome P-450 to reduce the rate of metabolism and clearance of
VF, thereby improving its peak plasma levels and its duration of action. Id.
at 32. The prior art, however, teaches that ODV has the same
pharmacological activity of VF, but that it has a longer duration of action
and is more potent than VF. Id. According to Patent Owner, the Petition
does not identify a reason why the ordinary artisan would want to deuterate
VF to inhibit ODV production given its useful pharmacologic activity,
arguing that “[t]his flaw exemplifies the unfounded generalizations that
characterize Petitioner’s arguments.” Id.
We recognize that an obvious analysis requires us to consider whether
an ordinary artisan would have had a reasonable expectation of success, not
absolute predictability of success. In re O’Farrell, 853 F.2d 894, 903–904
(Fed. Cir. 1988). We agree with Patent Owner, however, that Petitioner has
not demonstrated that the ordinary artisan would have combined Fogelman
with Miwa with a reasonable expectation of arriving at the invention claimed
by the ’317 patent. Although Fogelman teaches that ODV may account for
90% of the pathway for intrinsic clearance of VF (Ex. 1003, 483), Fogelman

9 Amanda Yarnell, Heavy Hydrogen Drugs Turn Heads, Again, 87(25)
Chem, Eng. News 36–39 (2009).
IPR2015-01313
Patent 7,456,317 B2

14
teaches also that ODV has a receptor affinity profile similar to its parent
compound VF (id. at 481). As noted by Patent Owner (Prelim. Resp. 32),
Petitioner has not explained, through evidence or adequate scientific
reasoning, why the ordinary artisan would have wanted to prevent the
metabolism of VF to its pharmaceutically active metabolite, ODV. Stated
differently, because ODV is a desired metabolite, as it has the same
pharmacological activity as its parent compound, VF, Petitioner has not
explained why the ordinary artisan would have had a reason to prevent VF
from being metabolized to ODV, rather than only preventing metabolism to
a non-active metabolite, or make a substitution that would prevent the
further metabolism of ODV.
In addition, Miwa teaches that isotope substitution may not give rise
to significant isotope effects in metabolism or clearance, which may be due
to the lack of contribution of C-H bond in the overall metabolism of the
drug. Ex. 1004, 218. Fisher, relied upon by Patent Owner, also states that if
cleavage of the C-H bond is the rate-limiting step, the turnover of the drug
would depend on deuterium substitution. Ex. 2020, 102. Fisher notes,
however, that other steps, such as product release, may be rate-limiting, and
thus, suppress any isotope effect. Id. Thus, according to Fisher, “deuterium
isotope effect theory and the mechanism of CYP enzymes taken together
suggest that the strategy will usually not result in significant alterations in
overall metabolic clearance of the substrate.” Id. at 101–102. In addition,
Harbeson, also cited by Patent Owner, teaches that “[i]t is difficult to predict
a priori which effect deuterium may have on a drug’s metabolism.”
Ex. 2021, 404. Harbeson notes that while a deuterium isotope effect has the
potential to affect the metabolism of drugs that are metabolized by the
IPR2015-01313
Patent 7,456,317 B2

15
cleavage of a C-H bond, in practice, the effect is often masked. Id. at 405.
Thus, the evidence of record demonstrates that it was not predictable what
would be the effect of replacing one or more hydrogens of VF with
deuterium on the metabolism of VF by the P-450 enzymes. That is,
although Petitioner argues that it would be obvious to substitute the two
main sites of VF acted upon by the P-450 enzymes, that is, -OCH3 and
–N(CH3)2 (Pet. 10–11), due to the presence of other possible rate-limiting
steps, as well as the possibility of metabolic switching, the ordinary artisan
would not have had a reasonable expectation that substitution of all of the
nine hydrogens at those sites for deuterium would result in a deuterated VF
derivative having enhanced bioavailability and which maintains its activity
for a longer period of time.
That conclusion is supported further by evidence relied upon by
Patent Owner. For example, Harbeson, cited by Patent Owner, teaches that
while one deuterated analog of paroxetine, whose structure is unknown,
mitigated inactivation by a P-450 enzyme in a clinical setting, two other
analogs, with structures 16 and 17 showed increased metabolism in vivo.
Ex. 2021, 413. Structures 16 and 17 are reproduced below.

IPR2015-01313
Patent 7,456,317 B2

16
Patent Owner notes that methylene hydrogens adjacent to an oxygen were
substituted with deuterium (Prelim. Resp. 28), which Petitioner argues
would have been obvious to do with VF (Pet. 29–30).
Patent Owner notes further that when phentermine was tested, which
has a N-di-(tri-deuteromethyl) group similar to VF, no deuterium kinetic
isotope effect was observed. Prelim. Resp. 30 (citing Ex. 2019, 22–23). The
structures of N,N-dimethylphenteramine (Formula 87), and its deuterated
derivatives (Formulas 88 and 89), are reproduced below:

Ex. 2019, 23. Foster teaches that it was found that the C-H bond did not
contribute to the rate-limiting step, and that the N-demethylation could
involve a transition state different from that associated with
O-demethylation. Id.
Shao, also cited by Patent Owner (Prelim. Resp. 30–31), demonstrates
that even if deuteration slows the formation of major metabolites, there may
be no in vivo effect. Ex. 2026, 693–94. Shao looked at deuteration of
tramadol, which is used in the treatment of moderate to moderately severe
pain. Id. at 691. The structures of tramadol (Formula 1), and its major
metabolite, M1, are reproduced below:
IPR2015-01313
Patent 7,456,317 B2

17

Id.
Shao attempted to slow CYP450-mediated metabolism by replacing
hydrogen with deuterium at metabolically active sites, that is, by replacing
the hydrogen atoms at the O-methyl and N-methyl groups, as demonstrated
below:

Id.
As reported by Shao:
In conclusion, the substitution of deuterium for hydrogen
in the methyl groups of tramadol did not adversely affect the in
vitro binding affinity. In vitro testing in human microsomes
confirmed that replacing hydrogen with deuterium in the
metabolically labile O-methyl position of 1 slowed the
formation of the primary metabolite M1 by approximately 5-
fold. The deuterated derivatives 7 (D6) and 9 (D9) were active
IPR2015-01313
Patent 7,456,317 B2

18
analgesics in the rat tail-flick model, but were not superior to
tramadol in terms of potency or duration of effect. Deuterium
for hydrogen replacement at metabolically active sites had no
obvious deleterious effects in vivo but did not result in a longer
duration of effect. In this case, deuteration at metabolically
active sites produced a pharmacological agent equipotent in
vivo with tramadol.

Id. at 693–694.
Thus, the evidence of record demonstrates that the effect of the
deuteration on the metabolic and pharmacologic properties of a drug are
unpredictable, and thereby supports Patent Owner’s contention that the
ordinary artisan would not have had a reasonable expectation of success at
arriving at the invention claimed by the ’317 patent. We have considered
the Declaration of Dr. Braunlin, relied upon by Petitioner to demonstrate a
reasonable expectation of success (Pet. 30), but it does not convince us
otherwise.
Dr. Braunlin states:
It is my opinion that a person of ordinary skill in the art
would have had a reasonable expectation of success of
achieving the claimed invention. As taught by Miwa, strategic
deuteration of active sites on drugs to alter their preferred
metabolic route and rate of clearance was known. And, in
terms of functionality, there are only two cytochrome P-450
enzyme active sites on venlafaxine that would be expected to be
successful sites for deuteration: -CD3 substitution of the
carboxymethyl oxygen and -CD3 substitution of the two methyl
groups on nitrogen.
Ex. 1002 ¶ 20. Dr. Braunlin opines further that as the primary metabolic
pathway involves O-demethylation, “it makes sense to fully deuterate the
single O-methyl group to enhance bioavailability and maintain activity for a
longer prior to elimination.” Id. ¶ 21. Relying on a reference to Foster (for
IPR2015-01313
Patent 7,456,317 B2

19
which an exhibit number was not provided nor appear does the reference
appear to be made of record), Dr. Braunlin states that O-methyl deuteration
has a “very large isotope effect.” Id. Because the second pathway involved
N-demethylation, Dr. Braunlin concludes “a person of ordinary skill in the
art would have had a reasonable expectation of success in determining sites
for deuteration that are recited in claim 1 of the ’317 patent.” Id.
As discussed above, although Miwa teaches that the use of deuteration
to alter drug clearance rate was known, Miwa teaches also that for some
drugs, isotope substitution may not give rise to significant isotope effects in
metabolism or clearance. Ex. 1004, 218. The lack of a kinetic isotope effect
may be due to the lack of contribution of C-H bond in the overall
metabolism of the drug, or because of metabolic switching, which results in
the potentiation of other metabolic pathways. Id. Thus, Miwa supports the
unpredictability of the effect of substituting deuterium for hydrogen on the
pharmacological and toxicological effects of a drug. Moreover, the
reference relied upon by Dr. Braunlin to support his statement that O-methyl
deuteration has a “very large isotope effect” was not provided; whereas
Shao, relied upon by Patent Owner demonstrates that deuteration of the
O-methyl group of tramadol had no in vivo effect. Ex. 2026, 693–694.
Patent Owner argues further that the Petition does not demonstrate
that it would have been obvious to try deuteration of VF to arrive at the
claims of the ’317 patent. Prelim. Resp. 32. In particular, Patent Owner
notes that there were not a finite number of identified, predictable solutions,
as there are approximately 227-1, or 124,217,727 deuterated forms of VF,
minus some number of forms which are equivalent due to symmetry or
rotatable bonds. Id. at 32–33, 35. According to Patent Owner, “[t]o explore
IPR2015-01313
Patent 7,456,317 B2

20
all of these possibilities would be to vary all parameters in the bare hope of
success.” Id. at 35.
We agree. In In re O’Farrell, the Federal Circuit set forth two
situations in which an “obvious to try” rationale was usually applied
improperly. In re O’Farrell, 853 F.2d at 903. The first improper situation
was 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 are critical or no direction as to which of
many possible choices is likely to be successful.” Id. The second improper
situation was to explore a new technology or general approach that seemed
to be a promising field of experimentation, where the prior art gave only
general guidance as to the particular form of the claimed invention or how to
achieve it.” Id.; see also In re Kubin, 561 F.3d 1351, 1358–1360 (Fed. Cir.
2009) (noting that the rationale in O’Farrell was “affirmed in the logical
inverse” in KSR, 550 U.S. at 417, in a statement that “§103 bars patentability
unless ‘the improvement is more than the predictable use of prior art
elements according to their established functions.’”).
Based on the above framework, we conclude that it would not have
been obvious to try to achieve the invention of claim 1 of the ’317 patent.
As noted by Patent Owner (Prelim. Resp. 35), and not disputed by Petitioner
(see Pet. 10–11), there are approximately 227-1, or 124,217,727 deuterated
forms of VF, minus some number of forms which are equivalent due to
symmetry or rotatable bonds. Although Petitioner contends that as P-450
enzymes act on two main sites of VF—that is, -OCH3 and –N(CH3)2,
arguing that it would have been obvious to deuterate only those sites (Pet.
10–11)—as discussed above, the ordinary artisan would not have had a
IPR2015-01313
Patent 7,456,317 B2

21
reasonable expectation that deuteration of those sites would result in
enhanced bioavailability and maintaining the activity of VF for a longer
period of time. Thus, the ordinary artisan would be left with trying the over
100,000,000 possible deuterated forms of VF until possibly arriving at a
successful result.
iii. Conclusion
For the reasons set forth above, we conclude that Petitioner has not
established a reasonable likelihood that claim 1 is rendered obvious by the
combination of Fogelman and Miwa.
C. Obviousness over the Combination of Fogelman (Ex. 1003),
Miwa (Ex. 1004), and Platteeuw (Ex. 1005), and the
Combination of Fogelman, Miwa, Platteeuw, and Jerussi (Ex. 1006).
Petitioner contends that claims 2 and 8 are unpatentable over the
combination of Fogelman, Miwa, and Platteeuw (Pet. 31–33), and that
claims 3–7, 9, and 10 are unpatentable as obvious over the combination of
Fogelman, Miwa, Platteeuw, and Jerussi (Pet. 33–49). Petitioner relies on
Platteeuw for teaching a therapeutically effective amount of VF (Pet. 31),
and Jerussi for teaching oral, parental, and intravenous infusion (id. at 34).
Thus, neither Platteeuw nor Jerussi remedy the deficiencies of the
combination of Fogelman and Miwa, as discussed above in relation to claim
1, upon which claims 2–10 depend.
As neither Platteeuw nor Jerussi remedy the deficiencies of the
combination of Fogelman and Miwa, discussed above, Petitioner has not
established a reasonable likelihood that claims 2–10 are rendered obvious by
the combination of Fogelman, Miwa, and Platteeuw, or the combination of
Fogelman, Miwa, Platteeuw, and Jerussi.
IPR2015-01313
Patent 7,456,317 B2

22
III. PENDING MOTIONS
Patent Owner filed a Motion for Additional Discovery (Paper 9). In
addition, Petitioner filed a Motion to Seal (Paper 18), as well as a Motion to
Expunge Paper 17 (Paper 19).
We grant Petitioner’s Motion to Expunge. We deny Patent Owner’s
Motion for Additional Discovery as moot in view of our denial of the
Petition. Finally, as we did not rely on the material Petitioner sought to seal,
we decline to address the merits of the Motion to Seal. Petitioner is
authorized to file a motion to expunge any material that it seeks to keep
confidential within thirty (30) days of the date of this decision, or within
thirty (30) days of a decision on rehearing, if rehearing is requested.
IV. CONCLUSION
For the foregoing reasons, we are not persuaded that the Petition
establishes a reasonable likelihood that Petitioner would prevail in showing
claims 1–10 of the ’317 patent are unpatentable under 35 U.S.C. § 103(a).
V. ORDER
In consideration of the foregoing, it is hereby:
ORDERED that the Petition is denied as to all of the challenged
claims of the ’317 patent;
FURTHER ORDERED that Paper 17 is expunged; and
FURTHER ORDERED that Petitioner is authorized to file a motion to
expunge any material that it seeks to keep confidential within thirty (30)
days of the date of this decision, or within thirty (30) days of a decision on
rehearing, if rehearing is requested.

IPR2015-01313
Patent 7,456,317 B2

23
PETITIONER:
Dr. Gregory J. Gonsalves
gonsalves@gonsalveslawfirm.com

Dr. Cynthia Soumoff
csoumoff@meagheremanuel.com

PATENT OWNER:
Marta Gross
mgross@goodwinprocter.com

Matthew Phillips
matthewphillips@globalpatentgroup.com

Marta E. Delsignore
mdelsiginore@goodwinprocter.com

Dennis Bennett
dennisbennett@globalpatentgroup.com