Court Opinion

ID: 803481
Source: CourtListenerOpinion
Date Created: 2012-07-02 15:33:13+00
Date Added: 2024-06-11T18:00:08.404502
License: Public Domain

United States Court of Appeals
    for the Federal Circuit
          __________________________

SCIELE PHARMA INC. (NOW KNOWN AS SHIONOGI
             PHARMA INC.),
            Plaintiff-Appellee,

                     and
      ANDRX CORPORATION, ANDRX
 PHARMACEUTICALS INC. (DOING BUSINESS AS
 WATSON LABORATORIES INC. – FLORIDA), ANDRX
    PHARMACEUTICALS L.L.C., ANDRX
LABORATORIES (NJ) INC., ANDRX EU LTD., AND
           ANDRX LABS L.L.C.,
                Plaintiffs,

                      v.
 LUPIN LTD. AND LUPIN PHARMACEUTICALS
                   INC.,
            Defendants-Appellants,

                     and
MYLAN INC. AND MYLAN PHARMACEUTICALS
                   INC.,
                Defendants.
          __________________________

                  2012-1228
          __________________________
SCIELE PHARMA   v. LUPIN LTD                               2

    Appeal from the United States District Court for the
District of Delaware in consolidated case no. 09-CV-0037,
Judge Robert B. Kugler.
               ___________________________

                   Decided: July 2, 2012
                ___________________________

   DAVID B. BASSETT, Wilmer Cutler Pickering Hale and
Dorr LLP, of New York, New York, argued plaintiff-
appellee. With him on the brief were DAVID A. MANSPEIZER
and CHRISTOPHER R. NOYES; and MARK C. FLEMING, of
Boston, Massachusetts.

    DOUGLAS C. HOCHSTETLER, Kelley Drye & Warren LLP,
of Chicago, Illinois, argued for defendants-appellants. With
him on the brief was BETH D. JACOB, of New York, New
York. Of counsel was CLIFFORD KATZ.
                 __________________________

   Before LOURIE, PROST, and MOORE, Circuit Judges.
MOORE, Circuit Judge.

    Lupin Ltd. and Lupin Pharmaceuticals Inc. (collectively
Lupin) submitted an Abbreviated New Drug Application
(ANDA) to the Food and Drug Administration seeking
approval to market a generic version of Fortamet, an ex-
tended-release tablet of metaformin hydrochloride. Shio-
nogi Pharma Inc. 1 (Shionogi), which markets Fortamet,
sued Lupin for patent infringement under 35 U.S.C.
§ 271(e)(2)(A) asserting, among others, U.S. Patent No.
6,866,866 (’866 patent), which is listed in the Approved
    1   Sciele Pharma Inc. is now known as Shionogi
Pharma. For simplicity we will refer only to Shionogi in this
opinion.
3                                  SCIELE PHARMA   v. LUPIN LTD

Drug Products with Therapeutic Equivalence Evaluations
(Orange Book) entry for Fortamet. Lupin attempted to
launch its generic Fortamet “at risk,” i.e., without a final
judgment on the merits in the litigation. Shionogi moved
for a preliminary injunction to stop Lupin from selling its
generic Fortamet and the district court granted Shionogi’s
request for injunctive relief. For the reasons discussed
below, we vacate the preliminary injunction and remand for
further proceedings consistent with this opinion.

                        BACKGROUND

    The ’866 patent is entitled “Controlled Release Met-
formin Compositions” and describes and claims, inter alia,
dosage forms with “a mean time to maximum plasma con-
centration (Tmax) of the drug which occurs at 5.5 to 7.5 hours
after oral administration on a once-a-day basis to human
patients.” ’866 patent, at [57]; see also col.21 ll.48-59. Other
claims narrow the Tmax range to, for example, between 5.5
and 7.0 hours after the administration of the dose of met-
formin. ’866 patent col.21 ll.64-67. Shionogi asserted
claims 1, 3, 4, 5, and 25 in this litigation. Claim 3 is the
only asserted claim explicitly limited to a narrower Tmax
range.

    The claimed Tmax range reflects a quirk in the ’866 pat-
ent’s prosecution history. During prosecution, the examiner
rejected a number of pending claims as obvious in light of
WO99/47125 (Cheng) in view of U.S. Patent No. 3,845,770.
J.A. 2634. In a subsequent examiner interview, the appli-
cant discussed the “importance of Tmax . . . and the relation-
ship to gluconeogenesis,” and the examiner indicated that
the “closest prior art”–Cheng–“suggest[s] the general teach-
ing of a Tmax of 8.” J.A. 2643. In response, the applicant
cancelled a number of claims including claim 1, which had
an upper Tmax range of 7.5 hours, and rewrote then-pending
SCIELE PHARMA   v. LUPIN LTD                                 4

claim 5, which had an upper Tmax range of 7 hours, into
independent form. J.A. 2668. The applicant indicated that
the examiner agreed during the interview “that [pending]
claim 5, which had an upper Tmax of 7.0 hours and which
value is directly supported by the working examples, is
patentably distinct over the Cheng, et al. reference.” J.A.
2675.

    Despite cancelling the rejected claims including claim 1,
the applicant received a notice of allowance for pending
claims 1, 4, 5, 7-27, and 29. J.A. 2645. The applicant con-
tacted the Patent Office and explained that the notice of
allowance mistakenly allowed cancelled claims, including
the previously cancelled claim 1. J.A. 2650. The applicant
provided “a listing of the pending claims,” which once again
indicated that claim 1 was cancelled. Id. The examiner
issued a supplemental notice of allowance acknowledging
the amendment after the interview, removing the cancelled
claims, and allowing the amended claims. J.A. 2686. The
supplemental notice of allowance thus accurately reflected
the applicant’s prior submission: the pending claims di-
rected to a Tmax with an upper limit of 7.5 hours (including
claim 1) were “[c]ancelled,” J.A. 2668, and claims 5, 7-27, 29,
30, and 43 (with an upper Tmax of 7 hours) were allowed,
J.A. 2668-73.

    After this, the ’866 patent issued with a surprise; the is-
sued patent contained the cancelled claims from the first
notice of allowance – not the supplemental notice of allow-
ance. Hence, the patent issued with claim 1’s original upper
Tmax limit of 7.5 hours, the exact Tmax limit that the exam-
iner found problematic, and that the applicant sought to
avoid by cancelling pending claim 1. J.A. 2675. After
issuance, the patentee did not pursue further action, and
claim 1 of the issued patent continues to recite the higher
Tmax limit of 7.5 hours. Because claim 1 is the only inde-
5                                  SCIELE PHARMA   v. LUPIN LTD

pendent claim in the patent, many of the dependent claims
also include the limitation that the upper end of the Tmax
range is 7.5 hours.

    The ’866 patent was eventually listed in the Orange
Book entry for Fortamet. When Lupin filed its ANDA
seeking permission to sell a generic version of Fortamet, the
application included a Paragraph IV certification that the
’866 patent was invalid, unenforceable, and/or would not be
infringed by Lupin’s ANDA products. Shionogi filed a suit
for patent infringement within the requisite time period,
thereby triggering the statutory 30-month stay of FDA
approval of Lupin’s ANDA. Although the patentee previ-
ously sought on several occasions to cancel what essentially
issued as claim 1 in the ’866 patent, Shionogi nevertheless
asserted claim 1, along with claims 3-5 and 25, in the pre-
sent litigation. Claim 3 is the only asserted claim limited to
dosage forms with an upper Tmax of 7 hours. The other
claims have an upper Tmax limit of 7.5 hours. The litigation
progressed but remained unresolved when the 30-month
stay expired. The expiration of the 30-month stay allowed
the FDA to give final approval to Lupin’s ANDA on June 29,
2011, and Lupin launched its ANDA product on September
30, 2011. Shionogi moved for a preliminary injunction and a
recall of Lupin’s generic products on October 12, 2011.

    On December 6, 2011, the district court granted a pre-
liminary injunction that prohibited Lupin from “further
importation and sales of its generic version of . . . Fortamet.”
 J.A. 1. After reviewing the standard for a preliminary
injunction, the court held that Shionogi was likely to prevail
on its infringement claim based primarily on Lupin’s pro-
posed labeling. J.A. 11. The court then rejected Lupin’s
argument that the claims of the ’866 patent were improperly
issued. J.A. 12. Although the court did not reach the merits
of Lupin’s obviousness arguments, it did note that in light of
SCIELE PHARMA   v. LUPIN LTD                                 6

the presumption of validity and “the very steep requirement
that the Defendant show clear and convincing evidence of
the invalidity of Plaintiff’s patent, the factual dispute con-
cerning the prosecution of the ’866 patent is not sufficient to
persuade the Court to resolve the question of validity in
Defendant’s favor at this preliminary stage.” J.A. 12.

     Lupin appealed. We vacated the preliminary injunction
and remanded it to the district court because the “district
court’s order imposing the preliminary injunction failed to
even address Lupin’s obviousness arguments.” Sciele
Pharma Inc. v. Lupin Ltd., No. 2012-1118, 2012 U.S. App.
LEXIS 2442, at *2 (Fed. Cir. Feb. 6, 2012). In particular, we
noted that the “district court did not make any findings of
fact or any conclusions of law regarding Lupin’s obviousness
arguments.” Id. at *2-3. We further indicated that the “fact
that prior art was before the PTO can not be the only reason
to reject an obviousness defense,” and that “Lupin is entitled
to have the district court make an independent assessment
of its defense and apply the proper burden of proof.” Id. at
*3. We remanded for the district court to make appropriate
findings and conduct an appropriate obviousness analysis in
the first instance. Id. at *4.

    On remand the district court noted that although Lu-
pin’s obviousness “argument relies heavily on the Supreme
Court’s ruling in KSR,” there is “a fundamental factual
difference between this case and KSR International Co. v.
Teleflex, Inc., 550 U.S. 398 (2007)–namely, that in this case
the prior art allegedly rendering the ’866 Patent obvious
was considered by the Patent and Trademark Office . . .
when it approved the ’866 Patent.” Sciele Pharma Inc. v.
Lupin Ltd., No. 09-0037, 2012 U.S. Dist. LEXIS 22782, at
*9-10 (D. Del. Feb. 14, 2012). The court also pointed out
that during the prosecution of the ’866 patent, “the PTO not
only had the opportunity to consider the prior art taught by
7                                SCIELE PHARMA   v. LUPIN LTD

Cheng, but in fact did consider it.” Id. at *11. The other
prior art reference relied upon by Lupin, Timmins
(WO99/47128), was also “before the PTO when the ’866
Patent was approved.” Id. at *12. The court found it impor-
tant that Timmins teaches a median Tmax while the ’866
patent claims a mean Tmax. Id. at *12-13.

     The district court also drew three legal conclusions.
First, the court concluded that it was required to defer to
the PTO as a “qualified government agency,” notwithstand-
ing the odd sequence of events that gave rise to the ’866
patent. Id. at *17. The court explained that because the
prior art references were previously before the PTO, Lupin
faced an “‘added burden of overcoming the deference that is
due to a qualified government agency presumed to have
done its job.’” Id. at *16-17 (quoting Pharmastem Therapeu-
tics, Inc. v. Viacell, Inc., 491 F.3d 1342, 1366 (Fed. Cir.
2007)). Second, the court held that KSR was not directly
applicable to the current case because the prior art was
before the PTO when the ’866 patent issued. Sciele, 2012
U.S. Dist. LEXIS 22782, at *18. In its analysis, the court
focused on the disclosure of a median, not mean, Tmax in
Timmins and concluded the differences between Timmins,
Cheng, and the claimed invention were too great in light of
“the deference owed to the PTO’s assessment of the prior art
before it.” Id. at *19. Finally, the court rejected Lupin’s
argument that statements from the prosecution regarding
enablement could also be used as proof of obviousness. Id.
at *20-21. The court then reinstated the preliminary in-
junction.

    Lupin moved for a stay of the preliminary injunction,
which the district court denied. Lupin then appealed the
grant of the preliminary injunction to our court and moved
for a stay of the injunction. We have jurisdiction pursuant
to 28 U.S.C. § 1292(c)(1). We ordered expedited briefing,
SCIELE PHARMA   v. LUPIN LTD                                 8

held oral arguments on the merits of the appeal, and
granted Lupin’s request for a stay of the injunction. We
now explain how the district court’s erroneous interpreta-
tion of the law led it to incorrectly grant a preliminary
injunction in this case.

                         DISCUSSION

    We review a decision to grant a preliminary injunction
for abuse of discretion. Abbott Labs. v. Sandoz, Inc., 566
F.3d 1282, 1298 (Fed. Cir. 2009). To constitute an abuse of
discretion, a district court decision must either make a clear
error of judgment in weighing relevant factors or exercise
discretion based upon an error of law. Id. To the extent the
court’s decision is based upon an issue of law, we review
that issue de novo. Sanofi-Synthelabo v. Apotex, Inc., 470
F.3d 1368, 1374 (Fed. Cir. 2006).

     In deciding whether to grant a preliminary injunction, a
district court assesses four factors: “(1) a reasonable likeli-
hood of success on the merits; (2) irreparable harm if an
injunction is not granted; (3) a balance of hardships tipping
in its favor; and (4) the injunction’s favorable impact on the
public interest.” Amazon.com, Inc. v. Barnesandnoble.com,
Inc., 239 F.3d 1343, 1350 (Fed. Cir. 2001). To demonstrate a
likelihood of success on the merits, a patentee must show
that, in light of the presumptions and burdens that will
inhere at trial on the merits: (1) the patentee will likely
prove that the accused infringer infringes the asserted
patent; and, (2) the patentee’s infringement claim will likely
withstand the accused infringer’s challenges to the validity
and enforceability of the patent. Id.

     A patent is obvious “if the differences between the sub-
ject matter sought to be patented and the prior art are such
that the subject matter as a whole would have been obvious
9                                  SCIELE PHARMA    v. LUPIN LTD

at the time the invention was made to a person having
ordinary skill in the art to which said subject matter per-
tains.” 35 U.S.C. § 103(a). Whether a patent claim is
obvious is ultimately a question of law based on underlying
facts:

    Under § 103, the scope and content of the prior art
    are to be determined; differences between the prior
    art and the claims at issue are to be ascertained;
    and the level of ordinary skill in the pertinent art
    resolved. Against this background, the obviousness
    or nonobviousness of the subject matter is deter-
    mined. Such secondary considerations as commer-
    cial success, long felt but unsolved needs, failure of
    others, etc., might be utilized to give light to the cir-
    cumstances surrounding the origin of the subject
    matter sought to be patented.

Graham v. John Deere Co. of Kansas City, 383 U.S. 1, 17-18
(1966). The obviousness analysis entails “an expansive and
flexible approach.” KSR, 550 U.S. at 415. “If a person of
ordinary skill can implement a predictable variation, § 103
likely bars its patentability.” Id. at 417. Ultimately, “a
court must ask whether the improvement is more than the
predictable use of prior art elements according to their
established functions.” Id. There need not be “precise
teachings directed to the specific subject matter of the
challenged claim, for a court can take account of the infer-
ences and creative steps that a person of ordinary skill in
the art would employ.” Id. at 418.

        I.   The Presumption of Validity

    Both parties argue that the presumption of validity and
the accompanying burden of proof is altered due to the facts
of this case. Lupin, who challenges the validity of the
SCIELE PHARMA   v. LUPIN LTD                                10

patent, argues that the presumption of validity should not
attach because of the erroneous issuance of the cancelled
claims. Shionogi argues that there should be a heightened
presumption of validity because the prior art references
relied upon by Lupin (Cheng and Timmins) were before the
Patent Office during prosecution. Both parties are wrong.
The presumption of validity attaches to all issued patents
and the clear and convincing evidence burden applies to all
issued patents. Under 35 U.S.C. § 282, an issued patent
“shall be presumed valid,” but this presumption can be
rebutted. Chore-Time Equip., Inc. v. Cumberland Corp., 713
F.2d 774, 780 (Fed. Cir. 1983). The presumption of validity
found in § 282 is reflected in the standard of proof required
to prove invalidity, clear and convincing evidence. Microsoft
Corp. v. i4i Ltd. P’ship, 131 S. Ct. 2238, 2245-46 (2011).

     The district court is correct that there is a “high burden
of proof created by the necessary deference to the PTO.”
Sciele, 2012 U.S. Dist. LEXIS 22782, at *21. This notion
stems from our suggestion that the party challenging a
patent in court “bears the added burden of overcoming the
deference that is due to a qualified government agency
presumed to have done its job.” Pharmastem, 491 F.3d at
1366 (internal quotation marks omitted). That high burden
is reflected in the clear and convincing evidence burden for
proving invalidity. See i4i, 131 S. Ct. at 2246 (The pre-
sumption of validity creates “‘a heavy burden of persuasion,’
requiring proof of the defense by clear and convincing evi-
dence . . . . [T]he presumption encompassed not only an
allocation of the burden of proof but also an imposition of a
heightened standard of proof.”).

    Whether a reference was previously considered by the
PTO, the burden of proof is the same: clear and convincing
evidence of invalidity. See id. at 2250 (“Nothing in § 282’s
text suggests that Congress meant . . . to enact a standard
11                               SCIELE PHARMA   v. LUPIN LTD

of proof that would rise and fall with the facts of each
case.”). As the Supreme Court explained in i4i, there is no
heightened burden of proof when a reference was previously
considered by the PTO, and no lowered burden of proof if a
defendant raises a new reference or argument during litiga-
tion. Id. The burden does not suddenly change to some-
thing higher–“extremely clear and convincing evidence” or
“crystal clear and convincing evidence”–simply because the
prior art references were considered by the PTO. In short,
there is no heightened or added burden that applies to
invalidity defenses that are based upon references that were
before the Patent Office. The burden is always the same,
clear and convincing evidence.

     While the ultimate burden of proof does not change, new
evidence not considered by the PTO “may ‘carry more
weight’ . . . than evidence previously considered by the
PTO,” and may “‘go further toward sustaining the attacker’s
unchanging burden.’” Id. at 2251 (quoting Am. Hoist &
Derrick Co. v. Sowa & Sons, Inc., 725 F.2d 1350 (Fed. Cir.
1984)). “[I]f the PTO did not have all material facts before
it, its considered judgment may lose significant force” and
the burden to persuade the finder of fact by clear and con-
vincing evidence may, therefore, “be easier to sustain.” Id.
Instead, the fact that references were previously before the
PTO goes to the weight the court or jury might assign to the
proffered evidence. Id.

    For example, it could be reasonable to give more weight
to new arguments or references that were not explicitly
considered by the PTO when determining whether a defen-
dant met its burden of providing clear and convincing evi-
dence of invalidity. Id. Conversely, it may be harder to
meet the clear and convincing burden when the invalidity
contention is based upon the same argument on the same
reference that the PTO already considered. Importantly,
SCIELE PHARMA   v. LUPIN LTD                              12

whether a reference was before the PTO goes to the weight
of the evidence, and the parties are of course free to, and
generally do, make these arguments to the fact finder. But
the presumption of validity and accompanying burden of
proof, clear and convincing evidence, are not altered.

    Lupin’s argument that we should hold that the claims of
the ’866 patent were improperly issued is similarly unavail-
ing. Lupin’s position, that we should reject the issued
claims of the ’866 patent because of the quirks in the prose-
cution history, is inconsistent with the presumption of
§ 282. The presumption applies to all issued claims. That
does not mean, however, that we should not consider the
prosecution history. We can take it all into account, includ-
ing both the fact that the Cheng and Timmins references
were before the Patent Office and the bizarre circumstances
surrounding the issuance of the claims in this patent. Other
than recognizing that the prosecution history was “puz-
zling,” the district court did not discuss the prosecution
history, which demonstrates that the examiner concluded
that the claims with an upper Tmax limit of 7.5 were not
patentable in view of Cheng and that the applicant acqui-
esced in that conclusion and cancelled those claims. The
Cheng reference was before the Patent Office, and rather
than allow the claims over Cheng, the examiner concluded
that claims with an upper Tmax limit of 7.5 were not allow-
able in light of Cheng. Yet the rejected and later cancelled
claims with the upper Tmax limit of 7.5 were ultimately
issued by the PTO. We take all of this into account in our
obviousness analysis.

        II. Cheng In View of Timmins Raises a
        Substantial Question of Validity

   We conclude that Lupin’s obviousness arguments re-
garding Cheng and Timmins, considered in light of the
13                                SCIELE PHARMA   v. LUPIN LTD

prosecution history and the correct standard of proof, raise a
substantial question of invalidity. Lupin argues that the
asserted claims are obvious over Cheng in view of Timmins.
 Cheng discloses all of the limitations of the asserted claims
except for the Tmax range of 5.5 to 7.5 hours (Cheng discloses
a Tmax of 8 to 12 hours). Lupin asserts that Timmins dis-
closes a Tmax within the range recited in the asserted claims,
and argues that the combination of Cheng and Timmins
thus renders the claims obvious to one skilled in the art. As
further evidence that the combination would be obvious to
one of ordinary skill in the art, Lupin points to the appli-
cant’s assertion during prosecution “that one skilled in the
art would be able to manipulate the processes and formula-
tions of the [prior art] by other methods to obtain the
claimed pharmacokinetic parameters of the present inven-
tion by routine experimentation.” J.A. 2621. Lupin claims
that this statement amounts to an admission of obviousness
and further bolsters its obviousness claim.

     Shionogi argues that the Tmax range of the asserted
claims is missing from Cheng, but does not dispute that
Cheng discloses the other limitations of the asserted claims.
 Its primary distinction with respect to Timmins is that
Timmins discloses a median Tmax and not the claimed mean
Tmax. Shionogi further argues that, regardless of the Tmax
disclosed in Timmins, there is no motivation to combine
Cheng with Timmins.

    We agree with Lupin that it has raised a substantial
question of validity with respect to the ’866 patent. Ama-
zon.com, 239 F.3d at 1350. We conclude that the district
court’s obviousness analysis was flawed. It failed to cor-
rectly apply KSR focusing on what it perceived was “a
fundamental factual difference between this case and KSR,”
namely that Cheng and Timmins were before the PTO
during prosecution. Sciele, 2012 U.S. Dist. LEXIS 22782, at
SCIELE PHARMA   v. LUPIN LTD                              14

*9-10; *17-20. The court incorrectly rejected Lupin’s sub-
stantive arguments regarding Timmins’s disclosure of a
Tmax within the claimed range and the motivation to com-
bine Cheng and Timmins.

    The ’866 patent admits that Cheng “discloses controlled
release metformin formulations providing a Tmax from 8 to
12 hours.” ’866 patent col.2 ll.46-47. Although Timmins
expressly discloses a median Tmax, it also provides the raw
data from which one skilled in the art could compute the
range of possible mean Tmax values. J.A. 2501-02. 2 Based
on this data, one skilled in the art would understand that
the mean Tmax in Timmins must fall between 4.67 and 6.33
hours. Counsel for Shionogi agreed that the only element
missing from Cheng is the Tmax range, and that Timmins
discloses a range of possible mean Tmax between 4.67 and
6.33 hours. See Oral Argument at 19:55-20:33, available at
http://www.cafc.uscourts.gov/oral-argument-
recordings/2012-1228/all. Timmins thus teaches one skilled
in the art to lower the Tmax of Cheng (8 hours).

    We also conclude that the district court clearly erred in
its conclusion that there was no motivation to combine
Cheng and Timmins. Timmins describes a controlled re-
lease formulation of metformin and explains that its formu-
lation releases metformin in the portion of the
gastrointestinal tract where better absorption of the drug
can occur. J.A. 2470-73. The earlier release of the drug
increases bioavailability and leads to a lower Tmax. Id.
Timmins explains that “improved bioavailability from an
extended release dosage form that releases metformin at a
rate likely to provide the desired plasma levels of drug for

    2   Timmins discloses that its study included 24 pa-
tients and resulted in a median Tmax of 5 hours, with a
minimum Tmax of 4 hours and a maximum Tmax of 8 hours.
15                               SCIELE PHARMA   v. LUPIN LTD

an extended time period [could result] from a dosage form
that has extended residence time in the upper gastrointes-
tinal tract.” J.A. 2472-73. In other words, that earlier
release, resulting in a lower Tmax, provides the benefit of
“the desired plasma levels of drug for an extended time
period.” Id. Timmins also identifies a number of benefits
stemming from an earlier extended release, including “re-
duction in dosing frequency, providing patient convenience
that would probably improve compliance” as well as “an
extended time period over which therapeutically beneficial
plasma levels of drug were maintained.” Id. These benefits
would motivate one skilled in the art to modify Cheng to
achieve a lower Tmax range. Cf. KSR, 550 U.S. at 424.

    Further motivation to pursue the approach in Timmins
comes from the fact that lowering the Tmax allows one skilled
in the art to approach the drug profile of Glucophage, the
industry standard drug. J.A. 2469. In fact, Timmins ex-
pressly compares its extended release formulations to
Glucophage with respect to various factors including Tmax.
J.A. 2502. Timmins explains that, in light of this analogous
kinetic profile and other identified benefits, the “formula-
tions of the invention thus represent a useful advance in the
administration of metformin hydrochloride to human[s] in
the treatment of diabetes.” Id. Timmins thus articulates an
explicit motivation to lower the Tmax in Cheng–to better
match the Tmax profile of Glucophage while providing the
convenience of an extended release.

    The applicant’s arguments during prosecution further
buttress our belief that Lupin has raised a substantial
question of validity with respect to the ’866 patent. During
prosecution the applicant indicated “that one skilled in the
art would be able to manipulate the processes and formula-
tions of the [prior art] by other methods to obtain the
claimed pharmacokinetic parameters of the present inven-
SCIELE PHARMA   v. LUPIN LTD                                16

tion by routine experimentation.” J.A. 2621. While Shio-
nogi argued, and the district court seemed to accept, that
this statement applies only to enablement, we are hard
pressed to understand this distinction. Coupled with the
motivation to lower the Tmax, as disclosed in Timmins, the
applicant’s characterization of the predictability and skill in
the art during prosecution provides further evidence that it
would have been a routine and obvious design choice to
make an extended release dosage form with a lower Tmax.
After all, “[i]f a person of ordinary skill can implement a
predictable variation, § 103 likely bars its patentability.”
KSR, 550 U.S. at 417.

    Shionogi fails to effectively rebut Lupin’s argument that
Timmins itself supplies a motivation to modify Cheng to
lower the Tmax of a controlled release formulation to match
that of an immediate release formulation. Likewise, Shio-
nogi does not establish that Lupin’s arguments regarding
the advantages of the lower Tmax disclosed in Timmins are
unsound. We therefore believe the combination of Cheng
and Timmins raises a substantial question as to the validity
of the ’866 patent. Amazon.com, 239 F.3d at 1350.

                        CONCLUSION

     Because the district court incorrectly concluded that
Lupin failed to raise a substantial question of validity
regarding the asserted claims of the ’866 patent, it abused
its discretion by issuing a preliminary injunction enjoining
Lupin from selling its generic product. Accordingly, we
vacate the preliminary injunction and remand to the district
court for further proceedings.

              VACATED and REMANDED
17                            SCIELE PHARMA   v. LUPIN LTD

                         COSTS

Costs to Defendants-Appellants.