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
`__________________________
`
`AUROBINDO EX. 1008, 1
`
`
`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
`__________________________
`
`AUROBINDO EX. 1008, 1
`
`
`
`
`
`
`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.
`
`AUROBINDO EX. 1008, 2
`
`
`
`
`
`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
`
`AUROBINDO EX. 1008, 3
`
`
`
`
`
`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-
`
`AUROBINDO EX. 1008, 4
`
`
`
`
`
`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
`
`AUROBINDO EX. 1008, 5
`
`
`
`
`
`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
`
`AUROBINDO EX. 1008, 6
`
`
`
`
`
`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,
`
`AUROBINDO EX. 1008, 7
`
`
`
`
`
`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
`
`AUROBINDO EX. 1008, 8
`
`
`
`
`
`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
`
`AUROBINDO EX. 1008, 9
`
`
`
`
`
`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
`
`AUROBINDO EX. 1008, 10
`
`
`
`
`
`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,
`
`AUROBINDO EX. 1008, 11
`
`
`
`
`
`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
`
`AUROBINDO EX. 1008, 12
`
`
`
`
`
`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
`
`AUROBINDO EX. 1008, 13
`
`
`
`
`
`*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.
`
`AUROBINDO EX. 1008, 14
`
`
`
`
`
`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-
`
`AUROBINDO EX. 1008, 15
`
`
`
`
`
`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
`
`AUROBINDO EX. 1008, 16
`
`
`
`17
`
`SCIELE PHARMA v. LUPIN LTD
`
`
`
`COSTS
`
`Costs to Defendants-Appellants.
`
`AUROBINDO EX. 1008, 17
`
`
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