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`13721373
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`407 F.3d 1371 (2005)
`SYNTEX (U.S.A.) LLC and ALLERGAN, INC., Plaintiffs-Appellees,
`v.
`APOTEX, INC., Apotex Corp., and Novex Pharma, Defendants-Appellants.
`No. 04-1252.
`United States Court of Appeals, Federal Circuit.
`May 18, 2005.
`Rehearing Denied June 13, 2005.
`*1372 *1373 David J. Harth, Heller Ehrman White & McAuliffe LLP, of Madison, Wisconsin, argued for plaintiffs-
`appellees. With him on the brief were Alexander L. Brainerd, Keith R. Weed, and Olga Rodstein, of Menlo Park,
`California, and Christine Saunders Haskett, of San Francisco, California.
`Manny D. Pokotilow, Caesar, Rivise, Bernstein, Cohen & Pokotilow, LTD., of Philadelphia, Pennsylvania, argued for
`defendants-appellants. With him on the brief were Robert S. Silver, Alan H. Bernstein, Mona Gupta and William J.
`Castillo. Of counsel on the brief was Ronald S. Lemieux, Squire, Sanders & Dempsey L.L.P., of Palo Alto, California.
`Before CLEVENGER, GAJARSA, and PROST, Circuit Judges.
`Opinion for the court filed by Circuit Judge GAJARSA.
`Concurring opinion filed by Circuit Judge PROST.
`GAJARSA, Circuit Judge.
`Apotex, Inc., Apotex Corp. and Novex Pharma (collectively "Apotex") appeal from the final judgment of the United
`States District Court for the Northern District of California, which, after a bench trial, held U.S. Patent No. 5,110,493 (the
`"'493 patent") owned by Syntex (U.S.A.) LLC not invalid, enforceable, and infringed by Apotex's Abbreviated New Drug
`Application ("ANDA"). Allergan, Inc., Syntex's distributor, has exclusive rights to manufacture the commercial
`embodiment of the '493 patent marketed under the trademark ACULAR.[1] Syntex (U.S.A.) LLC v. Apotex, Inc., No. 01-
`CV-2214 (January 27, 2004). Because we find the district court committed legal error in establishing certain factual
`predicates to its non-obviousness determination, we reverse the judgment of validity and remand for further
`consideration consistent with this opinion.
`
`BACKGROUND
`A. The Patents and Prosecution History
`
`The '493 patent, entitled "Ophthalmic NSAID Formulations Containing a Quaternary Ammonium Preservative and a
`Nonionic Surfactant," claims a formulation for sterile, preserved eye drops to treat eye inflammation such as that caused
`by conjunctivitis or eye surgery.
`The '493 patent teaches combining a nonsteroidal anti-inflammatory drug ("NSAID") such as ketoralac tromethamine
`("KT") and a quaternary ammonium preservative such as benzalkonium chloride ("BAC") with a surfactant such as
`octoxynol 40. The NSAID is the active ingredient for reducing eye inflammation. The quaternary ammonium preservative,
`*1374 in turn, kills any bacteria introduced into the eye during administration of the NSAID. However, quaternary
`ammonium preservatives, such as BAC, do not always mix well with NSAIDs. Neither ingredient is water soluble, and the
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`two active ingredients may react with each other to form complexes when mixed. These complexes will eventually cause
`the mixture to look cloudy or lose its antibacterial properties.
`The chemical arts often solve this type of mixing problem by using surfactants. A surfactant is a "surface active agent"
`used to make otherwise insoluble chemicals soluble in water. The '493 patent claims to solve the complex formation
`problem by adding octoxynol 40, a surfactant, to the KT/BAC mixture.
`The '493 patent claims ophthalmic formulations (eye drops) useful for treating eye inflammation, methods of using eye
`drops to treat eye disease, and preservative systems for use in eye drops. The claims of the '493 patent fall into three
`categories: claims 1 to 7 are composition claims, claims 8 to 14 are method claims, and claims 15 and 16 recite a
`"preservative system." Claims 1, 8, and 15 are independent claims, the others are all dependent. Claim 1, the basic
`embodiment of the compound, provides:
`1. An ophthalmologically acceptable non-steroidal anti-inflammatory drug formulation, comprising:
`an opthalmologically acceptable non-steroidal anti-inflammatory carboxyl group-containing drug in an
`effective amount for ophthalmic treatment between 0.001% and 10.0% wt/vol;
`a quaternary ammonium preservative in an antimicrobially effective amount between 0.0001% and 1.0%
`wt/vol;
`an ethoxylated alkyl phenol that conforms generally to the formula C8H17C6 H4(OCH2CH2)nOH[2]
`where n has an average value of 40 in a stabilizing amount between 0.001% and 1.0% wt/vol; and an
`aqueous vehicle q.s. to 100%.
`'493 patent, col. 8, II. 42-55.
`The '493 patent issued from U.S. Patent Application No. 07/624,027 ("the '027 application"), which was filed on
`December 7, 1990. The '027 application was a continuation of U.S. Patent Application No. 07/096,173 ("the '173
`application") filed on September 11, 1987. The two applications were reviewed by different examiners at the Patent and
`Trademark Office ("PTO").
`Each examiner rejected the application before him as obvious in view of U.S. Patent No. 4,349,563 to Gilbert and U.S.
`Patent No. 4,559,343 to Han in view of McCutcheon's Emulsifiers and Detergents p. 154 (1982) ("McCutcheon's"). U.S.
`Patent No. 4,454,151 to Waterbury, another patent assigned to Syntex, was listed on the '493 patent as prior art, but was
`not cited by the examiner in his obviousness rejection. The prior art patents Waterbury, Gilbert, and Han all teach
`ophthalmic formulations containing NSAIDs, quaternary preservatives, and nonionic surfactants to stabilize the
`formulation. While Waterbury, Gilbert, and Han do not teach the specific use of octoxynol 40, they do teach using the
`general class of water-soluble nonionic surfactants as stabilizers. Waterbury and Gilbert teach the use of polysorbate 80.
`[3] McCutcheon's, a comprehensive directory of emulsifiers and detergents, teach that *1375 octoxynol 40 was a known
`stabilizer. According to both examiners, it was well known in the art that surfactants such as octoxynol 40 have a
`stabilizing effect on ophthalmic compounds containing NSAIDs.[4] The examiner reviewing the '027 continuation
`application rejected what has become claim 1 on the grounds that "[t]he mere substitution of one [surfactant] for another .
`. . is not deemed a patentable distinction in the absence of a showing of some unobvious result."
`Syntex responded to that rejection by asserting that it had provided acceptable data demonstrating results superior to
`the formulations disclosed by the Han and Gilbert references. Syntex supported its superior results claim with a
`declaration from Deborah M. Lidgate ("Lidgate"), one of the named inventors. In the declaration, Lidgate stated that
`"octoxynol 40, and not octoxynol 3 or octoxynol 5, is suitable to use with benzalkonium chloride to prepare a
`preservative system for an ophthalmic formulation, or to prepare an ophthalmic formulation, of the present application."
`In presenting her findings of superior results, Lidgate excluded the additional experimental data that she had developed
`showing octoxynol 12.5 to be a surfactant capable of stabilizing a KT/BAC formulation.
`Following this submission, the examiner allowed the application to issue, stating that Syntex had "overcome the prior art
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`rejections . . . by showing that unexpected results are obtained when one uses [octoxynol 40]. These results are
`unobvious because one of ordinary skill in the art would not have known that one surfactant would outperform other
`surfactants." The patent issued on May 5, 1992.
`Syntex markets the patented ophthalmic formulation as ACULAR. ACULAR embodies the claims of the '493 patent and
`has been approved by the Food and Drug Administration ("FDA"). From 1993 to 2001, ACULAR captured a substantial
`market share for ophthalmic anti-inflammation drugs.
`B. The HatchWaxman Amendments
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`The Hatch-Waxman Amendments[5] to the Federal Food, Drug, and Cosmetic Act permit an applicant to file an ANDA
`with the FDA requesting approval of a bioequivalent ("generic") version of a drug that is already listed by the FDA as
`approved for safety and effectiveness without having to submit additional safety and efficacy data. See 21 U.S.C. § 355(j)
`(2)(A). The overall scheme of the Hatch-Waxman Amendments is described in detail in our decisions in Mylan
`Pharmaceuticals, Inc. v. Thompson, 268 F.3d 1323 (Fed.Cir.2001) and Andrx Pharmaceuticals, Inc. v. Biovail Corp., 276
`F.3d 1368 (Fed.Cir.2002) and need not be repeated here. For the purposes of this opinion it suffices to know that an
`ANDA may be filed for drugs currently protected by patents and listed in the FDA's Orange Book. Mylan
`Pharmaceuticals, Inc., 268 F.3d at 1325-26. In its filing, the applicant must certify either (1) that it will not market its drug
`prior to the expiration of the relevant patents, or (2) that the relevant patents "are invalid or will not be infringed by the
`manufacture, use or sale of the new drug for which the ANDA is submitted." 21 U.S.C. § 355(j)(2)(A)(vii)(IV). An ANDA
`applicant *1376 filing its application with the FDA and making a Section IV certification must notify the holder of the
`patent, who may then bring an action against the applicant for infringement under 35 U.S.C. § 271(e)(2). See 21 U.S.C.
`§§ 355(j)(2)(B)(i) and (j)(5)(B)(iii). In its notice the applicant must include "a detailed statement of the factual and legal
`basis [sic] of the opinion of the applicant that the patent is invalid or will not be infringed." 21 U.S.C. § 355(j)(2)(B)(iv).
`Such a notice can state that the patent is invalid on the basis of anticipation, obviousness or non-enforceable for patent
`misuse or inequitable conduct. Submission of an ANDA is an act of patent infringement if the ANDA seeks approval to
`manufacture, use, or sell a drug that is claimed in a patent or the use of which is claimed in a patent. 35 U.S.C. § 271(e);
`[6] Eli Lilly & Co. v. Medtronic, Inc., 496 U.S. 661, 676, 110 S.Ct. 2683, 110 L.Ed.2d 605 (1990) ("The function of [35
`U.S.C. § 271(e) is] to define a new (and somewhat artificial) act of infringement for a very limited and technical purpose
`that relates only to certain drug applications.").
`C. The District Court Proceedings
`
`Apotex manufactures generic pharmaceuticals. On April 25, 2001, Apotex notified Syntex that it had filed ANDA 76-109
`with the FDA to market a generic version of ACULAR including a Section IV certification. In its notice to Syntex, Apotex
`stated that it believed the '493 patent to be invalid on the grounds of obviousness and inequitable conduct, and not
`infringed by Apotex's proposed generic version of ACULAR. On June 6, 2001, Syntex filed suit against Apotex for
`patent infringement.
`The district court held a Markman hearing and issued a Claim Construction Order. In construing two disputed claim
`terms[7] of the '493 patent, the district court ruled that the term "in a stabilizing amount" in claim 1 was not a limitation, but
`merely described the intended results of using octoxynol 40 in an "amount between 0.001% and 1.0% wt/vol." '493
`patent, col. 8, line 55. The claim term makes clear that combining the recited ingredients in the claimed weight to volume
`ratio will stabilize the compound.
`Syntex moved for summary judgment of infringement based upon the court's specific claim construction. Apotex did not
`oppose Syntex's motion. The district court compared the claims of the '493 patent with the drug formulation and uses set
`forth in Apotex's ANDA 76-109 application and determined that there was no factual dispute. The district court found
`that the generic version of ACULAR identified in the ANDA 76-109 submission would infringe each claim of the '493
`patent, and granted Syntex's motion for partial summary judgment that Apotex had literally infringed each claim of the
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`'493 patent.
`*1377 After a bench trial on the issues of invalidity and unenforceablity, the district court restated its determination that
`Apotex's proposed generic version of ACULAR infringed all of the claims of the '493 patent. The district court found that
`ACULAR is coextensive with the method claims of the '493 patent. The district court also determined that Apotex's
`proposed generic drug is virtually identical to ACULAR in its composition, preservative system, and intended uses. On
`the basis of these findings, the district court reiterated that the formulation defined by ANDA 76-109 directly infringed
`claims 16, 8-13, and 15-16 of the '493 patent. The district court further stated that claims 7 and 14 were infringed under
`the doctrine of equivalents.[8]
`The district court held that the '493 patent was not invalid, rejecting Apotex's invalidity arguments based on
`obviousness. Moreover, the district court concluded that Syntex had overcome the PTO examiner's obviousness
`objection by making a showing that the prior art taught away from the use of octoxynol 40 in ophthalmic solutions
`containing BAC and NSAIDs, and that the use of octoxynol 40 generated unexpected results. The district court also
`found that the substantial success of ACULAR on the market confirmed that the '493 patent claims were non-obvious.
`Finally, the district court found no inequitable conduct. The court rejected Apotex's contentions that Syntex had
`affirmatively misrepresented the unexpected nature of octoxynol 40's ability to stabilize the KT/BAC combination by
`deliberately withholding test results concerning the ability of octoxynol 12.5 to accomplish the same objectives as the
`claimed surfactant. The district court found that the test results concerning octoxynol 12.5 were not material, and that
`Syntex lacked intent to deceive the PTO.
`Apotex appeals the district court's claim construction ruling, its judgment of infringement, its non-obviousness
`determination, and its finding of no inequitable conduct. We have jurisdiction pursuant to 28 U.S.C. § 1295(a)(1).
`
`DISCUSSION
`A. Standard of Review
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`1378
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`This court reviews de novo the grant of summary judgment. Genzyme Corp. v. Transkaryotic Therapies, Inc., 346 F.3d
`1094, 1096 (Fed.Cir.2003). Summary judgment is appropriate when there are no genuine issues of material fact and the
`moving party is entitled to judgment as a matter of law. Fed.R.Civ.P. 56(c); Anderson v. Liberty Lobby, Inc., 477 U.S. 242,
`247-48, 106 S.Ct. 2505, 91 L.Ed.2d 202 (1986). A determination of patent infringement consists of two steps: (1) the
`court must first interpret the claim, and (2) it must then compare the properly construed claims to the allegedly infringing
`device. See Cybor Corp. v. FAS Techs., Inc., 138 F.3d 1448, 1454 (Fed.Cir.1998) (en banc). Claim construction, the first
`step, is a matter of law that this court reviews de novo. Id. at 1456. Generally, the second step is a factual question that
`we review for clear error. Bai v. L & L Wings, Inc., 160 F.3d 1350, 1353 (Fed.Cir. 1998). However, factual inferences that
`are material to the grant of a summary judgment are not accorded such deference — they are reviewed to ascertain
`whether there is a genuine issue of material *1378 fact. Lemelson v. TRW. Inc., 760 F.2d 1254, 1260 (Fed.Cir.1985).
`This court reviews for clear error the district court's determination of the factual inquiries underlying obviousness, while it
`reviews de novo the legal conclusion that a claim is invalid as obvious. McNeil-PPC, Inc. v. L. Perrigo Co., 337 F.3d
`1362, 1368 (Fed.Cir.2003), cert. denied, 540 U.S. 1107, 124 S.Ct. 1061, 157 L.Ed.2d 893 (2004). The factual
`determinations relevant to the obviousness inquiry include: (1) the scope and content of the prior art; (2) the differences
`between the claimed invention and the prior art; (3) the level of ordinary skill in the art; and (4) secondary considerations,
`if any, such as commercial success, unexpected results, copying, long-felt but unresolved need, and the failure of others
`to develop the invention. Graham v. John Deere Co., 383 U.S. 1, 17-18, 86 S.Ct. 684, 15 L.Ed.2d 545 (1966). "What the
`prior art teaches, whether it teaches away from the claimed invention, and whether it motivates a combination of
`teachings from different references are questions of fact." In re Fulton, 391 F.3d 1195, 1199-1200 (Fed.Cir.2004).
`A finding of inequitable conduct is committed to the trial judge's discretion and is reviewed under an abuse of discretion
`standard. Kingsdown Med. Consultants, Ltd. v. Hollister, Inc., 863 F.2d 867, 876 (Fed.Cir.1988). "To overturn such a
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`determination, the appellant must establish that the ruling is based on clearly erroneous findings of fact or on a
`misapplication or misinterpretation of applicable law, or evidences a clear error of judgment on the part of the district
`court." Molins PLC v. Textron, Inc., 48 F.3d 1172, 1178 (Fed.Cir.1995) (citing Kingsdown Medical Consultants, 863 F.2d
`at 876). Findings of materiality and intent are factual findings subject to the clearly erroneous standard and, therefore,
`will not be disturbed on appeal unless this court has a definite and firm conviction that a mistake has been committed. Id.
`B. Claim Construction
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`Apotex challenges the district court's claim construction on the ground that the term "in a stabilizing amount" should
`properly be read as a claim limitation. We agree with the district court that the term "in a stabilizing amount" simply
`describes the intended result of using the weight to volume ratios recited in the claims. Accordingly, we conclude that the
`district court correctly construed the disputed term of the '493 patent and correctly determined that Apotex's proposed
`generic version of ACULAR would infringe all of the claims of the '493 patent. We now turn to Apotex's assertions of
`invalidity and unenforceability.
`C. Obviousness
`On appeal, the critical issue is whether the use of the surfactant octoxynol 40 in the claimed formulations is an obvious
`alteration of similar formulations taught in the prior art. Because the district court clearly erred in its fact findings
`regarding obviousness, we remand for further consideration.
`At trial, Apotex argued that based on the prior art, a person of ordinary skill in the art would expect to succeed in
`stabilizing a formulation containing an NSAID and BAC with a nonionic surfactant. Contending that the formulation
`claimed in the '493 patent is just such a formulation, Apotex argued that it is legally obvious.
`After conducting a bench trial, the district court made factual findings pertaining to the issue of obviousness. The district
`court noted that because the prior art at issue had been before the examiner during prosecution, the burden of proving
`the *1379 challenged claims obvious "is particularly high." Syntex (U.S.A.) LLC v. Apotex, Inc., No. 01-CV-2214, slip op.
`at 40, (Dec. 29, 2003). The trial court then concluded that Apotex had failed to meet this heightened burden. In
`particular, the court held that nonobviousness was demonstrated by the fact that octoxynol 40 had never been used in a
`drug formulation; there was no motivation to combine the prior art references, which teach away from the use of the
`surfactant octoxynol 40; that the use of octoxynol 40 in the claimed formulation produced unexpected results; and that
`Syntex had provided convincing evidence of the commercial success of ACULAR, the product purportedly covered by
`claims of the '493 patent. Syntex, slip op. at 45.
`Our review of the record reveals clear error by the district court in several of the grounds that led it to conclude that the
`invention claimed by the claims in suit would not have been obvious. First, the court clearly erred in finding that "[n]o
`pharmaceutical formulation other than ACULAR has ever included Octoxynol 40." Second, the court clearly erred in
`discussing the McCutcheon reference and in finding that each of the Waterbury, Gilbert, and Han references teach away
`from the use of octoxynol 40 in the claimed formulations. Further, the court was under the impression that, in the absence
`of evidence that those references teach away from combination, there was a failure of proof that there would have been
`any motivation by one of ordinary skill in the art to use octoxynol 40 in the claimed formulations. In so concluding, the
`district court failed to examine the expert testimony of Dr. Mitra on the question of whether one of ordinary skill in the art
`would have deemed the invention obvious, and as a subset of the overall obviousness question, whether octoxynol 40
`produced the unexpected results asserted by Syntex. In addition, we think the district court failed to appreciate that the
`prosecution history of the relevant patents, while not establishing inequitable conduct, casts some doubt on the final
`examiner's conclusion that the claimed surfactant produces unexpected results sufficient to overcome a prima facie case
`of obviousness. Finally, we feel the district court should reconsider the significance of the commercial success of the
`patented formulation in light of our recent decision in Merck & Co. v. Teva Pharmaceuticals USA, Inc., 395 F.3d 1364
`(Fed.Cir.2005).
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`On remand, the district court's reconsideration of the obviousness issue should proceed in light of our corrections of the
`record.
`1. Use of Octoxynol 40 in Pharmaceuticals
`
`The district court erred in finding that octoxynol 40 was not used in pharmaceuticals prior to its use in the patented
`invention. This finding is clearly contradicted by statements in the record made by Lidgate and Fu, inventors of the '493
`patent. Lidgate and Fu are both named authors of a Pharmaceutical Report published in September of 1987, that clearly
`states that octoxynol 40 was a well known ingredient in pharmaceutical products. Although Syntex contends that
`because this report was published five days after the priority date of the '493 patent it discloses no "prior uses" of
`octoxynol 40, we think it incredulous that octoxynol 40 could progress from no use, to "well known . . . in pharmaceutical
`products" in a matter of five days. Accordingly, this report reflects that the use of octoxynol 40 in pharmaceutical
`compositions was known in the art at the relevant time, an important fact to consider in assessing the obviousness of the
`claims in suit.
`2. Teaching Away
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`The district court clearly erred in concluding that the Waterbury, Han, and Gilbert *1380 references teach away from the
`use of octoxynol 40 as a nonionic surfactant in ophthalmic formulations involving NSAIDs and BAC. In addition, the
`district court incorrectly dismissed the relevance of the McCutcheon reference to the overall obviousness analysis. What
`a reference teaches or suggests must be examined in the context of the knowledge, skill, and reasoning ability of a
`skilled artisan. What a reference teaches a person of ordinary skill is not, as Syntex's expert appears to believe, limited
`to what a reference specifically "talks about" or what is specifically "mentioned" or "written" in the reference. Under the
`proper legal standard, a reference will teach away when it suggests that the developments flowing from its disclosures
`are unlikely to produce the objective of the applicant's invention. In re Gurley, 27 F.3d 551, 553 (Fed.Cir.1994). A
`statement that a particular combination is not a preferred embodiment does not teach away absent clear
`discouragement of that combination. In re Fulton, 391 F.3d at 1199-1200.
`The trial court found that the Waterbury reference teaches away from the use of octoxynol 40 because the only
`formulation disclosed in the patent did not include a surfactant, and the only surfactant mentioned in the reference was
`polysorbate 80. This is error because a prior art reference that does not specifically refer to one element of a
`combination does not, per se, teach away. If it did, only references that anticipate could be used to support an
`obviousness analysis. However, prior art references that are capable of rendering an invention obvious under a section
`103 analysis are not limited to reference that also anticipate the patent at issue. The trial court's finding that Waterbury
`teaches away is also error because at col. 13, II. 44-48, Waterbury discloses "ophthalmic formulations" with "active
`ingredient . . . stabilizer, and preservative."
`The Han reference was deemed to teach away because, although it disclosed the use of NSAIDs, BAC, and nonionic
`surfactants in ophthalmic formulations, col. 3, Example 1, the nonionic surfactants it mentioned did not include octoxynol
`40. This was error, because Han teaches NSAIDs, BAC, and nonionic surfactants. As with the Waterbury reference, the
`fact that octoxynol 40 was not one of the surfactants mentioned does not, without more, support the contention that the
`use of octoxynol 40 is nonobvious.
`Gilbert, according to the district court, teaches away because it "states explicitly that a stabilizer is not preferred." Syntex,
`slip op. at 35. This is error because although the preferred embodiment of Gilbert does not use a stabilizer, Gilbert
`discloses at col. 3, II. 11-22 ophthalmic formulations that "optionally . . . contain a stabilizer." Gilbert also discloses the
`combination of an NSAID, BAC, and a surfactant, and discloses a number of stabilizers, of which at least some,
`according to Apotex's expert Dr. Mitra, are nonionic surfactants.
`Finally, the district court discounted the significance of the McCutcheon's reference to the use of octoxynol 40 because
`although it identified octoxynol 40 as an emulsifier and a stabilizer, it did not describe the use of octoxynol 40 in
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`pharmaceuticals and indicated that it had other uses. McCutcheon's cannot be so lightly overlooked, because, as noted
`above, the record shows that octoxynol 40 was previously used in pharmaceuticals.
`On remand, the district court should reevaluate the importance of these references with the understanding that they
`provide material disclosure and do not teach away.
`3. Apotex's Expert Testimony
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`The district court, in concluding that the cited references teach away from combination, *1381 further found that the
`evidence produced no motivation to combine. While the question of whether to combine McCutcheon's with other
`references is a live issue on remand, there is another focus that needs to be appreciated to fully explore the obviousness
`issue.
`As the district court appreciated, the bare question of whether it would have been obvious to substitute one surfactant for
`another misplaces the proper focus on the obviousness of the invention as a whole, and likely invites hindsight
`conclusion, forbidden by our precedent. See Gillette Co. v. S.C. Johnson & Son., Inc., 919 F.2d 720, 724-25
`(Fed.Cir.1990).
`Apotex's expert testimony, however, cannot be lightly disregarded on the theory that Dr. Mitra only sought to show the
`obviousness of substituting octoxynol 40 for another surfactant. Mitra's testimony may be relevant on another level,
`which is the very point on which the examiner concluded that the otherwise suspect invention was non-obvious. Mitra's
`testimony has to be considered as well on the point of whether the results produced by use of octoxynol 40 are
`sufficiently unexpected as to secure the validity of the claims in suit.
`In this case, Apotex's expert provided his theory of why a person of skill in the art would not have found it unusual to
`seek, find, and employ octoxynol 40 in making formulations such as those claimed in the '493 patent. Dr. Mitra explained
`that the references at issue informed a scientist to use water-soluble, micelle-forming,[9] nonionic surfactants act as
`stabilizers in a KT/BAC ophthalmic formulation.[10] He also set forth a scientific rationale for the informed selection of
`certain nonionic surfactants, and testified that octoxynol 40 was known and used in many products, including cosmetics.
`[11] Dr. Mitra also opined that knowledge of the chemical qualities of surfactants useful to the claimed subject matter
`would cause a person, "as a matter of science" to "go into *1382 another nonionic surfactant like octoxynols."
`To be clear, we do not require that the district court credit all (or any) of this testimony. On remand, however, the district
`court should consider Apotex's claim of obviousness in light of the applicable legal principles and unencumbered by
`the factual errors identified above.
`4. The Prosecution History
`
`The prosecution history makes clear that the PTO initially believed a person of ordinary skill in the art would know to use
`a nonionic surfactant that possessed the qualities of octoxynol 40 in the claimed formulation. In an Office Action dated
`April 28, 1989, the examiner rejected claims in the '173 parent application directed to the formulation containing
`octoxynol 40 because "it is known to use nonionic surfactants." In particular, the examiner stated: "The mere substitution
`of one nonionic [surfactant] for another, that is, [octoxynol 40] for the nonionic of the primary reference is not deemed a
`patentable distinction in the absence of some unobvious result."
`Syntex responded to this rejection by providing data from a test comparing the efficacy of octoxynol 40, polysorbate 80,
`and myrj 52, purportedly demonstrating unexpected results. The PTO examiner deemed this showing insufficient:
`It has not been shown that the claimed nonionics provide any unexpected results over the nonionics of
`the primary references. The data at page 5 of the response shows only that "octoxynol 40" gave
`somewhat better results than some conventional nonionic surfactants. However, these data do not
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`https://scholar.google.com/scholar_case?case=1206977164379665184&q=syntex+v+apotex+2005&hl=en&as_sdt=40000003
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`SYNTEX (USA) LLC v. Apotex, Inc., 407 F. 3d 1371 - Court of Appeals, Federal Circuit 2005 - Google Scholar
`compare "octoxynol 40" to the nonionics of the primary references. Furthermore the concentrations of the
`Octoxynol 40 is [sic] greater than that of the other nonionic surfactants. Therefore, no conclusion can be
`drawn from said data. Also the showing is not commensurate with the claims which, except for claims 8, 9,
`and 13, recite no proportions and broadly set forth the NSAID, quarternary ammonium preservative and
`polyoxyethylatedoctylphenol surfactant. Finally, the data (1) do not specify the amount of the NSAID and
`(2) are not in declaration form. The response therefore does not overcome the rejection.
`(Emphases added). The '173 parent application was ultimately abandoned.
`The '027 continuation application was assigned to a different PTO examiner. In an Office Action dated February 25,
`1991, the new examiner entered the same rejection, restating, verbatim, that: "The mere substitution of one nonionic
`[surfactant] for another, that is, [octoxynol 40] for the nonionic of the primary reference is not deemed a patentable
`distinction in the absence of some unobvious result."
`Syntex responded by stating that it had "shown in the prosecution of the parent to this application [the '173 parent
`application] that other nonionic surfactants, such as [polysorbate 80] and myrj, fail to act as st