Smithkline Beecham Corporation v. Apotex Corporation

Full title: SMITHKLINE BEECHAM CORPORATION, SMITHKLINE BEECHAM, P.L.C., BEECHAM GROUP…

Court: United States District Court, E.D. Pennsylvania

Date published: Mar 31, 2005

Civil Action No. 99-CV-4304, No. 00-CV-4888, 01-CV-0159, 01-CV-2169, Civil Action No. 99-CV-2926, No. 00-CV-5953, 02-CV-1484, Civil Action No. 00-CV-1393, 00-CV-6464, 01-CV-2602, 01-CV-1027, 01-CV-3364, 02-CV-8493, 01-CV-2981, 03-CV-6117, 03-CV-3365 (E.D. Pa. Mar. 31, 2005)

Opinion

Civil Action No. 99-CV-4304, No. 00-CV-4888, 01-CV-0159, 01-CV-2169, Civil Action No. 99-CV-2926, No. 00-CV-5953, 02-CV-1484, Civil Action No. 00-CV-1393, 00-CV-6464, 01-CV-2602, 01-CV-1027, 01-CV-3364, 02-CV-8493, 01-CV-2981, 03-CV-6117, 03-CV-3365.

March 31, 2005

MEMORANDUM ORDER

RICHARD B. SURRICK, District Judge

Presently before the Court are: (1) Defendants Apotex Corporation, Apotex, Inc., and Torpharm, Inc.'s (collectively "Apotex") Motion for Summary Judgment of Noninfringement of Claims 1-10 and 14-16 of U.S. Patent No. 6,172,233 B1 (Doc. No. 105, 99-CV-4304; Doc. No. 64, 00-CV-4888; Doc. No. 57, 01-CV-0159; Doc. No. 52, 01-CV-2169); (2) Defendant Apotex's Motion for Partial Summary Judgment that Claims 1, 2, 4, 5, 7-10 and 14-16 of U.S. Patent No. 6,172,233 B1 Are Invalid Under 35 U.S.C. § 103 (Doc. No. 109, 99-CV-4304; Doc. No. 68, 00-CV-4888; Doc. No. 61, 01-CV-0159; Doc. No. 56, 01-CV-2169); and (3) Plaintiffs SmithKline Beecham Corporation, SmithKline Beecham, P.L.C., and Beecham Group, P.L.C.'s (collectively "SmithKline") Motion for Summary Judgment for Infringement by Apotex Corporation, Apotex, Inc., and Torpharm, Inc. of Claim 9 of U.S. Patent No. 6,172,233 (Doc. No. 42, 01-CV-2169). In its Motions, Apotex asserts that U.S. Patent No. 6,172,233 ("'233 Patent") is invalid for obviousness and that Apotex's production of paroxetine hydrochloride does not infringe the patent. In a cross-motion for summary judgment, SmithKline argues that Apotex's importation and sale of its generic paroxetine hydrochloride product into the United States infringes claim 9 of the '233 Patent in violation of 35 U.S.C. § 271(g). For the following reasons, we will deny Defendants' Motion for Partial Summary Judgment for invalidity, grant Defendants' Motion for Summary Judgment of Noninfringement, and deny Plaintiffs' Motion for Summary Judgment for Infringement under § 271(g).

I. BACKGROUND ¹

1 Additional background regarding this litigation and the applicable statutory framework may be found in our Memoranda and Orders dated September 28, 2001, September 30, 2002, October 31, 2002, and December 20, 2002. (Doc. Nos. 50, 71, 77, 85.)

A. Paroxetine and the Development of Paxil®

In the 1970s, scientists at a small Danish company named A/S Ferrosan ("Ferrosan") invented a new class of organic chemical compounds, including a compound that became known as paroxetine. Ferrosan applied for and obtained several U.S. patents covering these inventions, including U.S. Patent No. 4,007,196 (the "'196 Patent"), which was issued on February 8, 1977. The '196 Patent claims paroxetine and its pharmaceutically acceptable salts, including paroxetine hydrochloride, and discloses their antidepressant properties. '196 Patent, cols. 1, 9-10.

In 1980, Ferrosan licensed the '196 Patent and its other paroxetine-related technology to Beecham Group Limited, a predecessor of SmithKline. (Doc. No. 109 Ex. D.)² SmithKline's researchers attempted to improve Ferrosan's process for developing paroxetine hydrochloride. (Tr. 2/6/03 at 218, 220-22, SmithKline Beecham Corp. v. Apotex Corp., No. 98 C 3952 (N.D. Ill. 2003).) In 1985, SmithKline purportedly discovered a new crystalline form of paroxetine hydrochloride — crystalline paroxetine hydrochloride hemihydrate — that allegedly had different physical properties than the Ferrosan's original, anhydrous form of paroxetine hydrochloride.³ On January 26, 1988, SmithKline was issued U.S. Patent No. 4,721,723 (the "'723 Patent"), which claims paroxetine hydrochloride hemihydrate, as well as its use as an anti-depressant.⁴ '723 Patent, col. 10.

2 Unless otherwise specified, all docket numbers cited in this Memorandum refer to the filings in Civil Action No. 99-4304.

3 The anhydrous form of paroxetine hydrochloride is comprised of crystals of paroxetine hydrochloride without bound water molecules. The hemihydrate form of paroxetine hydrochloride is comprised of crystals of paroxetine hydrochloride with one bound water molecule for every two paroxetine hydrochloride molecules. SmithKline Beecham Corp. v. Apotex Corp., 365 F.3d 1306, 1308 (Fed. Cir. 2004).

4 On April 23, 2004, the Federal Circuit concluded that the '723 Patent was invalid for prior use under 35 U.S.C. § 102(b). SmithKline Beecham Corp., 365 F.3d at 1316-21. Both parties in that action (No. 03-1285) have petitioned for rehearing en banc pursuant to Federal Rule of Appellate Procedure 35 and Federal Circuit Rule 35. As of March 30, 2005, the Federal Circuit had not ruled on the petitions.

On November 20, 1989, SmithKline submitted New Drug Application ("NDA") No. 20-031 to the Food and Drug Administration ("FDA") for permission to market a drug for the treatment of depression.⁵ (Doc. No. 42, 01-CV-2169, Ex. 3.) This drug contained the crystalline paroxetine hydrochloride hemihydrate of the '723 patent as its active ingredient. ( Id.) The FDA approved SmithKline's NDA on December 29, 1992, and SmithKline began selling the drug under the trade name of Paxil®. ( Id.)

5 The introduction of new prescription drugs to the marketplace is governed by the Food, Drug Cosmetic Act, 21 U.S.C. §§ 301-397 (2000). Generally, any company seeking to market a new drug must first receive the approval of the FDA by submitting a NDA. See id. § 355(a). The NDA is a thorough, time-consuming, and costly process in part because the application must include data from clinical studies that support the proposed drug's safety and effectiveness. Mova Pharm. Corp. v. Shalala, 140 F.3d 1060, 1063 (D.C. Cir. 1998).

B. The '233 Patent

1. SmithKline's Experiments with Grignard Reactions

In 1996, Neal Ward, a SmithKline scientist, conducted experiments related to the production of paroxetine hydrochloride. (Ward Decl. ¶ 4.) According to Ward, the goal of his experiments "was to identify processes suitable for industrial scale production of paroxetine." ( Id.) Specifically, he experimented with various processes for synthesizing a compound known as 1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine, a chemical intermediate used in the manufacture of paroxetine hydrochloride. ( Id.)

Figure 1: 1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine

To synthesize this chemical intermediate, Ward stated that he used a process discussed in an article by John Plati published in the March 1957 issue of Journal of Organic Chemistry. ( Id. (citing John T. Plati et al., Pyridindene Derivatives. III. Synthesis from Arecoline, 22 J. Organic Chemistry 261 (1957) ("Plati article"))). The Plati article described a process that reacted a type of organic chemical compound called arecoline⁶ with what is known as a Grignard reagent. Plati, 22 J. Organic Chemistry at 261-63; see also Hollingsworth Decl. ¶ 14. Grignard reagents, named after their discoverer, Victor Grignard,⁷ are organomagnesium compounds — an organic molecule consisting of an alkyl halide⁸ bound to a magnesium atom.⁹ See Richard S. Lewis, Sr., Hawley's Condensed Chemical Dictionary 552 (13th ed. 1998) ("Hawley's") (stating that Grignard reagents are "[a]n important class of reagents used in synthetic organic chemistry, made by the union of metallic magnesium with an organic chloride, bromide, or iodide"). A Grignard reaction involves the combination of a Grignard reagent with another organic compound, and results in the combination of the two molecules. Because Grignard reagents are highly reactive with water, a Grignard reaction can be conducted only in a water-free solvent. See id. ("Since all Grignard reagents react rapidly with both water and oxygen, contact [with both] must be avoided."); K. Peter C. Vollhardt, Organic Chemistry 285 (1987) ("Organometallic reagents must be prepared in the absence of moisture because they react (in some cases, violently) with water. . . ."). Because of "their ease of reaction with water, carbon dioxide, alcohols, aldehydes, ketones, amines, etc. to produce a great variety of organic compounds, usually with good yields," Hawley's at 552, Grignard reagents are "among the most widely used reagents in organic chemistry." Alain Boudin et al., Grignard Reagents as Powders: Preparation and Reactivity, 45 Tetrahedron 171, 171 (1989); see also United States v. One 1986 Chevy Monte Carlo, 817 F. Supp. 729, 730 n. 1 (N.D. Ill. 1993) (noting that Grignard reagents are "widely used" in chemical reactions (citing Douglas C. Neckers Michael P. Doyle, Organic Chemistry § 11.8 (1978))).

6 Arecoline is a molecule consisting of seven carbon (C) atoms, eleven hydrogen (H) atoms, two oxygen (O) atoms, and one nitrogen (N) atom, arranged in the following shape:

7 Victor Grignard won the 1912 Nobel Prize in Chemistry for his discovery of Grignard reagents.

8 An alkyl halide is a "[c]ompound of the formula C _n H_{2 n +1}X," where C represents carbon atoms, H represents hydrogen atoms, and X is an atom of the halogen class. Maitland Jones, Jr., Organic Chemistry at A2 (2d ed. 2000); see also Grant Hackh's Chemical Dictionary at 24 (Roger Grant Claire Grant eds., 5th ed. 1984) (defining an alkyl halide as "a monovalent radical of an aliphatic hydrocarbon" molecule bound to a halogen atom). Halogens are nonmetallic elements of the seventh group of the period table. Grant Hackh's Chemical Dictionary at 274. Fluorine (F), chlorine (Cl), bromine (Br), and iodine (I) are all halogens. Id.

9 Grignard reagents have the common formula of RMgX, where R is an organic group, Mg is a magnesium (Mg) atom, and X is a halogen. Richard S. Lewis, Sr., Hawley's Condensed Chemical Dictionary 552 (13th ed. 1998).

The Plati article described a Grignard reaction that took place in a water-free ether solvent.¹⁰ Plati, 22 J. Organic Chemistry at 263. When Ward attempted to replicate the Plati process with an ether solvent, he noticed the formation of a sediment that fell out of the solution. (Ward Decl. ¶ 4.) According to Ward, this sediment took the form of either a sticky gum that adhered to the walls of the flask or a thick gel that was difficult to stir. ( Id.) Based on his experience, he concluded that the Plati process was not a viable method for large-scale, industrial production of paroxetine hydrochloride. ( Id.)

10 Ethers are "[c]ompounds of the general formula R-O-R," where O is an oxygen atom and R are organic radicals. Grant Hackh's Chemical Dictionary at 220, 491.

After numerous attempts to improve the Plati process, Ward discovered that replacement of some or all of the ether with a non-ether solvent resulted in a clear solution or a readily stirrable suspension.¹¹ ( Id. ¶ 5.) Ward considered this result to be "a significant and unexpected improvement" over the Plati method because it was, in his estimate, a particularly suitable approach for large-scale, industrial preparation of paroxetine hydrochloride. ( Id.)

11 In his Declaration in support of the application for the '233 Patent, Ward noted that he had initially employed non-ether solvents of toluene and dicholoromethane. (Ward Decl. ¶ 5.) Toluene is a cyclical hydrocarbon consisting of a phenyl group (a benzene radical) bonded to a methyl radical (C₆H₅-CH₃). Grant Hackh's Chemical Dictionary at 491, 595.
Dicholoromethane, also known as methylene dichloride, consists of a methylene group bonded to two chlorine atoms (Cl-CH₂-Cl). Id. at 182, 368. Toluene and dichloromethane are both colorless liquids at room temperature. Id. at 368, 595.

2. '233 Patent Prosecution History

a. Initial Application

On January 15, 1998, SmithKline filed a U.S. patent application for this process, naming Ward as the inventor.¹² U.S. Patent Application No. 09/007,475 (filed Jan. 15, 1998), reprinted in Doc. No. 109 Ex. I at 0013-0022 ("'233 Patent Application"). The original application contained ten separate claims. Claim 1, the only independent claim, read as follows:

12 Ward claimed foreign priority benefits under 35 U.S.C. §§ 119(a)-(d), 365(d), based on a patent application filed in the United Kingdom on January 15, 1997. (Doc. No. 109 Ex. I at 0040-0041.)

1. A process for the preparation of a compound of structure (2)

in which R and R' are independently selected from an alkyl, aryl, or arylalkyl group, X is one or more of hydrogen, halogen, hydroxy, alkoxy, nitro, nitrile, amino (optionally protected or substituted), trifluoromethyl, acyl, formyl, carboxyl or carboxylalkyl, which comprises reacting a compound of structure (4)

with an organometallic compound having one or more X-substituted phenyl groups, in a suitable organic solvent, provided that the solvent is not wholly diethyl ether when the organometallic compound is a Grignard reagent.

(Doc. No. 109 Ex. I at 0020.) Claim 2, a dependent claim, read as follows:

2. A process according to claim 1, in which the organometallic compound is a compound of structure (3)

in which M is a Group II metal and Y is a halogen or an X-substituted phenyl group.

( Id.) Thus, claims 1 and 2 of the '233 Patent Application claimed the following process of combining molecules of structure (4) and (3) in a solvent of not wholly diethyl ether¹³ to create a molecule of structure (2):

13 Diethyl ether is an ether consisting of two ethyl groups (CH₃CH₂-) bonded to an oxygen atom (CH₃CH₂OCH₂CH₃). Grant Hackh's Chemical Dictionary at 183-84, 220. Diethyl ether is commonly referred to simply as ether. Diethyl Ether, Encyclopaedia Brittanica Online, at http://www.britannica.com/eb/article?tocId=9033145 (last visited Jan. 5, 2005).

Figure 2: Claimed Process of '233 Patent Application

The remaining claims, numbered 3 through 10, were all dependent claims for several variations of the processes claimed in claims 1 and 2.

In the '233 Patent Application, SmithKline disclosed the '196 Patent, U.S. Patent No. 3,912,743 (issued Oct. 14, 1975) (the "'743 Patent"), and the Plati article as prior art. ( Id. at 0013-0014.) On July 23, 1998, the United States Patent and Trademark Office ("PTO") rejected all of the claims, finding them obvious under 35 U.S.C. § 103 in light of the prior art. ( Id. at 0061-0063.) Specifically, the Patent Examiner found the claims obvious in light of the '743 Patent, which disclosed a process for making intermediates and derivatives of the general class of compounds to which paroxetine hydrochloride belongs. ( Id. at 0062-0063.) The Patent Examiner stated that the only difference between the '233 Patent Application and the '743 Patent was the type of solvent used, and that such a change would be obvious to a person of ordinary skill in the art.¹⁴ ( Id.)

14 In the rejection letter, the Patent Examiner stated:

Claims 1 to 10 are rejected under 35 U.S.C. [§] 103(a) as being unpatentable. . . . Christensen et al [the '743 Patent] teach[es] preparing compounds of the type recited, 4-phenyl piperidine derivatives, where a tetra hydro pyridine-carboxylate is reacted with phenyl magnesium bromide. Patentees disclosure differs from that claimed in that it does not specifically disclose solvents other than ether. It is noted however, that other solvents, such as those recited in the claims, are known for use in Grignard type reactions. MacLeod et al [U.S. Patent No. 5,661,162] teach[es] [a] similar process in which a hydrocarbon solvent, toluene is used. Likewise Sarges [U.S. Patent No. 4,623,728] teaches an analogous process. In light of the prior art taken as a whole it would have been obvious to one of ordinary skill in the art to modify the process of [the '743 Patent] to use a solvent other than ether as the results, a condensation product, would not have been unexpected.

(Doc. No. 109 Ex. I at 0062-0063 (internal citations omitted).)

b. Amended Application

On November 12, 1999, SmithKline submitted amendments to the '233 Patent Application. ( Id. at 0072-0079 ("Amended '233 Patent Application").) The new submission's independent claim differed from the original '233 Patent Application's claim in three ways: (1) it replaced X in structure (2), which represented a variety of possible organic and non-organic radicals,¹⁵ with a fluorine (F) atom; (2) the solvent used in the process could not be wholly ether, rather than the not wholly diethyl ether solvent specified in the original application; and (3) the process had to be conducted on an "industrial scale." ( Id. at 0072.) Changes (1) and (2) are represented in Figure 3:

15 A radical is an "[a]n ionic group having one or more charges, either positive or negative." Hawley's at 953.

Figure 3: Claimed Process of Amended '233 Patent Application

Dependent claims 2-10 remained unchanged by the amendments, and three product-by-process claims were also added to the application.¹⁶ ( Id.)

16 These were the product-by-process claims that we held invalid in our December 22, 2002, Memorandum and Order. (Doc. No. 85.)

In its submission, SmithKline argued that the Amended '233 Patent Application was nonobvious because: (1) the prior art cited by the Patent Examiner related to "significantly different reactions" and "significantly different compounds" than the Plati article and the claimed process ( id. at 0076-0077); and (2) the claimed process solves a problem caused by the Plati process, namely that when the Plati process is conducted with X as a fluorine atom, as illustrated in structure (2) above, "the procedure generates a thick unstirrable gel that is unsuitable for large scale production," and that the use of a non-wholly-ether solvent corrects this problem. ( Id. at 0076.) On January 29, 2000, the Patent Examiner rejected these arguments, again finding that the claims were obvious in light of prior art cited in the previous decision. Explaining his decision, the Examiner stated:

Applicants['] comments have been noted and considered but are not deemed persuasive of patentability. Regarding the newly presented claims it is noted that the recited fluorine substituent falls within the scope of the disclosed halogen substitute taught in the prior art. Additionally, noting the comments in the next above paragraph, the process as taught by the cited prior art would be expected to give the same results at a so-called industrial scale.

( Id. at 0082.) The Examiner did not discuss SmithKline's assertion that the claimed process's correction of problems encountered in using the Plati process rendered the alleged discovery nonobvious.

c. Continued Prosecution Application ("CPA")

On July 11, 2000, counsel for Plaintiffs held a telephone conversation with the Patent Examiner. ( Id. at 0084-0088.) In the conversation, the parties discussed the rejection of the amended application, including the Examiner's determination that the claimed processes were obvious in light of the prior art. ( Id. at 0087.) According to Plaintiffs' counsel, "[t]he Examiner indicated that an affidavit, pointing out the inoperability of the prior art (i.e., the Plati reference) to the claimed large scale process would be useful" in finding that the claimed process was nonobvious. ( Id.) On July 25, 2000, SmithKline filed a request to continue the application. ( Id. at 0089, 0091-0095.) As part of its request, SmithKline submitted a declaration by Neal Ward to the Examiner. ( Id. at 0096-0097.) Ward recounted that when he used the Plati process to produce the paroxetine intermediate illustrated in Figure 1, supra, it resulted in the production of a sticky gum or thick gel unsuitable for industrial scale production. (Ward Decl. ¶ 4.) Ward stated that replacement of the diethyl ether solvent used in the Plati process with a non-ether solvent resulted in a clear solution or a readily stirrable suspension suitable for industrial scale production. ( Id. ¶ 5.) Ward asserted in his Declaration that the result obtained from using a nonether solvent was "a significant and unexpected improvement over the Plati reference." ( Id.)

Relying on Ward's declaration, the Examiner granted an allowance to issue a patent for the claimed processes on August 15, 2000. (Doc. No. 109 Ex. I at 0099-0101.) In his explanation for granting the allowance, the Examiner stated that "[t]he prior art neither teaches nor suggests the claimed process. Further, the declaration of Neal Ward demonstrates that prior art processes do not work in the manner prescribed nor do they give the claimed results. Accordingly, [the] claims . . . are allowed." ( Id. at 0100.) The '233 Patent was formally issued to Ward and assigned to SmithKline on January 9, 2001. ( Id. at 0001.)

C. Procedural History

On March 13, 2001, Apotex filed an Abbreviated New Drug Application ("ANDA") with the FDA pursuant to 21 U.S.C. § 355(j).¹⁷ (Doc. No. 42, 01-CV-2169, Ex. 11 at unnumbered 1.) In its ANDA, Apotex asserted that the '233 Patent was invalid under the doctrines of prior use ( 35 U.S.C. § 102(b)), anticipation by prior printed publication ( 35 U.S.C. § 102), obviousness ( 35 U.S.C. § 103), and double patenting ( Eli Lilly Company v. Barr Labs., Inc., 222 F.3d 973 (Fed. Cir. 2000)). ( Id. at unnumbered 3-4.) Apotex also asserted that its importation of anhydrous paroxetine hydrochloride would not infringe claims 1-7 and 14-16 of the '233 Patent under 35 U.S.C. § 271(g), which prohibits the importation, use, sale, or offer of sale of a product made by a process patent in the United States, because Apotex's process for manufacturing paroxetine was "materially changed" by subsequent processes under 35 U.S.C. § 271(g) (2000) prior to the drug's importation or sale in the United States. ( Id. at unnumbered 1-3.)

17 Pursuant to the Drug Price Competition and Patent Term Restoration Act, also known as the Hatch-Waxman Act ("Hatch-Waxman"), Pub.L. No. 98-417, 90 Stat. 1585 (1984) (codified in scattered sections of 21, 35, and 42 U.S.C.), a generic drug manufacturer may seek expedited approval to market a generic version of a previously approved drug by submitting an ANDA to the FDA. 21 U.S.C. § 335(j) (2000). Under Hatch-Waxman, an ANDA may rely on the FDA's previous determination with respect to the NDA that the drug is safe and effective if it can demonstrate that the generic drug is the bioequivalent of the previously approved drug. Id. An applicant filing an ANDA must certify that its proposed generic drug will not infringe an existing patent because (1) the required patent information has not been filed, (2) the patent has expired, (3) the patent has not yet expired, but will expire on a particular date, or (4) that the patent is invalid or will not be infringed by the drug for which the applicant seeks approval. Id. § 335(j)(2)(A)(vii).
A more detailed summary of Hatch-Waxman's procedures for submission and approval of an ANDA may be found in our Memoranda and Orders of September 28, 2001, December 20, 2002, July 16, 2004, and September 29, 2004. (Doc. Nos. 50, 85, 165; Doc. No. 113, 99-CV-2926.)

In response to the filing of Apotex's ANDA, SmithKline filed a Complaint against Apotex in this Court on May 11, 2001. (Doc. No. 1, 01-CV-2169.) We granted Plaintiffs' and Defendants' cross-motions to consolidate this action for purposes of pretrial discovery with several other patent infringement actions brought by SmithKline against Apotex and other prospective producers and sellers of generic versions of Paxil®. SmithKline Beecham Corp. v. Apotex Corp., Nos. 99-2926 et al., 2001 WL 1249694 (E.D. Pa. Sept. 26, 2001) (granting cross-motions for consolidation of actions for pretrial proceedings). On December 20, 2002, we issued a Memorandum and Order granting Apotex's motion for summary judgment regarding the product-by-process¹⁸ claims of the '233 Patent (claims 11, 12, and 13), concluding that they were invalid due to prior public use under 35 U.S.C. § 102(b).¹⁹ SmithKline Beecham Corp. v. Apotex Corp., Nos. 99-2926 et al., 2002 U.S. Dist. LEXIS 25275 (E.D. Pa. Dec. 20, 2002) (granting in part and denying in part Defendants' motion for summary judgment).

18 A product-by-process patent claim "is a product claim that defines the claimed product in terms of the process by which it is made." SmithKline Beecham Corp., Nos. 99-2926 et al., 2002 U.S. Dist. LEXIS 25275, at *10-11 (E.D. Pa. Dec. 20, 2002) (quoting U.S. Patent Trademark Office, Manual of Patent Examining Procedure § 2173.05 (8th ed. 2001)).

19 In the same decision, we determined that claims 1 and 2 of U.S. Patent No. 6,113,944 (issued Sept. 5, 2000) (the "`944 Patent") and claim 6 of U.S. Patent No. 6,080,759 (issued June 27, 2000) (the "`759 Patent") were invalid, and that Apotex had not infringed claim 6 of the '759 Patent. SmithKline Beecham Corp., 2002 U.S. Dist. LEXIS 25275, at *48. We denied Apotex's motion for summary judgment of invalidity and noninfringement regarding the '423 Patent and all remaining claims of the '759 Patent. Id.

In the instant Motions, Apotex asserts that it has not violated the '233 Patent for two reasons: (1) the Patent's remaining claims (claims 1-10 and 14-16) are invalid for obviousness under 35 U.S.C. § 103, and (2) Apotex's method of production of paroxetine hydrochloride does not infringe the process claims of the '233 Patent. (Doc. Nos. 105, 109.) SmithKline argues that Apotex's proposed importation and sale of its generic paroxetine hydrochloride product in the United States will infringe Claim 9 of the '233 patent under 35 U.S.C. § 271(g). (Doc. No. 42, 01-CV-2169.)

II. LEGAL STANDARD

The standards for summary judgment are well-established, and are "applied in patent cases no differently from their application in any other type of case." SRL Int'l v. Matsushita Elec. Corp. of Am., 775 F.2d 1107, 1116 (Fed. Cir. 1985). Summary judgment is appropriate "if the pleadings, depositions, answers to interrogatories, and admissions on file, together with the affidavits, if any, show that there is no genuine issue as to any material fact and that the moving party is entitled to a judgment as a matter of law." Fed.R.Civ.P. 56(c). The moving party bears the burden of proving that no genuine issue of material fact is in dispute. Adickes v. S.H. Kress Co., 398 U.S. 144, 157 (1970); see also Celotex Corp. v. Catrett, 477 U.S. 317, 323 (1986) ("[A] party seeking summary judgment always bears the initial responsibility of informing the district court of the basis for its motion, and identifying those portions of [the record] . . . which it believes demonstrate the absence of a genuine issue of material fact." (citing Fed.R.Civ.P. 56(c))). Once the moving party carries this initial burden, the nonmoving party "may not rest upon . . . mere allegations or denials of the adverse party's pleadings," but instead "must set forth specific facts showing that there is a genuine issue for trial." Fed.R.Civ.P. 56(e).

A genuine issue of material fact exists when a finder of fact could reasonably return a verdict in favor of the non-moving party with respect to that issue. Anderson v. Liberty Lobby, Inc., 477 U.S. 242, 248 (1986). The non-moving party must raise "more than a mere scintilla of evidence in its favor," and cannot survive by relying on unsupported assertions, conclusory allegations, or mere suspicions. Williams v. Borough of West Chester, 891 F.2d 458, 460 (3d Cir. 1989); see also Anderson, 477 U.S. at 248 ("Only disputes over facts that might affect the outcome of the suit under the governing law will properly preclude the entry of summary judgment. Factual disputes that are irrelevant or unnecessary will not be counted."). In making this determination, we must view facts and inferences in the light most favorable to the nonmoving party. Anderson, 477 U.S. at 255; In re Cruciferous Sprout Litigation, 301 F.3d 1343, 1346 (Fed. Cir. 2002). If there is no genuine issue of material fact, and the moving party is entitled to judgment as a matter of law, then we must grant summary judgment. Fed.R.Civ.P. 56(c).

III. OBVIOUSNESS

In their motion for partial summary judgment, Defendants argue that claims 1, 2, 4, 5, 7-10, and 14-16 of the '233 Patent are invalid for obviousness under 35 U.S.C. § 103(a). (Doc. No. 109.)

A. Legal Standards

Section 103(a) states that "[a] patent may not be obtained . . . if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains." 35 U.S.C. § 103(a) (2000). Whether a claim is obvious to a person of ordinary skill in light of prior art "`is a question of law based on underlying findings of fact.'" In re Fulton, 391 F.3d 1195, 1199 (Fed. Cir. 2004) (quoting In re Gartside, 203 F.3d 1305, 1306 (Fed. Cir. 2000)). These underlying factual determinations include: (1) the level of ordinary skill in the art at the time the invention was made; (2) the scope and content of the prior art; (3) the differences between the prior art and the claims at issue; and (4) objective evidence of nonobviousness, sometimes called secondary considerations.²⁰ Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966). Once these factual determinations are made, we must determine whether, "in light of all the evidence, . . . the patent challenger has convincingly established that the claimed invention as a whole would have been obvious" to a person of ordinary skill in the art at the time of the invention. Panduit Corp. v. Dennison Mfg. Co., 810 F.2d 1561, 1566 (Fed. Cir. 1987) (citation omitted).

20 We must make express findings for each factual determination. Loctite Corp. v. Ultraseal Ltd., 781 F.2d 861, 873 (Fed. Cir. 1985); see also Ruiz v. A.B. Chance Co., 234 F.3d 654, 663-64 (Fed. Cir. 2000) ("Our precedent clearly establishes that the district court must make Graham findings before invalidating a patent for obviousness.").

Under the Patent Act, a patent is presumptively valid, and each claim of a patent is presumed valid independently of the validity of the other claims. 35 U.S.C. § 282 (2000). The party challenging the validity of a patent has the burden of proving "facts supporting a conclusion of invalidity by clear and convincing evidence."²¹ Ryco, Inc. v. Ag-Bag Corp., 857 F.2d 1418, 1423 (Fed. Cir. 1988). Although the burden of proof is not reduced when prior art is presented to the court which was not considered by the PTO, Connell v. Sears, Roebuck Co., 722 F.2d 1542, 1549 (Fed. Cir. 1983), "reliance upon such art when that art is more pertinent than the art considered by the PTO may facilitate meeting the burden of proving invalidity." Uniroyal, Inc. v. Rudkin-Wiley Corp., 837 F.2d 1044, 1050 (Fed. Cir. 1988); see also Ryco, Inc., 857 F.2d at 1423 (stating that a challenger's burden "may be more easily met where the challenger produces prior art that is more pertinent than that considered by the [PTO]").

21 "Although not susceptible to precise interpretation, `clear and convincing evidence' has been described as evidence which produces in the mind of the trier of fact `an abiding conviction that the truth of [the] factual contentions are `highly probable.''" Buildex v. Kason Indus., Inc., 849 F.2d 1461, 1463 (Fed. Cir. 1988) (quoting Colorado v. New Mexico, 467 U.S. 310, 316 (1984)). The "clear and convincing" standard of proof is an intermediate standard that lies between a "preponderance of the evidence" and "beyond a reasonable doubt." Addington v. Texas, 441 U.S. 418, 425 (1979).

B. Person of Ordinary Skill in the Art

First, we must determine the appropriate level of ordinary skill in the art. Graham, 383 U.S. at 1. Because this is a factual determination, see, e.g., Custom Accessories, Inc. v. Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962 (Fed. Cir. 1986), we must view all facts and inferences in the light most favorable to the nonmoving party. In re Cruciferous Sprout Litigation, 301 F.3d at 1346.

A person of ordinary skill in the art "is a hypothetical person who is presumed to be aware of all the pertinent prior art." Custom Accessories, Inc., 807 F.2d at 962 (citing Standard Oil Co. v. Am. Cyanamid Co., 774 F.2d 448, 454 (Fed. Cir. 1985)). "A person of ordinary skill in the art is . . . presumed to be one who thinks along the line of conventional wisdom in the art and is not one who undertakes to innovate, whether by patient, and often expensive, systematic research or by extraordinary insights. . . ." Am. Cyanamid Co., 774 F.3d at 454. Factors that may be considered in determining the ordinary level of skill include the type of problems encountered in the art, prior art solutions to those problems, the sophistication of technology in the field, and educational level of active workers in the field. Custom Accessories, Inc. 807 F.2d at 962 (citing Envtl. Designs, Ltd. v. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983)). The actual inventor's level of skill is irrelevant to this inquiry. Am. Cyanamid Co., 774 F.3d at 454.

Here, the parties disagree, at least superficially, about the relevant qualifications for a person of ordinary skill in the art. See Doc. No. 120 at 8 (recounting Plaintiffs' statement that "there are factual disputes concerning the level of skill in the art"). Defendants assert that "[a] person of ordinary skill in the field of organic chemistry at the time of the alleged invention of the '233 [P]atent was a person with at least a Masters Degree in Organic Chemistry and/or several years['] practical experience" in the field. (Doc. No. 109 at 15; Hollingsworth Decl. ¶ 5.) In response, Plaintiffs claim that a person of ordinary skill in the art "would be a synthetic chemist with at least a bachelors degree and some industrial experience." (Doc. No. 120 at 8.) However, Plaintiffs' expert, Dr. Brian Adger, filed a declaration in which he asserted that "someone of ordinary skill [in] organic chemistry" would be a person who holds "a bachelors or masters degree with at least some industrial experience," and "who may be asked to carry out . . . experiments" in the field of organic chemistry. (Adger Decl. ¶ 2.) We may rely on expert witness reports and affidavits to assist us in determining the appropriate qualifications of a person of ordinary skill in the art. See, e.g., Pay Child Support Online, Inc. v. ACS State Local Solutions, Inc., Civ. No. 02-1321, 2004 U.S. Dist. LEXIS 6011, at *20-21 (D. Minn. Apr. 5, 2004); Elec. Planroom v. McGraw-Hill Cos., 135 F. Supp. 2d 805, 831 (E.D. Mich. 2001); Optical Prods. Dev. Corp. v. Dimensional Media Assocs., 134 F. Supp. 2d 320, 326 (S.D.N.Y. 2001). Viewing the expert affidavits in a light most favorable to Plaintiffs, who are the nonmoving parties, we determine that there is no genuine issue of material fact regarding a person of ordinary skill in the art, and find that such a person would have the following qualifications: (1) at least a bachelor's degree in chemistry, including coursework in organic chemistry; (2) several years' experience in conducting laboratory or industrial experiments in the field of organic chemistry; (3) knowledge of Grignard reagents and Grignard reactions, including the chemical molecules and solvents used in these reactions; and (4) some laboratory experience in conducting Grignard reactions. Cf. Cargill, Inc. v. Sears Petroleum Transp. Corp., 334 F. Supp. 2d 197, 215 (S.D.N.Y. 2004) (Peebles, M.J.) (determining, in a dispute regarding a patent that covered the use of organic compounds as deicing and anti-freezing agents, that a person of ordinary skill was one who "possess[es] a bachelors degree, or the equivalent, in chemistry or chemical engineering, with some coursework in the field of organic chemistry, and additional post-graduate involvement in research or practical experience in the field").

C. Scope of Prior Art

We also must determine the scope of the prior art. Graham, 383 U.S. at 1. Although the plain text of § 103 does not define what qualifies as "prior art," the Federal Circuit has "frequently couched [prior art] in terms of whether the art is analogous or not" — "i.e., whether the art is `too remote to be treated as prior art.'" In re Clay, 966 F.2d 656, 658 (Fed. Cir. 1992) (quoting In re Sovish, 769 F.2d 738, 741 (Fed. Cir. 1985)). "Two criteria have evolved for determining whether prior art is analogous: (1) whether the art is from the same field of endeavor, regardless of the problem addressed; and (2) if the reference is not within the field of the inventor's endeavor, whether the reference still is reasonably pertinent to the particular problem with which the inventor is involved." In re Clay, 966 F.2d at 658-59; see also Ruiz v. A.B. Chance Co., 234 F.3d 654, 665 (Fed. Cir. 2000) ("The scope of the prior art includes art that is `reasonably pertinent to the particular problem with which the invention was involved.'" (quoting Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530, 1535 (Fed. Cir. 1983)).²²

22 A prior art reference also must be available before the date of alleged invention. Bausch Lomb, Inc. v. Barnes-Hind/Hydrocurve, Inc., 796 F.2d 443, 449 (Fed. Cir. 1986). "[T]he date of invention" is "presumed to be the filing date of the application," unless an earlier date is proved. Id. Here, the parties do not allege that any of the asserted prior art was not available at the date of invention.

In addition to the Plati article and the '196 Patent, which were both mentioned as prior art in the '233 Patent Application (Doc. No. 109 Ex. I at 0013-0014) and in the text of the '233 Patent itself, '233 Patent col. 1 ll. 44-67,²³ Defendants assert that two other sources — (1) an article by Lifen Xu and Mark L. Trudell, published in the November-December 1996 issue of the Journal of Heterocyclic Chemistry ("Xu article") and (2) an entry on Grignard reactions from the Encyclopedia of Chemical Technology (3d ed. 1980) — are prior art to the '233 Patent.²⁴ (Doc. Nos. 109 at 22-28; 147 at 5.) We agree. Knowledge of prior art references in the same field as the patentee's invention is presumed. In re Dance, 160 F.3d at 1343. Here, the publications cited by Defendants are in the field of organic chemistry, the same field as the '233 Patent. More specifically, the '233 Patent and the publications both deal with Grignard reactions and the use of non-ether solvents for these reactions. The Xu article discloses a Grignard reaction structurally similar to claim 1 of the '233 Patent, and discusses the benefits of substituting an ether solvent with a non-ether solvent (specifically, dichloromethane) for that reaction. Lifen Xu Mark L. Trudell, Stereoselective Synthesis of 2-Carbomethoxy-3-phenyltropane Derivatives. Enhanced Stereoselectivity Observed for the Conjugate Addition Reaction of Phenylmagnesium Bromide Derivatives with Anhydro Dichloromethane, 33 J. Heterocyclic Chemistry 2037, 2037-38 (1996); see also Hollingsworth Decl. ¶ 16 ("The 1996 Xu reference . . . discloses a conjugate addition that is very closely related to the process defined in the '233 Patent. Xu discloses a process for reacting the same Grignard reagent shown in the '196 Patent (4-fluorophenylmagnesium bromide) with a compound that is a chemical analogue of arecoline to give isomeric 1,4 addition products."); id. ¶ 17 ("[T]he Xu reference discloses a process in which the conjugate addition is carried out in a solvent that `is not wholly an ether solvent when the organometallic compound is a Grignard reagent.'" (quoting Xu Trudell, 33 J. Heterocyclic Chemistry at 2037-38)). The Encyclopedia of Chemical Technology entry discusses the Grignard reactions in general, and specifically discloses the use of various ether and non-ether solvents and their relative advantages and disadvantages. Grignard Reaction, 12 Encyclopedia of Chemical Technology 30, 32 (3d ed. 1980). Because both the Xu article and the Encyclopedia of Chemical Technology entry on Grignard reactions are in the "same field of endeavor" as the '233 Patent, we find that they are analogous prior art to the '233 Patent.

23 A patent "applicant's admission as to the relevant prior art — both in terms of available sources and in terms of the scope of the art — will be accepted as binding upon him." 2 Donald S. Chisum, Chisum on Patents § 5.03[3][e], at 5-179 to 5-180 (2003) (footnotes omitted).

24 We note that Plaintiffs do not appear to dispute that the '196 Patent and Xu article are prior art. See Doc. No. 120 at 6-7 (discussing why a person of ordinary skill would not be motivated to combine the '196 Patent and the Xu article, without questioning whether either source qualifies as prior art).

D. Content of Prior Art, and Differences Between Claims and Prior Art

Next, we must determine the content of the prior art, and the differences between the claimed processes of the '233 Patent and the prior art. Graham, 383 U.S. at 17. These factual determinations are central to the ultimate issue of obviousness. See Dann v. Johnston, 425 U.S. 219, 228 (1976) (stating that "the `obviousness' test of § 103 . . . turns on . . . whether the difference between the prior art and the subject matter in question `is a difference sufficient to render the claimed subject matter nonobvious to one skilled in the applicable art. . . .'" (quoting In re Johnson, 502 F.2d 765, 777 (C.C.P.A. 1974) (Markey, C.J, dissenting)); see also Robert L. Harmon, Patents and the Federal Circuit (6th ed. 2003) ("The patent examination process centers on prior art and the analysis thereof."). "The consistent criterion for determination of obviousness is whether the prior art would have suggested to one of ordinary skill in the art that this process should be carried out and would have a reasonable likelihood of success, viewed in the light of the prior art." In re Dow Chem. Co., 837 F.2d 469, 473 (Fed. Cir. 1988).

Defendants first assert that claim 1 of the '233 Patent would have been obvious in light of the '196 Patent alone. (Doc. Nos. 109 at 20-27; 147 at 6-7.) "In appropriate circumstances, a single prior art reference can render a claim obvious." Sibia Neurosciences, Inc. v. Cadus Pharm. Corp., 225 F.3d 1349, 1356 (Fed. Cir. 2000). Two requirements must be satisfied for a claim to be obvious in light of prior art. Brown Williamson Tobacco Corp. v. Phillip Morris, Inc., 229 F.3d 1120, 1124-25 (Fed. Cir. 2000). First, there must be a reason, suggestion, or motivation to modify the teachings of the prior art reference to the claimed invention. Sibia Neurosciences, Inc., 225 F.3d at 1356; see also B.F. Goodrich Co. v. Aircraft Braking Sys. Corp., 72 F.3d 1577, 1582 (Fed. Cir. 1996) ("When obviousness is based on a particular prior art reference, there must be a showing of a suggestion or motivation to modify the teachings of that reference."). This reason, suggestion, or motivation may be found, either "explicitly or implicitly": (1) "in the prior art references themselves"; (2) "in the knowledge of those of ordinary skill in the art that certain references, or disclosures in those references, are of special interest or importance in the field"; or (3) "from the nature of the problem to be solved, `leading inventors to look to references relating to possible solutions to that problem.'" Ruiz, 234 F.3d. at 665 (quoting Pro-Mold Tool Co. v. Great Lakes Plastics, Inc., 75 F.3d 1568, 1572 (Fed. Cir. 1996)). The purpose of this requirement is to prevent a hindsight-based inquiry into obviousness, which the Federal Circuit has repeatedly instructed is inappropriate. See, e.g., id. at 664-65; In re Dembiczak, 175 F.3d 994, 999 (Fed. Cir. 1999) ("Our case law makes clear that the best defense against the subtle but powerful attraction of a hindsight-based obviousness analysis is rigorous application of the requirement for a showing of the teaching or motivation to combine prior art references."). Whether there was a reason, suggestion, or motivation to modify the teachings of prior art is a question of fact. McGinley v. Franklin Sports, Inc., 262 F.3d 1339, 1351 (Fed. Cir. 2001).

Second, the prior art must suggest to a person of ordinary skill in the art that the allegedly obvious process, if undertaken, would have a reasonable likelihood of success. Brown Williamson Tobacco Corp., 229 F.3d at 1125; In re Dow Chem. Co., 837 F.2d at 473. This does not require "absolute predictability of success," but rather a reasonable expectation that the process would be successful. In re O'Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988). An assertion that, in light of the prior art, it would have been "obvious to try" the allegedly obvious process is insufficient to meet this requirement. Ecolochem, Inc. v. S. Cal. Edison Co., 227 F.3d 1361, 1374 (Fed. Cir. 2000).

1. Reason, Suggestion, or Motivation to Modify or Combine Prior Art

Defendants claim that the '196 Patent "discloses the precise process that is claimed in claim 1 of the '233 [P]atent, except for the use of a `solvent [that] is not wholly an ether solvent.'" (Doc. No. 109 at 20 (quoting '233 Patent col. 1 l. 56 to col. 2 l. 28, col. 6 ll. 12-13).) They assert that the substitution of a not wholly ether solvent is a "minor [difference]" to the '196 Patent "achievable by simple modification," ( id. (quoting Miles Lab., Inc. v. Shandon, Inc., 997 F.2d 870, 878 (Fed. Cir. 1993))), and that the substitution of solvents would have been obvious to a person of ordinary skill in the art because of the safety problems associated with using pure diethyl ether on a commercial scale. ( Id. at 21.) Plaintiffs respond that the use of a not wholly ether solvent was not obvious to a person of ordinary skill in the art because, based on the teachings of the '196 Patent alone, he or she would not have a reasonable expectation that a change in solvents would be successful. (Doc. No. 120 at 8 n. 4.) They point to the declaration of Neal Ward, the inventor of the processes claimed in the '233 Patent, and assert that he attempted to use other solvents that were less flammable than diethyl ether, but these experiments were initially unsuccessful. ( Id.)

As an initial matter, we must compare the two patents to determine their differences. The '196 Patent teaches that a 3-substituted 1-alkyl-4-phenylpiperidine molecule can be produced by a process described in the Plati article.²⁵ '196 Patent, col. 1 ll. 16-32, col. 2 ll. 4-14. The Plati article discloses that such a molecule can be created by a process combining a Grignard reagent (phenylmagnesium bromide) with arecoline in an ether solvent. Plati, 22 J. Organic Chemistry at 261-62. This process is illustrated in Figure 4.²⁶

25 The '196 Patent specifically discloses the Plati article. '196 Patent col. 2 ll. 4-10.

26 R and R' represent a hydrogen atom or an alkyl group of 1-4 carbons. '196 Patent col. 1 ll. 29-32.

Figure 4: Teaching of '196 Patent and Plati Article

In comparison, the process of claim 1 of the '233 Patent, when conducted with a Grignard reagent of phenylmagnesium bromide (as in claim 2), is illustrated in Figure 5.²⁷

27 R and R' represent "an alkyl, aryl, or arylalkyl group." '233 Patent col. 5 ll. 64-65.

Figure 5: Claimed Process of the '233 Patent

Thus, the only difference between the teachings of the '196 Patent and process claimed by the '233 Patent is the solvent used to conduct the Grignard reaction.

We agree with Defendants that the potential safety hazards of using diethyl ether as a solvent is a "reason" or "motivation" for a person of ordinary skill in the art to use a not wholly ether solvent in conducting the process claimed by the '233 Patent. It has long been recognized that use of ether as a solvent "is a dangerous, expensive, and commercially impractical method" of producing chemical compounds, U.S. Indus. Chem. Co. v. Theroz Co., 25 F.2d 387, 389 (4th Cir. 1928), and a person with a bachelor's degree in chemistry and several years' laboratory experience would be aware of the fact that diethyl ether is a highly flammable, even explosive, compound in the laboratory. For example, in a textbook on basic laboratory safety published by the National Research Council, diethyl ether is classified as one of the "dirty dozen" most hazardous chemicals in conducting moderate- to large-scale synthetic chemistry because of its fire and explosive hazards. Comm. on Prudent Practices for Handling, Storage, and Disposal of Chemicals in Laboratories, Nat'l Research Council, Prudent Practices in the Laboratory: Handling and Disposal of Chemicals 57, 58 tbl.3.14 (1995), available at http://books.nap.edu/catalog/4911.html. It explains that:

Diethyl ether is extremely flammable (NFPA rating = 4)²⁸ and is one of the most dangerous fire hazards commonly encountered in the laboratory, owing to its volatility and extremely low ignition temperature. Ether vapor may be ignited on hot surfaces such as hot plates and static electricity discharges, and since the vapor is heavier than air, it may travel a considerable distance to an ignition source and flash back. Ether vapor forms explosive mixtures with air at concentrations of 1.9% to 36% (by volume). . . . Diethyl ether forms unstable peroxides on exposure to air in a reaction that is promoted by light; the presence of these peroxides may lead to explosive residues upon distillation.

Id. at 296-97 (footnote added); see also Grignard Reaction, 12 Encyclopedia of Chemical Technology at 32 ("Ethyl ether is the most common solvent used for the preparation of Grignard reagents. The principal disadvantage in its use lie[s] in its extremely flammable nature. . . ."). As a result of these dangerous characteristics, special precautions must be taken for use and storage of diethyl ether in a laboratory. Nat'l Research Council at 298. A person with knowledge of organic chemistry, Grignard reactions, and some laboratory experience would also know that Grignard reactions could be conducted in organic solvents other than diethyl ether. See, e.g., Grignard Reaction, 12 Encyclopedia of Chemical Technology at 32 ("Other ethers have been used in Grignard reactions. Tetrahydrofuran,²⁹ THF, has wide usage. . . . Other ethers have found limited use; amyl and butyl ethers have been employed and the use of glycol and polyglycol ethers has been described. . . ."). Based on the hazard of using diethyl ether as a solvent and the availability of other organic solvents to conduct Grignard reactions, we find that a person of ordinary skill in the art would have a reason or motivation to substitute the diethyl ether solvent taught in the '196 Patent and used in the Plati article with a solvent not composed wholly of diethyl ether.

28 The NFPA rating system classifies hazardous chemicals into three categories of potential danger — flammability, reactivity, and health — and classifies a chemical with a zero to four rating in each category, with zero as least hazardous and four as most hazardous. NFPA Hazard Rating System, http://www.sefsc.noaa.gov/HTMLdocs/nfpahazard.htm (last visited March 30, 2005).

29 Tetrahydrofuran is a molecule consisting of four carbon atoms, eight hydrogen atoms, and an oxygen atom arranged in a cyclical structure. Grant Hackh's Chemical Dictionary at 102, 582.

2. Reasonable Likelihood of Success

The prior art also must suggest to a person of ordinary skill in the art that the allegedly obvious process, if undertaken, would have a reasonable likelihood of success. Brown Williamson Tobacco Corp., 229 F.3d at 1125. This does not require "absolute predictability of success," but rather a reasonable expectation that the process would be successful. In re O'Farrell, 853 F.2d at 903. An assertion that, in light of the prior art, it would have been "obvious-to-try" the allegedly obvious process is insufficient to meet this requirement. Ecolochem, Inc., 227 F.3d at 1374. "An `obvious-to-try' situation exists when a general disclosure may pique the scientist's curiosity, such that further investigation might be done as a result of the disclosure, but the disclosure itself does not contain a sufficient teaching of how to obtain the desired result, or that the claimed result would be obtained if certain directions were pursued." In re Eli Lilly Co., 902 F.2d 943, 945 (Fed. Cir. 1990); see also In re O'Farrell, 853 F.2d at 903 (defining an obvious-to-try situation as one where prior art gives "only general guidance as to the particular form of the claimed invention or how to achieve it"). The party challenging a patent's validity must establish that combining references of prior art "would suggest to one of ordinary skill in the art how to perform the missing process step with a reasonable likelihood of success." Rockwell Int'l Corp. v. United States, 147 F.3d 1358, 1365 (Fed. Cir. 1998).

Defendants assert that a person of ordinary skill in the art would anticipate that, through a combination of the teachings of the '196 Patent and the Xu article,³⁰ it would be reasonably likely that the process taught by the '196 Patent could be successfully performed in a solvent that is not wholly ether. (Doc. No. 109 at 21-22.) As previously discussed, the only difference between the teachings of the '196 Patent and process claimed by the '233 Patent is the solvent used to conduct the Grignard reaction. Defendants point to the Xu article, which describes a Grignard reaction that occurs in a solvent of diethyl ether and dichloromethane (i.e., a solvent that is not wholly ether) and produces a 2$-carbomethoxy-3$-phenyltropane derivative that has some structural similarities to the 1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine product produced by the process claimed in the '233 Patent. (Doc. No. 109 at 14-15, 22-24; Hollingsworth Decl. ¶¶ 16-18.) Based on the Xu article, Defendants assert that a person of ordinary skill would recognize that the process taught by the '196 Patent could be successfully conducted in a solvent that is not wholly ether. This is the process claimed by claim 1 of the '233 Patent.

30 A "hypothetical person of ordinary skill in the art . . . is charged with knowledge of all the contents of the relevant prior art." In re Carlson, 983 F.2d 1032, 1037 (Fed. Cir. 1992) (emphasis added) (citing Kimberly-Clark Corp. v. Johnson Johnson, 745 F.2d 1437, 1454 (Fed. Cir. 1984)).

Viewing the disputed facts in a light most favorable to Plaintiffs, the non-moving party, we conclude that there is a genuine issue of material fact as to whether a person of ordinary skill in the art would have an expectation of a reasonable likelihood of success in performing the process taught by the '196 Patent using a solvent that is not wholly ether. The Xu article describes the reaction of an ecgonine methyl ester and a Grignard reagent to create a cocaine derivative. The Xu article also teaches that this reaction may be performed in a dichloromethane solvent. This process is graphically represented in Figure 6.

Figure 6: Xu Article

At first glance, the process described in the Xu article appears to be similar to the process claimed by the '233 Patent. According to Defendants' expert, Dr. Mark Hollingsworth, a professor of organic and physical chemistry, the only difference between the '233 Patent and the Xu article is that the substrate in Xu contains an ethylene-bridged piperidine ring not contained by the arecoline molecule in the '196 Patent and the '233 Patent. (Hollingsworth Decl. ¶¶ 16-18.) The Xu article also differs from the '196 Patent because it employs a solvent that is not wholly ether. ( Id. ¶ 17.) Therefore, it is Dr. Hollingsworth's opinion that, based on (1) the process taught by the '196 Patent and (2) the similarity of the process described in the Xu article, which used a solvent that was not wholly diethyl ether, a person of ordinary skill in the art would reasonably expect that "the reaction disclosed in the '196 Patent would provide the desired addition product when performed in a solvent that is not wholly an ether solvent, as claimed in the '233 [P]atent." ( Id. ¶ 27.)

We find, however, that the Xu article contains other teachings which would lead a chemist of ordinary skill in the art to conclude that he might not reasonably expect that the reaction disclosed in the '196 Patent would function in the same way if a non-wholly ether solvent was used. The Xu article teaches that a change in either the solvent or the compound used in a Grignard reaction can result in significant differences in the reaction, resulting in the synthesis of an entirely different molecule. It states that:

The effect of solvent polarity and concentration (ether, THF, benzene) on the reactions of Grignard reagents with a variety of substrates has been the subject of numerous investigations. It has been shown that variations of the reagent concentrate or substitution of one solvent (ether) for another (THF) can dramatically alter the course of the reaction and lead to the formation of different products.

Xu Trudell, 33 J. Heterocyclic Chemistry at 2037 (emphasis added). Thus, based on Xu, a person of ordinary skill in the art might reasonably conclude that the use of a different solvent in conducting the process taught by the '196 Patent would not have a reasonable likelihood of producing the same product as the '233 Patent.

The Xu article also teaches that when an organic compound with a carbonyl group (a carbon atom double-bonded to an oxygen atom) is combined with a Grignard reagent in a mixture of diethyl ether and dichloromethane, a 1,2 addition reaction may occur. Id. This 1,2 addition reaction is significantly different from the 1,4 conjugate addition reaction that occurs in the '196 Patent and '233 Patent. (Adger Decl. ¶ 11.) In fact, when Neal Ward, the inventor of the '233 Patent, began experimenting with the Plati process, he found that the use of other ether solvents, such as tetrahydrofuran and diisopropyl ether, resulted in "little if any of the desired 1,4 [conjugate] addition product." '233 Patent at col. 2, ll. 15-16. This unfavorable result may be explained by the 1,2 addition reaction explained in the Xu article. (Adger Decl. ¶ 11.) Based on Xu's teachings, the change of compounds from the ecgonine methyl ester used in the Xu article to the arecoline used in the '196 Patent might also lead a person of ordinary skill in the art to conclude that this change in substrates might not be reasonably likely to result in the 1,4 conjugate addition reaction claimed by the '233 Patent. We therefore find that there is a genuine issue of material fact for trial as to whether a person of ordinary skill in the art would anticipate that altering the process taught in the '196 Patent by using a non-wholly ether solvent would be reasonably likely to synthesize the same product (1-methyl-3-carbomethoxy-4-(4-fluorophenyl)piperidine) created by the processes described in the '196 Patent and '233 Patent.

E. Secondary Considerations

Finally, we must determine whether there are any secondary considerations, also know as objective evidence, that weigh in favor of or against a finding of obviousness. Graham, 383 U.S. at 17; Ecolochem, Inc., 227 F.3d at 1376-79. The Federal Circuit has stated that:

Objective evidence of nonobviousness "must always when present be considered en route to a determination of obviousness" because

evidence of secondary considerations may often be the most probative and cogent evidence in the record. It may often establish that an invention appearing to have been obvious in light of the prior art was not. It is to be considered as part of all the evidence, not just when the decisionmaker remains in doubt after reviewing the art.

Uniroyal, Inc., 837 F.2d at 1053 (quoting Stratoflex, Inc., 713 F.2d at 1538-39). "Evidence of secondary considerations . . . [is] . . . part of the `totality of the evidence' that is used to reach the ultimate conclusion of obviousness." Richardson-Vicks, Inc. v. Upjohn Co., 122 F.3d 1476, 1483 (Fed. Cir. 1997) (quoting Kansas Jack, Inc. v. Kuhn, 719 F.2d 1144, 1151 (Fed. Cir. 1983)). While secondary considerations "`do not control the obviousness conclusion,'" id. (quoting Newell Cos. v. Kennedy Mfg. Co., 864 F.2d 757, 768 (Fed. Cir. 1988)), "[i]n some cases such evidence is the most probative of obviousness." Id.; see also Ruiz, 234 F.3d at 667 ("Evidence of secondary considerations may often be the most probative and cogent evidence in the record. It may establish that an invention appearing to have been obvious in light of prior art was not.").

The secondary considerations that we must consider include commercial success, long felt but unsolved needs, failure of others, near-simultaneous inventions, and unexpected results. Graham, 383 U.S. at 17; see also CFMT, Inc. v. Yieldup Int'l Corp., 349 F.3d 1333, 1342 (Fed. Cir. 2003); Ruiz, 234 F.3d at 662-63.

1. Commercial Success

First, we must assess whether the '233 Patent is a "commercial success." Graham, 383 U.S. at 17. There is a presumption that the patented invention is commercially successful "`when a patentee can demonstrate commercial success, usually shown by significant sales in a relevant market, and that the successful product is the invention disclosed and claimed in the patent.'" Ecolochem, Inc., 227 F.3d at 1337 (quoting J.T. Eaton Co. v. Atlantic Paste Glue Co., 106 F.3d 1563, 1571 (Fed. Cir. 1997)). In order to find that a patent is commercially successful, however, "the asserted commercial success of the product must be due to the merits of the claimed invention beyond what was readily available in the prior art." J.T. Eaton Co., 106 F.3d at 1571.

The parties dispute whether the '233 Patent is a commercial success. (Doc. Nos. 109 at 36-37; 120 at 10-11.) We find that there is no genuine issue of material fact regarding this issue. In order to establish commercial success, there must be some "nexus" between the "merits of the claimed invention" and the "commercial success of [the] product." Cable Elec. Prods., Inc. v. Genmark, Inc., 770 F.2d 1015, 1027 (Fed. Cir. 1985); see also J.T. Eaton Co., 106 F.3d at 1571 ("[A patentee] cannot demonstrate commercial success, for purposes of countering the challenge of obviousness, unless it can show that the commercial success of the product results from the claimed invention. . . . [T]he asserted commercial success of the product must be due to the merits of the claimed invention beyond what was readily available in the prior art." (footnote omitted) (emphasis added)). While Paxil® is one of the most commercially successful drugs currently on the market, it was widely produced, marketed, and sold beginning almost a decade prior to the '233 Patent's approval. (Doc. No. 109 Ex. H at SB16001-000172 to SB16001-000173, SB16001-000176.) More importantly, Defendants have submitted unrebutted evidence that Plaintiffs do not use the processes set forth in the '233 Patent to produce paroxetine hydrochloride.³¹ ( Id. Ex. R at SB02001-192070 A 74, SB02001-192070 A 122.) Thus, because there is no "nexus" between the '233 Patent and the commercial success of Paxil®, we do not find that the '233 Patent is a commercial success.

31 The fact that Apotex and/or its subsidiaries may have produced paroxetine hydrochloride in its overseas plants using the method claimed in the '233 Patent, as Plaintiffs allege (Doc. No. 120 at 10-11), is irrelevant, because Apotex has not sold or offered to sell any paroxetine hydrochloride produced by this process in the United States.

2. Long-Felt Need

Another secondary factor is whether the claimed invention solved a "long felt but unsolved need" in the field. Graham, 383 U.S. at 18. "[T]he nature of the problem `which persisted in the art,' and the inventor's solution, are factors to be considered in determining whether the invention would have been obvious to a person of ordinary skill in that art." N. Telecom, Inc. v. Datapoint Corp., 908 F.2d 931, 935 (Fed. Cir. 1990) (quoting In re Rothermel, 276 F.2d 393, 397 (C.C.P.A. 1960)). Recognition of a long-felt need, and difficulties encountered by those skilled in the art in attempting to solve that need, "are classical indicia of unobviousness." In re Dow Chem. Co., 837 F.2d at 472.

Here, the parties disagree as to whether there was a long-felt need for the process claimed in the '233 Patent. Plaintiffs assert that there was a "long-felt need for the invention claimed in the '233 patent" based on the problems of gel formation in the production of paroxetine hydrochloride precursors. (Doc. No. 120 at 11.) Defendants disagree, noting that SmithKline does not even use the process claimed in the '233 Patent to produce paroxetine hydrochloride. (Doc. Nos. 109 at 37; 147 at 10.)

Viewing the evidence in a light most favorable to Plaintiffs, we find that the '233 Patent does not serve to fulfill a long-felt need. According to documents produced from SmithKline's files, Plaintiffs produce paroxetine hydrochloride through processes other than those claimed in the '233 Patent. Plaintiffs refer to an April 1993 document entitled "Paroxetine Strategy Plan," which lists two SmithKline scientists as authors. (Doc. No. 109 Ex. R.) This document "sets out the strategy for development of the manufacturing process for paroxetine[,] including changes to the manufacturing process between [1993] and 1997." ( Id. at SB02001-192070 A 70.) This document explains that SmithKline considered the processes covered by U.S. Patent No. 4,902,801, U.S. Patent No. 4,861,893, and U.S. Patent No. 5,039,803 to be "commercially viable, safe production methods" for the industrial synthesis of paroxetine hydrochloride, and that, of these methods, the process claimed by the '803 Patent was "by far the preferred process." ( Id. at SB02001-192070 A 119 to A 120, SB02001-192070 A 122.) Plaintiffs have not submitted any evidence showing that since the release of this document, they have begun employing the claimed process of the '233 Patent to manufacture paroxetine hydrochloride on an industrial scale. Thus, we find that the '233 Patent does not fulfil any long-felt need.

3. Prior Failure/Near Simultaneous Invention

A third secondary factor we must consider is whether other inventors failed to solve the problems addressed by the '233 Patent or, conversely, whether inventors operating independently developed the same process around the same time (i.e., near simultaneous invention). Graham, 383 U.S. at 18; Ecolochem, Inc., 227 F.3d at 1379. Failure of others to provide a feasible solution to a long-standing problem is probative of nonobviousness. Intel Corp. v. U.S. Int'l Trade Comm'n, 946 F.2d 821, 835 (Fed. Cir. 1991). In contrast, "`near simultaneous invention by two or more equally talented inventors working independently . . . may . . . be an indication of obviousness.'" Ecolochem, Inc., 227 F.3d at 1379 (quoting Lindemann Maschinenfabrik GMBH v. Am. Hoist Derrick Co., 730 F.2d 1452, 1460 (Fed. Cir. 1984)).

Plaintiffs do not claim that other inventors attempted, but failed, to solve the problems addressed by the '233 Patent — namely, the use of flammable diethyl ether as a solvent, and the resulting production of a product that could be easily extracted for the industrial scale development of paroxetine hydrochloride. Thus, we cannot find that there were prior failures to solve the problems addressed by the '233 Patent. As evidence of near simultaneous invention, Defendants point to a patent issued to Brantford Chemicals, Inc. ("BCI"), which claims a separate process that employs a Grignard reaction in either diethyl ether or non-ether solvents for the production of paroxetine hydrochloride precursors. U.S. Patent No. 5,962,689 (issued Oct. 5, 1999) (the '689 Patent). The application for this patent was filed in August, 1997, more than five months before SmithKline filed its application for the '233 Patent. Id. Therefore, we find that the near-simultaneous claim of an analogous process to the '233 Patent that can be conducted in a solvent that is not wholly ether is another secondary consideration in favor of a finding of obviousness.

4. Unexpected Results

Finally, we must consider whether the process claimed by the '233 Patent had unexpected results. Unexpected results exist when the "`claimed invention exhibits some superior property or advantage that a person of ordinary skill in the relevant art would have found surprising or unexpected.'" In re Glaug, 283 F.3d 1335, 1341 (Fed. Cir. 2002) (quoting In re Soni, 54 F.3d 746, 750 (Fed. Cir. 1995)). "[W]hen an applicant demonstrates substantially improved results, as [plaintiff] did here, and states that the results were unexpected, this should suffice to establish unexpected results in the absence of evidence to the contrary." In re Soni, 54 F.3d at 751 (emphases omitted). The Federal Circuit has noted that the principle of unexpected results "applies most often to the less predictable fields, such as chemistry, where minor changes in a product or process may yield substantially different results." In re Mayne, 104 F.3d 1339, 1343 (Fed. Cir. 1997) (emphasis added). A finding of unexpected results may provide strong support for a conclusion of nonobviousness. Lindemann Maschinenfabrik GMBH, 730 F.2d at 1461 (citing Kansas Jack, Inc., 719 F.2d at 1150).

Viewing the evidence in a light most favorable to Plaintiffs, we find that the process claimed by the '233 Patent had unexpected results. Neal Ward, the inventor of the '233 Patent, stated in an affidavit to the PTO that he conducted experiments relating to the production of paroxetine using the process taught by the Plati article. (Ward Decl. ¶ 4.) He closely replicated the process described in the Plati article, except for a substitution in the Grignard reaganet (4fluorophenylmagnesium bromide for the phenylmagnesium bromide described in Plati). ( Id.) The result was a sticky gum or thick gel that Ward deemed poorly suited for the large-scale production of paroxetine hydrochloride. ( Id.)

After attempting numerous alternations to the Plati process, Ward discovered that the replacement of some or all of the diethyl ether solvent described in Plati with a solvent that was not wholly ether resulted in the creation of a paroxetine precursor (1-methyl-3-carbomethoxy-4-(4-fluorophenyl)-piperidine) in a clear solution or readily stirrable suspension. ( Id. ¶ 5.) Ward considered this a "significant and unexpected improvement" over the Plati process because it resulted in a product that could be used to manufacture paroxetine hydrochloride in large-scale production. ( Id.)

During the prosecution of the '233 Patent application, the Patent Examiner initially rejected the claims as obvious in light of the prior art. (Doc. No. 109 Ex. I at 061-0063.) Ward then submitted an affidavit, explaining his discovery that while the Plati process resulted in a product of sticky gum or thick gel, a change to a not wholly ether solvent resulted in the production of a clear solution or readily stirrable suspension useful for industrial production. (Ward Decl. ¶¶ 4-5.) Ward stated that this result was unexpected in light of the prior art. ( Id. ¶ 5.) The Examiner agreed that the claimed result was unexpected, and found this persuasive evidence of nonobviousness. See Doc. No. 109 Ex. I at 0100 ("The prior art neither teaches nor suggests the claimed process. Further, the declaration of Neal Ward demonstrates that prior art processes do not work in the manner prescribed nor do they give the claimed results.").

Under 35 U.S.C. § 282, a patent is presumed valid, and "that presumption can be overcome only by clear and convincing evidence of facts to the contrary." Poly-America, L.P. v. GSE Lining Tech., Inc., 383 F.3d 1303, 1308 (Fed. Cir. 2004). When the party challenging a patent's validity relies on "no prior art[,] other than that which was considered by the PTO examiner is relied on by the attacker, he has the added burden of overcoming the deference that is due to a qualified government agency presumed to have properly done its job." Am. Hoist Derrick Co. v. Sowa Sons, Inc., 725 F.2d 1350, 1359 (Fed. Cir. 1984); see also Bristol-Myers Squibb Co. v. Pharmachemie B.V., 361 F.3d 1343, 1353 (Fed. Cir. 2004). This deference extends to the determinations of patent examiners because of their "`expertise in interpreting [prior art] references'" and their "`familiar[ity] . . . with the level of skill in the art.'" Bristol-Myers Squibb Co., 361 F.3d at 1353 (quoting Am. Hoist Derrick Co., 725 F.2d at 1359). Here, Defendants do not present any new evidence regarding the unexpected results of the '233 Patent — that the process resulted in a clear solution or a readily stirrable suspension of a paroxetine precursor that was well-suited for large-scale production of paroxetine hydrochloride. (Doc. No. 147 at 8-10.) Instead, they argue that the allegedly unexpected result was a natural consequence of the prior art. See id. at 8 ("[T]he fact that the '233 [P]atent purports to recognize a second reason to use a mixed solvent in the Grignard reaction, i.e., a reduction in gelling/sediment, does not change the obviousness analysis, because that reduction . . . would flow naturally and inherently from following the prior art's suggestion to use a mixed solvent system in the Grignard reaction."). However, Defendants point to no prior art or other evidence not considered by the Patent Examiner that would indicate to a person of ordinary skill in the art that a change in solvent from diethyl ether to one that is not wholly ether would likely result in a reduction in the gelling and sedimentation of the final product of the Grignard reaction. Thus, in light of the deference we must grant to the unchallenged findings of the Patent Examiner, we find that the '233 Patent had an unexpected result because it produced a product that was well-suited for the industrial-scale preparation of paroxetine hydrochloride.

F. Legal Conclusion on Obviousness

The ultimate conclusion as to patent validity is an issue of law. Graham, 383 U.S. at 17. As previously mentioned, to determine that a patent is invalid, we must find that the prior art must suggest to a person of ordinary skill in the art that the allegedly obvious process, if undertaken, would have a reasonable likelihood of success. Brown Williamson Tobacco Corp., 229 F.3d at 1125. Here, we determined that there was a genuine issue of material fact as to whether the prior art — specifically, the Xu article — suggested that the process of the '233 Patent was reasonably likely to succeed. Supra pp. 29-32. Because there is a genuine issue of material fact regarding a prerequisite for a finding of obviousness, see Cooper v. Ford Motor Co., 713 F.2d 677, 680-81 (Fed. Cir. 1984), we will deny Defendants' motion for partial summary judgment.

Evidence of secondary considerations, taken as a whole, also supports our decision that summary judgment is inappropriate. A patentee may use objective evidence of nonobviousness "to rebut a prima facie case of obviousness based on prior art." WMS Gaming, Inc., 184 F.3d at 1359. Here, we found that the '233 Patent had an unexpected result because it produced a solution or suspension that was well-suited for large-scale production of paroxetine hydrochloride. A finding of unexpected results may provide "strong support for a conclusion of nonobviousness." Lindemann Maschinenfabrik GMBH, 730 F.2d at 1461.

V. INFRINGEMENT

Defendants assert that summary judgment of noninfringement should be granted because the process they use to manufacture paroxetine hydrochloride does not infringe, either literally or under the doctrine of equivalents, the '233 Patent. (Doc. No. 105 at 15-27.)

A. Two-Step Infringement Analysis

Determination of patent infringement requires a two-step analysis. Innova/Pure Water, Inc. v. Safari Water Filtration Sys., 381 F.3d 1111, 1115 (Fed. Cir. 2004) (citing Markman v. Westview Instruments, Inc., 52 F.3d 967, 976 (Fed. Cir. 1995) (en banc), aff'd, 517 U.S. 370 (1996)). First, we must ascertain the meaning and scope of the terms of the claim. Markman, 52 F.3d at 976. This issue, called claim construction, is a pure question of law. Id. at 979; see also Cybor Corp. v. FAS Techs., Inc., 138 F.3d 1448, 1456 (Fed. Cir. 1998) (en banc) (reaffirming that claim construction is a "purely legal question"). Second, the properly construed claims are compared to the allegedly infringing product or process. Innova/Pure Water, Inc., 381 F.3d at 1115; Durel Corp. v. Osram Sylvania, Inc., 256 F.3d 1298, 1303 (Fed. Cir. 2001). A finding of infringement requires a determination that every claim limitation, or its equivalent, is found in the accused device or process. Warner-Jenkinson Co. v. Hilton Davis Chem. Co., 520 U.S. 17, 29 (1997); see also Mas-Hamilton Group v. LaGard, Inc., 156 F.3d 1206, 1211 (Fed. Cir. 1998) ("To prove literal infringement, the patentee must show that the accused device contains every limitation in the asserted claims. If even one limitation is missing or not met as claimed, there is no literal infringement." (citations omitted)). This issue is a question of fact. Bai v. L L Wings, Inc., 160 F.3d 1350, 1353 (Fed. Cir. 1998).

B. Claim Construction

1. Disputed Claim Language

We must first determine the meaning of the claims of the '233 Patent. Markman, 52 F.3d at 976. Here, Defendants assert that they have not literally infringed claim 1 of the '233 Patent because their process for manufacturing a precursor to paroxetine hydrochloride does not contain "an alkyl, aryl, or arylalkyl group" in positions R and R' in structures (2) and (4) of claim 1.³² (Doc. No. 105 at 16, 19-26.) Instead, Defendants state they use a "much larger and more complicated molecular piece in the R' position," a cycloalkyl group consisting of 10 carbon atoms and 19 hydrogen atoms arranged in a cyclic structure, with a chemical name of (-)2-isopropyl, 5-methylcyclohexyl. ( Id. at 14; Cunningham Decl. ¶ 11; Murthy Decl. ¶ 8.) This radical has the following chemical structure:

32 Plaintiffs also assert that because dependent claims 2-10 and 14-16 contain claim 1's limitation of "an alkyl, aryl, or arylalkyl group" in positions R and R', Plaintiffs' manufacturing process does not infringe these claims.

Figure 7: (-)2-isopropyl, 5-methylcyclohexyl

Defendants argue that this structure, which they call a chiral menthyl group, is not an "alkyl, aryl, or arylalkyl group" as claimed by the '233 Patent.

Plaintiffs respond that Defendants' process for manufacturing paroxetine hydrochloride does include an alkyl group in position R' (the (-)2-isopropyl, 5-methylcyclohexyl radical illustrated Figure 7), and therefore literally infringes the '233 Patent.³³ (Doc. No. 119 at 3-8.) Thus, the meaning of the word "alkyl" is key to determining whether Defendants' production of paroxetine hydrochloride literally infringes the '233 Patent.

33 Plaintiffs do not argue that the chemical structure in Figure 7 is either an "aryl" or "arylalkyl" group as claimed by the '233 Patent (Doc. No. 119 at 6-8), and both chemists who filed declarations in support of Plaintiffs' memorandum of law, Dr. Brian Adger and Dr. G. Patrick Stahly, concede this point. See Adger Decl. ¶ 11 ("Of the three possibilities given for R' in claim 1 of . . . the '233 [P]atent . . ., menthyl only fits the alkyl definition. . . ."); Stahly Decl. ¶ 11 ("[Defendants'] menthyl structure is cyclic and not aromatic. Accordingly, it cannot be described as either an aryl group or an arylalkyl group." (footnote omitted)).

2. Legal Standards

In claim construction, we must begin our analysis with the words of the claim. Vitronics Corp. v. Conceptronic, Inc., 90 F.3d 1576, 1582 (Fed. Cir. 1996); see also Interactive Gift Express, Inc. v. Compuserve, Inc., 256 F.3d 1323, 1331 (Fed. Cir. 2001) ("In construing claims, the analytical focus must begin and remain centered on the language of the claims themselves, for it is that language that the patentee chose to use to particularly point out and distinctly claim the subject matter which the patentee regards as his invention." (citations omitted)). A court construing a patent claim must accord a claim "the meaning it would have to a person of ordinary skill in the art at the time of the invention," Innova/Pure Water, Inc., 381 F.3d at 1116, "unless it is apparent from the patent and the prosecution history that the inventor used the term with a different meaning." Hoechst Celanese Corp. v. BP Chems. Ltd., 78 F.3d 1575, 1578 (Fed. Cir. 1996). The meaning of a claim's words to a person of ordinary skill in the art may be determined by reviewing a variety of sources, including "the words of the claims themselves, the remainder of the specification, the prosecution history, and extrinsic evidence concerning relevant scientific principles, the meaning of technical terms, and the state of the art." Id. (citing Markman, 52 F.3d at 979-80); see also Ferguson Beauregard v. Mega Sys., LLC, 350 F.3d 1327, 1338 (Fed. Cir. 2003) (stating that in claim construction, a court may consider "the claims themselves; dictionaries and treatises; and the written description, the drawings, and the prosecution history." (citations omitted)).

At the outset, we note an apparent conflict in Federal Circuit precedent regarding the appropriate procedure and weight in considering the sources relied upon in claim construction. In Vitronics Corp. v. Conceptronic, Inc., a panel of the Federal Circuit stated that a district court should first examine a patent's "intrinsic evidence," which includes the claims themselves, the patent specification, and the prosecution history, to determine the meaning of the words in a claim. 90 F.3d at 1582. Only if there is still "genuine ambiguity" after consideration of the intrinsic evidence may we consider "extrinsic evidence," such as expert testimony, and other sources, such as dictionaries and treatises, to determine the words' ordinary meaning.³⁴ Id. at 1583-84. Numerous subsequent Federal Circuit decisions have echoed this "intrinsic evidence first, extrinsic evidence second" approach. See, e.g., Vanderlande Indus. Nederland BV v. Int'l Trade Comm., 366 F.3d 1311, 1318 (Fed. Cir. 2004) ("While extrinsic evidence can shed useful light on the relevant art — and thus better allow a court to place itself in the shoes of a person of ordinary skill in the art — the `intrinsic evidence is the most significant source of the legally operative meaning of disputed claim language.' Indeed, a `court should look first to the intrinsic evidence of record'. . . ." (citations omitted)); Frank's Casing Crew Rental Tools, Inc. v. PMR Techs., Ltd., 292 F.3d 1363, 1374 (Fed. Cir. 2002) ("In construing patent claims, we first look to the intrinsic evidence of record — the claims, the specification, and, if in evidence, the prosecution history. If ambiguity remains after consideration of the intrinsic evidence, `extrinsic evidence may also be considered, if needed to assist in determining the meaning or scope of technical terms in the claims.'" (citations omitted)).

34 The Vitronics court stated in relevant part:

It is well-settled that, in interpreting an asserted claim, the court should look first to the intrinsic evidence of record, i.e., the patent itself, including the claims, the specification and, if in evidence, the prosecution history. Such intrinsic evidence is the most significant source of the legally operative meaning of disputed claim language.

. . . .

In most situations, an analysis of the intrinsic evidence alone will resolve any ambiguity in a disputed claim term. In such circumstances, it is improper to rely on extrinsic evidence. In those cases where the public record unambiguously describes the scope of the patented invention, reliance on any extrinsic evidence is improper. The claims, specification, and file history, rather than extrinsic evidence, constitute the public record of the patentee's claim, a record on which the public is entitled to rely. . . .

. . . .

. . . . Only if there were still some genuine ambiguity in the claims, after consideration of all available intrinsic evidence, should the trial court have resorted to extrinsic evidence, such as expert testimony, in order to construe [a] claim. . . .

Vitronics, 90 F.3d at 1582-84 (emphases added) (citations and parentheticals omitted).

Other recent Federal Circuit decisions, however, adopt a different approach toward claim construction. In Texas Digital Systems, Inc. v. Telegenix, Inc., 308 F.3d 1193 (Fed. Cir. 2002), a panel of the Federal Circuit emphasized the importance of first considering dictionaries, treatises, and other "objective resources" to determine the ordinary meaning attributed to the words of a claim by a person of ordinary skill in the art. Id. at 1202-03; see also id. (describing dictionaries, treatises, and encyclopedias as "the most meaningful sources of information" in claim construction). While recognizing that an examination of intrinsic evidence is still necessary to determine (1) whether the inventor used words in a manner inconsistent with their ordinary meaning and (2) if there are multiple dictionary definitions for a word, to determine which definitions are consistent with the inventor's use, the Texas Digital court clearly stated that it is inappropriate for a court to consider intrinsic evidence prior to determining the ordinary and customary meaning of the words in a claim. See id. at 1204 ("Consulting the written description and prosecution history as a threshold step in the claim construction process, before any effort is made to discern the ordinary and customary meanings attributed to the words themselves, invites a violation of our precedent counseling against importing limitations into the claims."). The Texas Digital approach therefore appears to contradict the Vitronics decision, which held that dictionaries and other "extrinsic" sources should be relied upon only after considering the intrinsic evidence.³⁵ See Jennifer R. Johnson, Out of Context: Texas Digital, The Indefiniteness of Language, and the Search for Ordinary Meaning, 35 IDEA 521, 521 (2004) ("[T]he [Federal Circuit's] [recent] focus on dictionaries as primary sources departs from earlier precedent, including Markman and Vitronics, which place primary emphasis on intrinsic evidence in the claim construction analysis."); Ruoyu Roy Wang, Note, Texas Digital Systems v. Telegenix, Inc. : Toward A More Formalistic Patent Claim Construction Model, 19 Berkeley Tech L.J. 153, 174 (2004) ("[T]he [ Texas Digital] court stressed that dictionaries ought to be consulted before the intrinsic record, not the other way around, as was often done before.").

35 Several recent Federal Circuit decisions have followed or approved the Texas Digital approach. See, e.g., Intellectual Prop. Dev., Inc. v. UA-Columbia Cablevision of Westchester, Inc., 336 F.3d 1308, 1315 (Fed. Cir. 2003).

In light of this apparent conflict, we follow the Federal Circuit's rule that "prior decisions of a panel of the court are binding precedent on subsequent panels unless and until overturned in banc. Where there is direct conflict, the precedential decision is the first." Newell Cos. v. Kenney Mfg. Co., 864 F.2d 757, 765 (Fed. Cir. 1988); see also SmithKline Beecham Corp. v. Geneva Pharms., 2002 U.S. Dist. LEXIS 25275, at *16 ("In the absence of an en banc decision, when there are directly conflicting panel decisions, `the precedential decision is the first.'" (quoting Newell Cos., 864 F.2d at 765)).³⁶ We therefore follow the approach of the Vitronics case, the prior panel decision, and first consider the intrinsic evidence of the '233 Patent to determine the inventor's meaning in using the word "alkyl." If we determine that the inventor's use of the disputed word is "genuinely ambiguous," then we may consider other evidence, including treatises, dictionaries, and extrinsic evidence, to determine the ordinary meaning of the word. See Unitherm Food Sys. v. Swift-Eckrich, Inc., 375 F.3d 1341, 1352 (Fed. Cir. 2004) (approving, after Texas Digital, a district court's use of the Vitronics approach to claim construction).

36 We note that the Federal Circuit has granted rehearing en banc in Phillips v. AWH Corp., 363 F.3d 1207 (Fed. Cir.), vacated and reh'g granted en banc, 376 F.3d 1382 (Fed. Cir. 2004) (per curiam), on numerous important issues in claim construction, including the appropriate procedure and weight for using intrinsic evidence, dictionaries, treatises, and extrinsic evidence to determine the meaning of the words in a claim. This case may resolve the current conflict in authority. C.R. Bard, Inc. v. U.S. Surgical Corp., 388 F.3d 858, 863 (Fed. Cir. 2004).

3. Claims and Patent Specification

We first look to "the words of the claims themselves, both asserted and nonasserted, to define the scope of the patented invention." Vitronics, 90 F.3d at 1582; see also Bell Communs. Resarch v. Vitalink Communications Corp., 55 F.3d 615, 619-20 (Fed. Cir. 1995) ("`[R]esort must be had in the first instance to the words of the claim. . . .'" (quoting Envirotech Corp. v. Al George, Inc., 730 F.2d 753, 759 (Fed. Cir. 1984))). Because "[i]t is the claims that measure the invention," SRI Int'l v. Matsushita Elec. Corp., 775 F.2d 1107, 1121 (Fed. Cir. 1985) (en banc), we must take care to ascertain the proper scope of the claims, lest we import into the claims limitations that were unintended by the patentee. See, e.g., Hoganas AB v. Dresser Indus., Inc., 9 F.3d 948, 950 (Fed. Cir. 1993) ("It is improper for a court to add extraneous limitations to a claim, that is limitations added wholly apart from any need to interpret what the patentee meant by particular words or phrases in the claim." (citation omitted)).

As mentioned above, words in a claim "take on the full breadth of the ordinary and customary meanings attributed to them by those of ordinary skill in the art," unless there is an express intent in the patent specification "to impart a novel meaning to the claim terms." Ferguson Beauregard, 350 F.3d at 1338 (citing Teleflex, Inc. v. Ficosa N. Am. Corp., 299 F.3d 1313, 1325 (Fed. Cir. 2002)); see also Vitronics Corp., 90 F.2d at 1582 ("[A] patentee may choose to be his own lexicographer and use terms in a manner other than their ordinary meaning, as long as the special definition of the term is clearly stated in the patent specification or file history."). "A technical term used in a patent document is interpreted as having the meaning that it would be given by persons experienced in the field of the invention, unless it is apparent from the patent and the prosecution history that the inventor used the term with a different meaning." Hoechst Celanese Corp., 78 F.3d at 1578. In considering the intrinsic evidence, we must consider that "there is a `heavy presumption' in favor of the ordinary meaning of claim language as understood by one of ordinary skill in the art." Bell Atlantic Network Servs., Inc. v. Covad Communications Group, Inc., 262 F.3d 1258, 1268 (Fed. Cir. 2001).

As used in the '233 Patent, the word "alkyl" is a technical term from the field of organic chemistry. "Organic chemistry is traditionally described as the chemistry of carbon-containing compounds." Maitlin Jones, Jr., Organic Chemistry at xxxv (2d ed. 2000). Organic compounds may range in size from a simple methane molecule, which contains one carbon atom bonded to four hydrogen atoms (CH4), to enormously complex collections of thousands of carbon, hydrogen, and other atoms arranged in an almost infinite combination of chains, rings, and branches. Id. at xxxvi, 45-46. Carbon atoms may also form single, double, or triple bonds between carbon atoms, further expanding the discrete number of different organic compounds. Id. at 1-123. The near-limitless number of organic molecules presents an obvious problem for their naming and classification. A systematic naming protocol for organic compounds was first developed in 1892 by the Commission for the Reform of Nomenclature in Organic Chemistry of the International Union of Chemistry ("IUC"), and has been amended and updated several times by the IUC's successor, the International Union of Pure and Applied Chemistry ("IUPAC"). Int'l Union of Pure Applied Chemistry, Nomenclature of Organic Chemistry at xvii (J. Rigaudy S.P. Klesney eds., 1979 ed.) (hereafter "Nomenclature of Organic Chemistry (1979 ed.)"). Thus, we must look at the claim and the patent specification to determine whether the inventor expressly intended to impart the word "alkyl" with a novel meaning.

Defendants assert that an alkyl group is a hydrocarbon (a molecule consisting only of carbon and hydrogen atoms) of the formula C _n H_{2 n +1}, where n refers to the number of atoms. (Doc. No. 105 at 18; Cunningham Decl. ¶ 10.) Under this definition, the simplest alkyl group is methyl, which consists of a carbon atom and three hydrogen atoms (— CH₃). (Doc. No. 105 at 18-19 n. 8.) Defendants argue that the chemical compound used in the R' position of structure (2) and (4), a cyclical hydrocarbon known as (-)2-isopropyl, 5-methylcyclohexyl, is not an alkyl group because it has 10 carbon and 19 hydrogen atoms and therefore does not fall within the formula C _n H_{2 n +1}.

Plaintiffs disagree, asserting that Defendants' chemical compound is an alkyl group. They point to the expert declarations of Dr. Adger and Dr. Stahly, who define an alkyl group as any hydrocarbon containing only carbon-carbon and carbon-hydrogen single bonds, regardless of whether it has the formula C _n H_{2 n +1} or contains a cyclical structure. (Adger Decl. ¶ 11; Stahly Decl. ¶¶ 7, 13.) Thus, in agreement with Defendants' definition, the simplest alkyl group would be methyl (— CH₃), which contains only carbon-carbon and carbon-hydrogen single bonds. Under Plaintiffs' definition, however, Defendants' (-)2-isopropyl, 5-methylcyclohexyl radical would qualify as an alkyl group, because it contains only carbon-carbon and carbon-hydrogen single bonds. (Doc. No. 119 at 4-7.) Plaintiffs also assert that (-)2-isopropyl, 5-methylcyclohexyl's cyclical structure is irrelevant, because alkyl groups may include cyclical hydrocarbons. ( Id.)

There is no evidence here, from either the words of the claims themselves or the patent specification, to indicate that the inventor of the '233 Patent meant to impart a novel definition to the word "alkyl" in claim 1. The claim itself does not attempt to define the word alkyl. '233 Patent, col. 5 l. 65. The patent specification, however, does describe what may constitute an alkyl. It refers to the Plati process, where a methyl group was present in the R' position in structure (2) and (4). As mentioned, methyl is the simplest alkyl group. The specification continues by stating that after experimenting with the Plati process, the inventor developed an allegedly novel process for producing paroxetine hydrochloride. It observes that the "first aspect of this invention" is the preparation of structure (2), where R' is "independently an alkyl, aryl, or arylalkyl group, most suitably a lower alkyl." '233 Patent, col. 2 ll. 29, 46-47 (emphasis added). According to Defendants, lower alkyl groups would include relatively simple hydrocarbons of the formula C _n H_{2 n +1}, where there were no more than four carbon atoms.³⁷ (Doc. No. 105 at 19; Cunningham Decl. ¶ 22.)

37 These alkyl groups would include methyl (— CH₃), ethyl (— CH₂CH₃), propyl (three carbon atoms and seven hydrogen atoms), and butyl (four carbon atoms and nine hydrogen atoms). (Doc. No. 105 at 19.)

The '233 Patent specification also gives five examples of the types of R' groups envisioned by the invention. All five use methyl (— CH₃) as the R' group. '233 Patent col. 4 l. 42 to col. 5, l. 45. As previously explained, methyl is the simplest alkyl group under either definition. Thus, there is no indication from the patent specification that the inventor intended to impart the word "alkyl" with anything other than its ordinary meaning. See (Doc. No. 119 at 4) (stating Plaintiffs' claim that "the specification and prosecution history do not indicate that [the inventor] used the terms `alkyl, aryl, or arylalkyl' differently from the way those terms are commonly used by those of ordinary skill.").)

4. Patent Prosecution History

Next, we must consider the prosecution history of the patent, which can assist us in determining whether the inventor made any express representations regarding the scope or meaning of the claims or disclaimed or disavowed a particular interpretation of the claims during prosecution. Abbott Labs. v. TorPharm, Inc., 300 F.3d 1367, 1372 (Fed. Cir. 2002); Bell Atlantic Network Servs., Inc., 262 F.3d at 1268. The prosecution history includes "the complete record of all the proceedings before the Patent and Trademark Office, including any express representations made by the applicant regarding the scope of the claims. Bell Atlantic Network Servs., Inc., 262 F.3d at 1268 (citing Vitronics, 90 F.3d at 1582).

The '233 Patent's prosecution history does not indicate that the inventor intended to give the word "alkyl" anything other than its ordinary meaning to a person of ordinary skill in the art. The initial patent application contains the same language as claim 1 of the '233 Patent, stating that the R' group in structure (4) must be "independently selected from an alkyl, aryl, or arylalkyl group." (Doc. No. 105 Ex. I. at 0020.) The patent application's specification is also similar to the '233 Patent — both used a methyl group, the simplest alkyl, in the R' position in all five examples. ( Id. at 0018-0019.) Additionally, in the "Remarks" section of the amended patent application, the claimed process was illustrated by using a methyl group in the R' position. ( Id. at 0077.) There is no indication anywhere else in the prosecution history that the inventor made any express representations limiting the scope of the word alkyl or giving it anything other than its ordinary meaning.

Because there is no clear intent or express indication that the inventor of the '233 Patent used the word alkyl to mean anything other than its ordinary meaning, we conclude that the inventor's use of the word alkyl in the '233 Patent has its ordinary and customary meaning as understood by a person of ordinary skill in the art. Also, in light of the inventor's use of a methyl group in the R' position of structures (2) and (4) in all examples of the claimed process, which is consistent with both of the proposed definitions of the word "alkyl," we conclude that the intrinsic evidence is "genuinely ambiguous" as to which of the parties' competing definitions, if any, the inventor intended to adopt. We therefore turn to the relevant treatises, dictionaries, and extrinsic evidence to determine the meaning and scope of the word alkyl in the '233 Patent.

5. Dictionaries and Treatises

The ordinary meaning of a claim term may be determined by reviewing a variety of sources, including dictionaries, treatises, and encyclopedias. See, e.g., Inverness Med. Switz. GmbH v. Warner Lambert Co., 309 F.3d 1373, 1378 (Fed. Cir. 2002); Teleflex, Inc., 299 F.3d at 1325. As the Texas Digital court has explained, these secondary sources are particularly important because they are objective, unbiased evidence of the ordinary meaning of the words of the claim:

Dictionaries, encyclopedias and treatises, publicly available at the time the patent is issued, are objective resources that serve as reliable sources of information on the established meanings that would have been attributed to the terms of the claims by those of skill in the art. Such references are unbiased reflections of common understanding not influenced by expert testimony or events subsequent to the fixing of the intrinsic record by the grant of the patent, not colored by the motives of the parties, and not inspired by litigation. Indeed, these materials may be the most meaningful sources of information to aid judges in better understanding both the technology and the terminology used by those skilled in the art to describe the technology.

Tex. Digital Sys., Inc., 308 F.3d at 1202-03; see also Union Carbide Chems. Plastics Tech. Corp. v. Shell Oil Co., 308 F.3d 1167, 1178 n. 4 (Fed. Cir. 2002) (stating that dictionaries and treatises have a "special place" in claim construction).

A technical term often has an "ordinary meaning" as understood by one of ordinary skill in the art, although these same terms may not be readily familiar to a judge. Dow Chem. Co. v. Sumitomo Chem. Co., 257 F.3d 1364, 1373 (Fed. Cir. 2001). "Thus, in determining the ordinary meaning of a technical term, courts are free to consult scientific dictionaries and technical treatises at any time." Id. (citing Vitronics, 90 F.3d at 1584 n. 6); see also Tex. Digital Sys., Inc., 308 F.3d at 1202-03 ("Dictionaries are always available to the court to aid in the task of determining meanings that would have been attributed by those of skill in the relevant art to any disputed terms used by the inventor in the claims."). As with other non-intrinsic evidence, however, a dictionary definition must be disregarded if "the specification uses the words in a manner clearly inconsistent with the ordinary meaning reflected . . . in a dictionary definition." Texas Digital Sys., Inc., 308 F.3d at 1204 (citations omitted).

a. IUPAC Nomenclature

To determine the meaning of the term alkyl, we first consider the international standard for nomenclature (naming) of organic chemistry, as promulgated by IUPAC. (Cunningham Decl. ¶ 7.) For more than a century, IUPAC has developed and adopted a systematic nomenclature for naming organic molecules. Nomenclature of Organic Chemistry (1979 ed.) at xvii. In the IUPAC system, organic molecules are named and classified "by dividing the [molecule] into a core structure and various substituents." Dow Agrosciences LLC v. Crompton Corp., No. 03-CV-0654, 2004 WL 1087362, at *3 (S.D. Ill. May 12, 2004). As the standardized, comprehensive international system of organic nomenclature, we find that the IUPAC system's meaning of the word alkyl would be given great weight by a person of ordinary skill in the art.³⁸ (Cunningham Decl. ¶ 13.)

38 Plaintiffs rely upon the declarations of two chemists, Dr. Brian Adger and Dr. G. Patrick Stahly, to assert that a person of ordinary skill in the art would not rely upon IUPAC's nomenclature to determine the meaning of the word alkyl. (Adger Decl. ¶ 16; Stahly Decl. ¶ 14.) We disagree. Introductory organic chemistry textbooks, which a person of ordinary skill in the art would rely upon in determining the name and classification of a chemical compound, routinely use the IUPAC nomenclature system to name most organic compounds. See, e.g., Jones, Organic Chemistry at 77 ("[O]nce we reach five carbons the IUPAC system largely takes over. . . .").

i. 1979 Edition

In the 1979 edition of IUPAC's nomenclature of organic chemistry, Rule A-1.2 defines an alkyl as a "[u]nivalent radical derived from [a] saturated unbranched acyclic hydrocarbon by removal of hydrogen from a terminal carbon." Nomenclature of Organic Chemistry (1979 ed.) at 5. In organic chemistry, a "saturated" hydrocarbon is an "organic compound containing only single bonds between carbon atoms." Webster's Third New International Dictionary 2018 (Philip Babcock Grove ed., 1993). An "acyclic" hydrocarbon is a hydrocarbon that does not contain carbon atoms bonded in the shape of a ring. See id. at 23 (defining acyclic as "not cyclic" or "having an open-ended chain structure"); see also 1 Oxford English Dictionary 135 (J.A. Simpson E.S.C. Weiner eds., 2d ed. 1989) (defining acyclic as "an organic compound that has no `cycle' or ring of atoms"), available at http://www.oed.com. Thus, under the 1979 IUPAC nomenclature, an alkyl is a hydrocarbon radical that contains only single bonds between carbon atoms, and no carbon atoms bonded in the shape of a ring.

Defendants assert that under IUPAC nomenclature, (-)2-isopropyl, 5-methylcyclohexyl may be classified as a cycloalkyl, which Defendants assert is a mutually exclusive category from alkyls. Rule A-11.2 defines a "cycloalkyl" as a "univalent radical derived from cycloalkanes." Nomenclature of Organic Chemistry (1979 ed.) at 16. A cycloalkane is defined in turn by Rule A-11.1 as a "saturated monocyclic hydrocarbon" radical. Id. A "monocyclic" hydrocarbon is a hydrocarbon that has one group of carbons bonded in the shape of a ring. See Webster's Third New International Dictionary at 1462 (defining monocyclic as "containing one ring in the molecular structure"). Thus, a cycloalkyl is a saturated hydrocarbon radical with one group of carbons in the shape of a ring. From these definitions, it logically follows that a cycloalkyl may not be an alkyl, because a cycloalkyl contains one carbon ring, while an alkyl may not contain any carbon rings.

ii. 1993 Edition

The 1993 IUPAC nomenclature defines an alkyl group as a radial of an alkane. Int'l Union of Pure Applied Chemistry, A Guide to IUPAC Nomenclature of Organic Compounds: Recommendations 1993, at 64 tbl. 6, 132 (R. Panico et al. eds, 1993) (hereafter "Nomenclature of Organic Compounds (1993 ed.)") (R-3.2.1 tbl. 6, R-5.8.1).³⁹ An alkane is defined as a "saturated acyclic hydrocarbon (branched or unbranched)." Id. at 36 (R-2.2.1). Because an "acyclic" hydrocarbon does not contain any carbon atoms bonded in the shape of a ring, Webster's Third New International Dictionary at 2018, the 1993 IUPAC nomenclature thus defines an alkyl as a hydrocarbon radical containing only single bonds between carbon atoms, and no carbon atoms bonded in the shape of a ring. Id. This is consistent with the 1979 IUPAC nomenclature definition of an alkyl.

39 "R-" indicates the relevant rule number in 1993 edition.

Likewise, the 1993 IUPAC nomenclature of a cycloalkyl is consistent with the 1979 IUPAC nomenclature. A cycloalkyl is defined as a cycloalkane radical. Id. at 64 tbl. 6, 132 (R-3.2.1 tbl. 6, R-5.8.1). A cycloalkane is defined as "the generic name of monocyclic hydrocarbons." Id. at 39 (R-2.3.1.1); see also id. ("The names of saturated monocyclic hydrocarbons are formed by attaching the prefix `cyclo-' to the name of the acyclic saturated unbranched hydrocarbon with the same number of carbon atoms."). Thus, consistent with the 1979 IUPAC definition, a cycloalkyl is a hydrocarbon radical with a group of carbons in the shape of a ring. Accordingly, a cycloalkyl is mutually exclusive from an alkyl under the 1993 IUPAC nomenclature.

b. Technical Dictionaries

Next, we consider the definition of the word alkyl in technical dictionaries. Technical dictionaries are particularly useful for defining technical terms because they "provid[e] specialized meanings as used in particular fields of art." Inverness Med. Switz. GmbH, 309 F.3d at 1378; see also Linear Tech. Corp. v. Impala Linear Corp., 379 F.3d 1311, 1320 (Fed. Cir. 2004) (stating that "[t]echnical dictionaries . . . are evidence of the understandings of persons of skill in the technical arts"). The Federal Circuit has routinely relied on chemical dictionaries, such as Hawley's Condensed Chemical Dictionary and Grant Hackh's Chemical Dictionary (" Grant Hackh's"), to determine the ordinary meaning of chemical words and phrases as understood by a person of ordinary skill in the art. See, e.g., E.T. Horn Co. v. United States, 367 F.3d 1326, 1333 (Fed. Cir. 2004); Fromson v. Advance Offset Plate, Inc., 720 F.2d 1565, 1571 (Fed. Cir. 1983).

Here, the chemical dictionaries' use of the word alkyl is consistent with the IUPAC's definition of an alkyl as a hydrocarbon radical that does not contain carbon atoms bonded in the shape of a ring. Grant Hackh's defines an alkyl group as a "monovalent radical derived from an aliphatic hydrocarbon by removal of 1 [hydrogen atom]." Grant Hackh's Chemical Dictionary at 24 (emphasis added). An "aliphatic" hydrocarbon is a compound that does not have a carbon structure in the shape of a ring. Id. at 22 (defining "aliphatic" as an "open-chain carbon compound"); see also Robert B. Fox Warren H. Powell, Nomenclature of Organic Compounds: Principles and Practice 65 (2001) ("The general term `aliphatic' should be used with care. . . . The definition does not encompass cyclic compounds of any kind." (emphasis added)). In addition, Grant Hackh's states than an alkyl has a formula of C _n H_{2 n +1}, which is inconsistent with a cyclical hydrocarbon radical.⁴⁰ Therefore, we conclude that under Grant Hackh's definition, a hydrocarbon radical with a cyclical or ring structure cannot be classified as an alkyl.⁴¹

40 In a cyclical hydrocarbon compound, every carbon atom in the ring is bonded to at least two other carbon atoms. Because a carbon atom may form only four bonds with other atoms, the maximum number of hydrogen atoms a cyclical hydrocarbon may have is C _n H_{2 n} .

41 Grant Hackh's defines a cycloalkyl as the "[g]eneric name for radicals derived from cycloalkanes." Grant Hackh's Chemical Dictionary at 167. Cycloalkanes are defined as the "[g]eneric name for saturated, monocyclic hydrocarbons." Id. Thus, a cycloalkyl, which has one cyclical carbon structure (monocyclic), cannot be an alkyl, which has no cyclical carbon structures.

Another dictionary, Hawley's Condensed Chemical Dictionary (" Hawley's"), provides a similar definition. It defines an alkyl as a "paraffinic hydrocarbon which may be derived from an alkane by dropping one hydrogen from the formula," and states that alkyl groups "have the generic formula C _n H_{2 n +1}."⁴² Hawley's at 34. Alkanes, in turn, are defined as "[a] class of aliphatic hydrocarbons characterized by a straight or branches carbon chain." Id. at 33, 838. As explained above, an aliphatic hydrocarbon may not contain a cyclical or ring-shaped carbon structure. Thus, under Hawley's definition, a cyclical hydrocarbon radical may not be classified as an alkyl.

42 Hawley's also lists several examples of alkyls, all of which (methyl, ethyl, propyl, and isopropyl) are not cyclical hydrocarbon radicals. Hawley's at 34.

c. Textbooks and Treatises

We also consider the meaning of the word alkyl in other sources that would be relied upon by a person of ordinary skill in the art, such as treatises or textbooks on organic chemistry. See, e.g., In re '639 Patent Litig., 154 F. Supp. 2d 157, 161 (D. Mass. 2001) (holding that a person of ordinary skill in the art, which the court defined as a chemist with an advanced degree in the field and at least several years' experience, would rely on chemistry textbooks), aff'd on other grounds, No. 01-1611, 2002 U.S. App. LEXIS 16594 (Fed. Cir. Aug. 15, 2002) (per curiam).

Defendants point to a treatise on nomenclature of organic compounds, Nomenclature of Organic Compounds: Principles and Practice, in support of their argument that (-)2-isopropyl, 5-methylcyclohexyl is not an alkyl group. (Cunningham Decl. ¶ 16.) In this treatise, alkanes are defined as saturated branched or unbranched hydrocarbons. Fox Powell, Nomenclature of Organic Compounds: Principles and Practice at 60. According to this definition, cyclic hydrocarbons are not alkanes. The treatise also distinguishes alkanes from cycloalkanes, defining cycloalkanes as saturated monocyclic hydrocarbons. Id. at 67. Cycloalkyls are defined as cycloalkane radicals. Id. at 68. Therefore, according to this treatise, a monocyclic hydrocarbon radical like (-)2-isopropyl, 5-methylcyclohexyl would not be defined as an alkyl because it is a cyclic, rather than a branched or unbranched, structure.

Another objective resource — an introductory organic chemistry textbook by Maitland Jones, Jr., the David B. Jones Professor of Chemistry at Princeton University — also supports Defendants' argument that a cyclical hydrocarbon radical may not be classified as an alkyl. This textbook defines alkyl as a "generic term for derivatives of alkanes." Jones, Organic Chemistry at 57. Alkanes are defined as "[t]he series of saturated hydrocarbons of the general formula C nH2 n+2." Id. at A2; see also id. at 81 (repeating this definition). In contrast, the Jones textbook explains that cyclical hydrocarbons are unsaturated compounds of the general formula C nH2 n. Id. at 81. It teaches that cyclical-shaped hydrocarbons "are named by adding the prefix `cyclo' to the name of the parent hydrocarbon." Id.; see also id. at 81-84 (describing the properties of "cycloalkanes"). The Jones textbook thus explains that unsaturated cycloalkanes may not be classified as alkanes, which are saturated hydrocarbons.

6. Extrinsic Evidence ⁴³

43 We note that neither side requested a Markman hearing to present expert witness testimony regarding the construction of the '233 Patent. Accordingly, we will consider the declarations of the three organic chemists submitted by the parties as extrinsic evidence. See, e.g., Goldenberg v. Cytogen, Inc., 373 F.3d 1158, 1166 (Fed. Cir. 2004) (considering expert declarations); Honeywell Int'l, Inc. v. U.S. Int'l Trade Comm'n, 341 F.3d 1332, 1340 (Fed. Cir. 2003) (same).

Finally, we may consider extrinsic evidence, such as expert testimony or affidavits, to assist us in determining how a person of ordinary skill in the art would understand terms in a claim, so long as it is not inconsistent with the intrinsic evidence. Vitronics, 90 F.3d at 1584; see also id. ("[E]xtrinsic evidence in general, and expert testimony in particular, may be used only to help the court come to the proper understanding of the claims; it may not be used to vary or contradict the claim language."). Unlike dictionaries or treatises, however, expert testimony is not an objective source constituting "an unbiased reflection of common understanding . . . not colored by the motives of the parties, and not inspired by litigation." Tex. Digital Sys., Inc., 308 F.3d at 1203. "We must always be conscious that our objective is to interpret the claims from the perspective of one of ordinary skill in the art, not from the viewpoint of counsel or expert witnesses retained to offer creative arguments in infringement litigation." Dayco Prods. v. Total Containment, Inc., 258 F.3d 1317, 1324 (Fed. Cir. 2001) (citation omitted); see also Goldenberg v. Cytogen, Inc., 373 F.3d 1158, 1166 (Fed. Cir. 2004) ("[A]lthough expert testimony and declarations are useful to confirm that the construed meaning is consistent with the denotation ascribed by those in the field of the art, such extrinsic evidence cannot be used to vary the plain language of the patent document." (quoting Omega Eng'g, Inc. v. Raytek Corp., 334 F.3d 1314, 1332 (Fed. Cir. 2003))).

Defendants submit the declaration of Dr. Ian M. Cunningham, an organic chemist with over twenty years' experience as a pharmaceutical chemist and manager.⁴⁴ (Cunningham Decl. ¶¶ 1-2, Ex. A.) Dr. Cunningham states that it is his opinion that "a chemist skilled in the art would understand the term `alkyl' to mean a simple, straight or branched acyclic saturated hydrocarbon group."⁴⁵ ( Id. ¶ 10.) In support of his opinion, Dr. Cunningham states that he relied upon the IUPAC conventions for the nomenclature of organic compounds. ( Id. ¶¶ 13-15.) As previously explained, supra, IUPAC defines alkyl groups as acyclic hydrocarbon radicals. ( Id. ¶ 14.) IUPAC defines monocyclic hydrocarbon radicals, such as (-)2-isopropyl, 5methylcyclohexyl, as cycloalkyls. ( Id. ¶ 15.) Dr. Cunningham also states that he relied upon the treatise Nomenclature of Organic Compounds: Principles and Practice, which defines alkyl groups as alkanes joined to an organic compound by a single bond, and which defines alkanes as saturated, branched or unbranched, acyclic hydrocarbons. ( Id. ¶ 16.) This treatise also classifies saturated monocyclic hydrocarbons as cycloalkanes, a mutually exclusive group from alkanes. ( Id.) Finally, Dr. Cunningham states that in his opinion, a chemist of ordinary skill in the art reading a description of chemical reaction calling for an alkyl group would not consider that description to encompass a cycloalkyl group. ( Id. ¶ 18.)

44 Dr. Cunningham was also Senior Vice President of Chemical Development at GlaxoSmithKline from 2001-2002 and Wordwide Director of Chemical Development of GlaxoWellcome from 1995-2001. (Cunningham Decl. ¶ 2, Ex. A.)

45 Dr. Cunningham also states that, in his opinion, the generic formula for an alkyl group is C nH2 n+1.

Plaintiffs submit the declarations of Dr. Brian Adger, an organic chemist with over thirty years' experience, and Dr. G. Patrick Stahly, an organic chemist with over twenty years' experience. (Adger Decl. ¶ 4; Stahly Decl. ¶¶ 2-5, Ex. A.) Both scientists conclude that a person of ordinary skill would find that Apotex used an alkyl group in the R' position. Dr. Adger states that in his opinion, "the term `alkyl,' as used in the '233 [P]atent, encompasses straight chain, branched, and cyclic alkyl groups." (Adger Decl. ¶ 5.) Similarly, Dr. Stahly asserts that "the term `alkyl' as used in claim 1 [of the '233 Patent], would be interpreted by chemists of ordinary skill to include cycloalkyls . . . and a number of substituted cycloalkyl groups such as the menthyl group." (Stahly Decl. ¶ 7.)

As evidence for their conclusion, Drs. Adger and Stahly rely on a patent application (Pub. No. 2003/0220370 A1), by Dr. Keshava Murthy and several co-inventors published on November 27, 2003. (Adger Decl. ¶ 6, Ex. B; Stahly Decl. ¶¶ 8, 11.) Dr. Murthy is the President of BCI, a company affiliated with Apotex. (Murthy Decl. ¶ 1.) Drs. Adger and Stahly note that in his patent application, Dr. Murthy described a cyclical hydrocarbon radical called a "menthyl group" as an "alkyl group." (Adger Decl. ¶ 6; Stahly Decl. ¶¶ 10-11.)

Dr. Murthy's patent application and its definition of an "alkyl group" are irrelevant, however, for two reasons. First, it is elementary that "[a] court construing a patent claim seeks to accord a claim the meaning it would have to a person of ordinary skill in the art at the time of the invention." Innova/Pure Water, Inc., 381 F.3d at 1116 (emphasis added); see also Markman, 52 F.3d at 986 ("The focus is on the objective test of what one of ordinary skill in the art at the time of the invention would have understood the term to mean."). Dr. Murthy is not a person of ordinary skill in the art, but rather a person of exceptional skill — a highly trained and educated chemist with a Ph.D., and an inventor who has received numerous patents for developing processes to produce various pharmaceutical products.⁴⁶ As the Federal Circuit has repeatedly instructed, an invention "must be evaluated not through the eyes of [an] inventor, who may have been of exceptional skill, but as by one of `ordinary skill.'" Interconnect Planning Corp. v. Feil, 774 F.2d 1132, 1138 (Fed. Cir. 1985); see also Arkie Lures, Inc. v. Gene Larew Tackle, Inc., 119 F.3d 953, 956 (Fed. Cir. 1997). Thus, it is clearly inappropriate for an expert to rely on the statement of an individual who is not a person of ordinary skill (i.e., Dr. Murthy) to determine what a person of ordinary skill would have understood a term in a claim to mean. Second, the court's inquiry into the meaning of a claim is what a person of ordinary skill would have understood the words of the claim to mean at the time of the invention. Home Diagnostics, Inc. v. LifeScan, Inc., 381 F.3d 1352, 1356 (Fed. Cir. 2004); Moba v. Diamond Automation, Inc., 325 F.3d 1306, 1315 (Fed. Cir. 2003). Here, Dr. Murthy's patent application's definition of an "alkyl group" is irrelevant because it occurred well after the time of the '233 Patent's invention. The '233 Patent was issued on January 9, 2001, while Dr. Murthy's patent application was not published until November 27, 2003. (Adger Decl. Exs. A, C.) Even allowing for an eighteen-month delay in the publication of Dr. Murthy's patent application, as required by 35 U.S.C. § 122(b)(1)(A), Dr. Murthy's patent application was submitted no earlier than May, 2002, at least fifteen months after the issuance of the '233 Patent. Thus, Dr. Murthy's application cannot inform us as to the meaning of the claims at the time of the '233 Patent's invention.

46 See, e.g., U.S. Patent No. 6,635,753 (issued Oct. 21, 2003) (naming Dr. Murthy as an inventor of a process for the preparation of substantially pure stavudine and related intermediates useful in the preparation thereof); U.S. Patent No. 6,600,044 (issued July 29, 2003) (naming Dr. Murthy as an inventor of a process for recovery of the desired cis-1,3-oxathilane nucleosides from their undesired trans-isomers); U.S. Patent No. 6,436,956 (issued Aug. 20, 2002) (naming Dr. Murthy as an inventor of a useful form of anhydrous paroxetine hydrochloride); '689 Patent (naming Dr. Murthy as an inventor of processes for preparing 3-substituted-4-aryl piperidines and methods for controlling their stereochemistry).

Second, Dr. Adger states that he relied on an organic chemistry textbook by Seyhan N. Ee, a professor of chemistry at the University of Michigan. (Adger Decl. ¶ 15.) Dr. Adger states that this textbook supports his opinion because it "defines alkanes as having two classes: open chain alkanes (acyclic compounds) as well as cyclic alkanes. Thus, Ee recognizes that cycloalkanes are a class of alkanes, and, therefore, cyclo alkyls are alkyls." ( Id.) However, we find other statements in the Ee textbook that undercut Dr. Adger's conclusion. For example, the textbook states that cycloalkanes have a different general formula from alkanes. See Seyhan N. Ee, Organic Chemistry 163 (2d ed. 1989) ("Cycloalkanes are hydrocarbons that have the general formula C nH2 n. . . ."). More importantly, the Ee textbook makes a clear distinction between cycloalkyls and alkyl groups, stating that "[c]ycloalkyl groups are derived from cycloalkanes, just as alkyl groups are derived from alkanes." Id. at 164. Thus, contrary to Dr. Adger's statements, the Ee textbook appears to view cycloalkyls and alkyls as mutually exclusive groups.

Dr. Adger relies on one other source, an organic chemistry textbook by L.G. Wade, Jr., a professor of chemistry at Whitman College. (Adger Decl. ¶ 14.) He states that the Wade textbook states that "cycloalkanes are alkanes in the form of a ring." ( Id. (quoting id. Ex. D. at 70).) Based on this brief reference, Dr. Adger concludes that cycloalkyls must be a form of alkyl. ( Id.) Similarly, Dr. Stahly relies on one other source, an organic chemistry textbook by Ralph J. Fessenden and Joan S. Fessenden, which states that "an alkyl group contains only -sp3-hybridized carbon atoms plus hydrogen." (Stahly Decl. ¶ 13 (quoting id. Ex. F at 66).) The textbook then includes an example of a cyclohexyl radical as an alkyl. ( Id.)

7. Conclusion

As the Federal Circuit has noted, "[i]t has been long recognized in our precedent . . . that dictionaries, encyclopedias and treatises are particularly useful resources to assist the court in determining the ordinary and customary meanings of claim terms." Tex. Digital Sys., Inc., 308 F.3d at 1202. These "objective resources . . . serve as reliable sources of information on the established meanings that would have been attributed to the terms of the claims by those of skill in the art." Id. at 1202-03. They are the "most meaningful sources of information to aid judges in better understanding . . . the terminology used by those skilled in the art to describe the [relevant] technology." Id. at 1203.

In light of the objective evidence discussed in Part IV.B.5, we conclude that a person of ordinary skill in the art at the time of the '233 Patent's invention would understand the word "alkyl" to mean an acyclic saturated hydrocarbon radical. This conclusion is supported by IUPAC's international standard nomenclature for organic compounds, which explicitly defined an alkyl group in both the 1979 and 1993 editions as an acyclic saturated hydrocarbon radical. Supra Part IV.B.5.a. It is also supported by two chemical dictionaries, Grant Hackh's Chemical Dictionary and Hawley's Condensed Chemical Dictionary, which defined an alkyl as an aliphatic⁴⁷ hydrocarbon radical. Supra Part IV.B.5.b. Finally, we note that this definition is consistent with two treatises, including a specialized treatise on the nomenclature of organic compounds. Supra Part IV.B.5.c.

47 As previously explained, an aliphatic hydrocarbon is acyclic — that is, it does not contain any carbons bonded in the shape of a ring. See Fox Powell at 65 ("The general term `aliphatic' should be used with care. . . . The definition does not encompass cyclic compounds of any kind." (emphasis added)).

This definition is also consistent with the intrinsic evidence. There is no evidence, from either the words of the claims themselves or the patent specification, to indicate that the inventor of the '233 Patent meant to impart a novel definition to the word "alkyl" in claim 1. The claim itself does not attempt to define the word alkyl, and the patent specification states that the "most suitabl[e]" alkyl is a "lower alkyl." '233 Patent, col. 2 ll. 29, 46-47. The examples of alkyls contained in the prosecution history and the patent specification all employ a methyl radical (— CH3), the simplest alkyl group.

We find the declarations of Drs. Adger and Stahly to be unconvincing. Their definitions contradict the ordinary meaning of the term alkyl as determined by IUPAC nomenclature, chemical dictionaries, a treatise on organic chemistry nomenclature, and several textbooks. The overwhelming weight of objective evidence, when coupled with expert evidence from Dr. Cunningham, compels us to reject Plaintiffs' chemists' assertion that the word alkyl encompasses monocyclic saturated hydrocarbon radicals.

C. Literal Infringement

1. Legal Standard

The second step in an infringement analysis is to compare the properly construed claims to the allegedly infringing process. Markman, 52 F.3d at 976. A finding of infringement requires a determination that every claim limitation, or its equivalent, is found in the accused device or process. Warner-Jenkinson Co., 520 U.S. at 29 (1997); see also Mas-Hamilton Group, 156 F.3d at 1211 ("To prove literal infringement, the patentee must show that the accused device contains every limitation in the asserted claims. If even one limitation is missing or not met as claimed, there is no literal infringement." (citations omitted)). This issue is a question of fact. Markman, 52 F.3d at 976 (citing Envirotech Corp., 730 F.2d at 758).

2. Comparing Claims With the Accused Process

We have construed the word "alkyl" in claim 1 of the '233 Patent to mean an acyclic saturated hydrocarbon radical. As previously mentioned, an acyclic hydrocarbon radical is a hydrocarbon radical that does not contain carbon atoms bonded in the shape of a ring. Supra Part IV.B.5.a.i. Thus, a ring-shaped hydrocarbon radical, such as (-)2-isopropyl, 5-methylcyclohexyl, illustrated in Figure 7 above, is not an alkyl group.

Claim 1, the only independent claim of the '233 Patent, states as follows:

1. A process for industrial scale preparation of a compound of structure (2)

in which R and R' are independently selected from an alkyl, aryl, or arylalkyl group, X is fluorine which comprises reacting a compound of structure (4)

with an organometallic compound having one or more X-substituted phenyl groups, in a suitable organic solvent, provided that the solvent is not wholly an ether solvent when the organometallic compound is a Grignard reagent.

'233 Patent, col. 5 l. 46 to col. 6 l. 13. Claims 2-10 and 14-16, which are all dependent claims, contain claim 1's limitation that an "an alkyl, aryl, or arylalkyl group" must be located in positions R and R' of structure (2). ( Id. col. 6 ll. 14-65, col. 7 l. 5 to col. 8 l. 5.)

According to the unrebutted declaration of Darren Hall, Director of Corporate Supply Chain Management at BCI, Defendants first began commercial scale production of paroxetine hydrochloride in 1997. (Hall Decl. ¶¶ 1-2.) Since BCI commenced commercial scale production of anhydrous paroxetine chloride, it has employed a process that uses a (-)2-isopropyl, 5methylcyclohexyl radical in the R' position of structure (4). This structure is represented in

(Cunningham Decl. ¶ 11, Fig. 2; Hall Decl. ¶ 3.)

Claim 1 claims a process where "R and R' are independently selected from an alkyl, aryl, or arylalkyl group." '233 Patent, col. 5, ll. 65-66. As illustrated above, Defendants employ a process that uses the cyclical (-)2-isopropyl, 5-methylcyclohexyl radical in the R' position. We find that this radical is not an alkyl, aryl, or arylalkyl group. There is no dispute that Defendants' process does not contain an aryl or arylalkyl group in the R' position. Plaintiffs' experts, Dr. Brian Adger and Dr. G. Patrick Stahly, clearly concede this point. See Adger Decl. ¶ 11 ("Of the three possibilities given for R' in claim 1 of . . . the '233 [P]atent . . ., menthyl only fits the alkyl definition. . . ."); Stahly Decl. ¶ 11 ("[Defendants'] menthyl structure is cyclic and not aromatic. Accordingly, it cannot be described as either an aryl group or an arylalkyl group." (footnote omitted)). Under our construction of claim 1, an alkyl is an acyclic saturated hydrocarbon radical. The radical used by Defendants is monocyclic; it has six carbon atoms arranged in a cyclical shape. Thus, Defendants' process is missing a required element of claim 1 — that R' is an alkyl, aryl, or arylalkyl group. We therefore find that Defendants' process does not infringe claim 1 of the '233 Patent.

Claims 2-10 and 14-16 of the '233 Patent are all dependent claims which incorporate independent claim 1s limitation that R' contains an alkyl, aryl, or arylalkyl group. '233 Patent, col. 6 l. 14 to col. 8 l. 5. A dependent claim containing the same limitations as the independent claim cannot be infringed unless the independent claim is also infringed. See Wahpeton Canvas Co., Inc. v. Frontier, Inc., 870 F.2d 1546, 1552 n. 9 (Fed. Cir. 1989) ("One who does not infringe an independent claim cannot infringe a claim dependent on (and thus containing all the limitations of) that claim."). Because claim 1 is not infringed, we find that Defendants' process also does not infringe claims 2-10 and 14-16 of the '233 Patent.

D. Doctrine of Equivalents

In the alternative, Plaintiffs argue that summary judgment of noninfringement should not be granted because there is a genuine question of material fact as to whether Defendants' process infringes the '233 Patent under the doctrine of equivalents. (Doc. No. 42, 01-CV-2169, at 8-9.)

The doctrine of equivalents "allows the patentee to claim those insubstantial alterations that were not captured in drafting the original patent claim but which could be created through trivial changes" to the claimed product or process. Festo Corp. v. Shoketsu Kinzoku Kogyo Kabushiki Co., 535 U.S. 722, 733 (2002). "Under this doctrine, a product or process that does not literally infringe upon the express terms of a patent claim may nonetheless be found to infringe if there is `equivalence' between the elements of the accused product or process and the claimed elements of the patented invention." Warner-Jenkinson Co., 520 U.S. at 21. Infringement under the doctrine of equivalents occurs when a claimed limitation and the accused product or process "`perform substantially the same function in substantially the same way to obtain substantially the same result.'" Id. at 40 (quoting Mach. Co. v. Murphy, 97 U.S. 120, 125 (1878)). There is no infringement under the doctrine of equivalents "if even one limitation of a claim or its equivalent is not present in the accused device." Lockheed Martin Corp. v. Space Sys./Loral, Inc., 324 F.3d 1308, 1321 (Fed. Cir. 2003). Infringement under the doctrine of equivalents is an issue of fact, Gemstar-TV Guide Int'l, Inc. v. U.S. Int'l Trade Comm'n, 383 F.3d 1352, 1360 (Fed. Cir. 2004), and the patentee bears the burden of proving equivalence. Zelinski v. Brunswick Corp., 185 F.3d 1311, 1317 (Fed. Cir. 1999).

Defendants assert that Plaintiffs cannot carry their burden of establishing that Defendants' process performs substantially the same function in substantially the same way as the processes claimed in the '233 Patent. (Doc. No. 105 at 22-26.) According to the '233 Patent, when the inventor attempted to replicate the Plati process using a methyl group in the R' and ether solvents such as THF or diisopropyl ether, the Grignard reagent bonded to the substrate in the wrong position. '233 Patent, col. 2 ll. 13-18. Specifically, the Grignard reagent engaged in a 1,2 addition reaction and bonded to the ester group, rather than bonding to the carbon atom on the piperidine ring with the carbon-carbon double bond (a 1,4 conjugate addition reaction) as in the Plati process. ( Id.) To solve this problem, the inventor substituted a non-ether solvent, which resulted in the desired 1,4 addition reaction and formation of the desired paroxetine hydrochloride precursor. ( Id.) The inventor's use of a non-ether solvent to conduct the Plati article's process was the basis for awarding the '233 Patent.

In contrast, Defendants assert that their production of paroxetine hydrochloride employs a significantly different mechanism. Instead of using a methyl (alkyl) group, Defendants deviated from the '233 Patent's process by using a (-)2-isopropyl, 5-methylcyclohexyl group in the R' position. (Murthy Decl. ¶ 8.) According to Defendants, the use of this substituted cyclohexyl group, which is a significantly larger molecule (10 carbon atoms and 19 hydrogen atoms) compared to methyl (1 carbon atom and 3 hydrogen atoms), employed a different chemical mechanism than Plaintiffs' process. (Doc. No. 105 at 25; Murthy Decl. ¶¶ 8-9.) Defendants' process relied on the chemical characteristic of "steric hindrance" to perform the desired 1,4 conjugate addition reaction between the Grignard reagent and the substrate. (Murthy Decl. ¶ 9.) Steric hindrance is "[a] characteristic of molecular structure in which the molecules have a spatial arrangement of their atoms such that a given reaction with another molecule is prevented or retarded." Hawley's at 1048. In other words, in Defendants' process, the size of the (-)2isopropyl, 5-methylcyclohexyl group in the R' position prevented the Grignard reagent from bonding onto the ester group (the undesired 1,2 addition reaction), and instead bonded to the carbon atom in the piperidine ring (the desired 1,4 conjugate addition reaction). See also '689 Patent col. 2 ll. 56-64 (employing steric hindrance by using other large chemical compounds in the R' position to perform the desired 1,4 conjugate addition reaction and synthesize paroxetine hydrochloride). In fact, unlike Plaintiffs' process, Defendants' steric hindrance process results in a 1,4 conjugate addition reaction even if it is conducted in a solvent that is wholly ether.⁴⁸ '689 Patent col. 2 ll. 14-65, col. 4 ll. 1-8. Based on these differences, we find that Defendants have established a prima facie case that the accused process is not equivalent to the process claimed in the '233 Patent because it does not "perform substantially the same function in substantially the same way." Warner-Jenkinson Co., 520 U.S. at 40.

48 The '233 Patent states that when the patentee attempted to use "other ether solvents . . . such as tetrahydrofuran or diisopropyl ether" to conduct the Grignard reaction, it "result[ed] in little if any of the desired 1,4 conjugate addition product." '233 Patent, col. 2 ll. 13-16.

Once a moving party has established a prima facie case for summary judgment, the nonmoving party must produce evidence demonstrating that there is a genuine issue of material fact for trial. Cable Elec. Prods., Inc. v. Genmark, Inc., 770 F.2d 1015, 1022 (Fed. Cir. 1985) (citing Fed.R.Civ.P. 56(e)); see also Celotex Corp., 477 U.S. at 333 n. 3 (1986) ("Once the moving party has attacked whatever record evidence — if any — the nonmoving party purports to rely upon, the burden of production shifts to the nonmoving party. . . ."). A "mere scintilla" of evidence is insufficient to sustain this burden. Golan v. Pingel Enter., Inc., 310 F.3d 1360, 1368 (Fed. Cir. 2002) (citing Anderson, 477 U.S. at 251). Thus, Plaintiffs must point to sufficient evidence that Defendants' process performs substantially the same function in the same way as the '233 Patent to create a genuine issue of material fact.

Here, Plaintiffs have failed to meet their burden. Plaintiffs point to the expert declarations of Drs. Adger and Stahly, and assert that these declarations set forth "numerous factual disputes" concerning Defendants' process and the '233 Patent. (Doc. No. 119 at 8.) Reviewing these expert declarations, however, we find that their unsupported assertions do not create a genuine issue of material fact. Dr. Adger states that Defendants' use of a substituted cyclohexyl group in the R' position "is not important" and "irrelevant" because it "does not take part directly in the reaction." (Adger Decl. ¶ 20.) This conclusory statement, however, does not contradict Defendants' evidence that although the substituted cyclohexyl group used in Defendants' process does not take part directly in the reaction, its size and spatial arrangement is responsible for producing the desired 1,4 conjugate addition reaction, rather than the undesired 1,2 addition reaction. Dr. Adger also states that, in his opinion, other alkyl groups would also provide steric hindrance in the Grignard reaction. ( Id. ¶ 22.) Again, Dr. Adger does not provide any evidence for this unsupported opinion, nor does he explain why, if this is true, Defendants' process results in a 1,4 conjugate addition reaction in a wholly ether solvent, while Plaintiffs' process does not. Finally, Dr. Stahly asserts that it is his "opinion that a menthyl alkyl group performs in the same manner as when R' is a methyl alkyl group." (Stahly Decl. ¶ 4.) As with Dr. Adger, however, Dr. Stahly's conclusory statement provides no evidence why a menthyl group is no different than a methyl group in the Grignard reaction, despite the obvious difference in molecular size of the two groups, nor does he rebut Defendants' evidence that its process, which uses a menthyl group for steric hindrance to perform the 1,4 conjugate addition reaction, is substantially different from Plaintiffs' claimed process, which relies on a change in solvents to perform the same reaction.

The Federal Circuit has repeatedly instructed that "an expert's unsupported conclusion on the ultimate issue of infringement is insufficient to raise a genuine issue of material fact." Dynacore Holdings Corp. v. U.S. Philips Corp., 363 F.3d 1263, 1278 (Fed. Cir. 2004); see also Phillips Petroleum Co. v. Huntsman Polymers Corp., 157 F.3d 866, 876 (Fed. Cir. 1998) (reasoning that a conclusory expert declaration devoid of facts upon which the conclusions were reached failed to raise a genuine issue of material fact); cf. In re Am. Acad. of Sci. Tech Ctr., 367 F.3d 1359, 1368 (Fed. Cir. 2004) ("Lack of factual support for expert opinion going to factual determinations . . . render[s] the testimony of little probative value." (quoting Ashland Oil, Inc. v. Delta Resins Refractories, Inc., 776 F.2d 281, 294 (Fed. Cir. 1985))). Here, Plaintiffs have produced only the unsupported conclusions of Dr. Adger and Dr. Stahly that Defendants' process performs substantially the same function in substantially the same way as the '233 Patent. We therefore find that there is no genuine issue of material fact on this issue and that summary judgment of noninfringement in favor of Defendants is appropriate. V. INFRINGEMENT UNDER 35 U.S.C. § 271(g)

Finally, Plaintiffs move for summary judgment of infringement against Defendants under 35 U.S.C. § 271(g). (Doc. No. 42, 01-CV-2169.) Section 271(g) provides as follows:

Whoever without authority imports into the United States or offers to sell, sells, or uses within the United States a product which is made by a process patented in the United States shall be liable as an infringer, if the importation, offer to sell, sale, or use of the product occurs during the term of such process patent. In an action for infringement of a process patent, no remedy may be granted for infringement on account of the noncommercial use or retail sale of a product unless there is no adequate remedy under this title for infringement on account of the importation or other use, offer to sell, or sale of that product. A product which is made by a patented process will, for purposes of this title, not be considered to be so made after —

(1) it is materially changed by subsequent processes; or

(2) it becomes a trivial and nonessential component of another product.

35 U.S.C. § 271(g) (2000).

Plaintiffs allege that Defendants' process for manufacturing paroxetine hydrochloride infringes claim 9 of the '233 Patent, and that the product produced by that process has not been materially changed prior to import or sale in the United States. (Doc. No. 42, 01-CV-2169, at 1-2.) We have concluded, however, that Defendants' process for manufacturing industrial scale paroxetine hydrochloride does not infringe dependent claim 9 of the '233 Patent because it does not contain an alkyl, aryl, or arylalkyl group in the R' position of structure (2) of claim 1, the only independent claim.⁴⁹ We therefore deny Plaintiffs' motion for summary judgment.

49 Dependent claim 9 incorporates the limitations of claim 1.

An appropriate Order follows.

ORDER

AND NOW, this 31st day of March, 2005, upon consideration of: (1) Defendants Apotex Corporation, Apotex, Inc., and Torpharm, Inc.'s Motion for Partial Summary Judgment that Claims 1, 2, 4, 5, 7-10 and 14-16 of U.S. Patent No. 6,172,233 B1 Are Invalid Under 35 U.S.C. § 103 (Doc. No. 109, 99-CV-4304; Doc. No. 68, 00-CV-4888; Doc. No. 61, 01-CV-0159; Doc. No. 56, 01-CV-2169); (2) Defendants Apotex Corporation, Apotex, Inc., and Torpharm, Inc.'s Motion for Summary Judgment of Noninfringement of Claims 1-10 and 14-16 of U.S. Patent No. 6,172,233 B1 (Doc. No. 105, 99-CV-4304; Doc. No. 64, 00-CV-4888; Doc. No. 57, 01-CV-0159; Doc. No. 52, 01-CV-2169); and (3) Plaintiffs' Motion for Summary Judgment for Infringement by Apotex Corporation, Apotex, Inc., and Torpharm, Inc. of Claim 9 of U.S. Patent No. 6,172,233 (Doc. No. 42, 01-CV-2169), and all documents filed in support or opposition, it is ORDERED that:

1. Defendants' Motion for Partial Summary Judgment for Invalidity (Doc. No. 109, 99-CV-4304; Doc. No. 68, 00-CV-4888; Doc. No. 61, 01-CV-0159; Doc. No. 56, 01-CV-2169) is DENIED; and

2. Defendants' Motion for Summary Judgment of Noninfringement of Claims 1-10 and 14-16 (Doc. No. 105, 99-CV-4304; Doc. No. 64, 00-CV-4888; Doc. No. 57, 01-CV-0159; Doc. No. 52, 01-CV-2169) is GRANTED; and

3. Plaintiffs' Motion for Summary Judgment for Infringement under 35 U.S.C. § 271(g) (Doc. No. 42, 01-CV-2169) is DENIED.

IT IS SO ORDERED.