Citations
- 718 F. Supp. 2d 382
Full opinion text
FINDINGS OF FACT AND CONCLUSIONS OF LAW
JOHN G. KOELTL, District Judge:
INTRODUCTION...............................................................388
LEGAL BACKGROUND AND FINDINGS OF FACT..............................390
I. Jurisdiction.........................................................390
II. Relevant Statutory and Regulatory Provisions.........................390
III. The Presumption of Validity and the Standard of Proof................391
IV. The Parties.........................................................391
V. Background of the ’ 052 Patent........................................392
A. The '052 Patent Technology Permits Injection of Argatroban With Less Fluid Volume.......................................395
B. The Ability to Supply Argatroban in 2.5 ml 100 mg/mL Vials Provides Substantial Advantages ...............................396
C. Clinical Background Relevant to the '052 Patent...................397
1. HIT ........................................................397
2. Treatment of HIT............................................399
D. Background on Pharmaceutical Development and Formulation in the Prior Art Period ........................................401
E. Development of Argatroban Injection.............................401
1. The Surprising Nature of the Discoveries Claimed in the '052 Patent................................................401
2. Concurrent and Subsequent Failures of Others.................402
F. The '052 Patent Claims..........................................403
VI. The Prior Art .......................................................403
A. Ordinary Skill in the Art.........................................403
B. Relevance of the Chemical Structure of Argatroban................404
VII. Claim Construction..................................................407
A. The Law Governing Claim Construction ..........................407
1. Claims Are To Be Given Their Ordinary Meaning..............408
2. Limitations From the Specification Should Not Be Read Into the Claims............................................408
3. The Role of Prosecution History and Extrinsic Evidence........409
B. The Construction of Claim Terms ................................410
C. The Proper Construction of “Pharmaceutical Composition For Injection” ....................................................411
VIII. Anticipation ........................................................413
A. The Law of Anticipation.........................................413
B. Yamamoto......................................................416
1. The Yamamoto Translations..................................416
i. The Hartmann Translation..............................417
ii. The Aschmann Translation..............................418
iii. The FDA Translation....................................418
iv. The Cross Translation...................................419
v. The Yamamoto Reference ...............................419
2. Yamamoto Did Not Anticipate Claims 1 and 2 of the '052 Patent....................................................420
i. Yamamoto Did Not Disclose the Patented Method for Dissolving Argatroban in Ethanol, Water, and a Saccharide ...........................................420
ii. Yamamoto Was Not Enabling............................422
3. Yamamoto Did Not Anticipate Claims 3 and 4 of the '052 Patent....................................................423
i. Yamamoto Did Not Disclose a Pharmaceutical Composition for Injection Comprising Argatroban, Water, Ethanol, and a Saccharide......................423
ii. Yamamoto Did Not Enable Claims 3 and 4 of the '052 Patent...............................................424
IX. Obviousness.........................................................425
A. The Law of Obviousness.........................................425
1. The Defendants’ Burden of Proof.............................427
B. The Defendants’ Prima Facie Case................................428
1. The Prior Art Provided No Basis for One Skilled in the Art to Create the Invention.....................................428
i. Prior Art References Involving Argatroban................428
ii. One Skilled in the Art Would Not Have Been Motivated to Pursue the '052 Invention in View of the Prior Art Regarding Argatroban....................429
iii. Prior Art References Not Involving Argatroban............431
iv. One Skilled in the Art Would Not Have Been Motivated to Pursue the '052 Invention in View of the Other Prior Art ...................................432
2.A Person Skilled in the Art Would Have Had No
Reasonable Expectation of Success Prior to the Issuance of the '052 Patent..........................................434
i.The Claimed Inventions of the '052 Patent Would Not Have Been Obvious in View of the Prior Art in 1987.....434
C. Secondary Considerations........................................435
1. Commercial Success .........................................435
i. Argatroban Injection Has Significant Sales ...............436
ii. Argatroban Injection Embodies the Invention of the '052 Patent...........................................437
iii. The Plaintiffs Are Entitled to a Presumption of Nexus Between the Commercial Success of Argatroban Injection and the '052 Patent...........................440
iv. The Defendants Have Not Overcome the Presumption of Nexus .............................................440
2. Unexpected Results..........................................441
3. Long-Felt Need .............................................442
4. Failure of Others............................................443
5. Copying.....................................................443
6. Skepticism by Others ........................................444
CONCLUSIONS OF LAW.......................................................444
I. Anticipation ........................................................444
A. Legal Standard for Anticipation Under 35 U.S.C. § 102 .............444
B. Claims 1-4 of the '052 Patent Are Not Anticipated by the Yamamoto Article.............................................444
II. Obviousness.........................................................444
A. Legal Standard for Obviousness Under 35 U.S.C. § 103..............444
B. Claims 1-4 of the '052 Patent Are Not Obvious in Light of the Prior Art.....................................................445
CONCLUSION.................................................................445
INTRODUCTION
This patent infringement action presents a challenge to the validity of a patent covering the formulation of Argatroban Injection, a lifesaving drug for the treatment of heparin-induced thrombocytopenia (“HIT”). Patients who develop HIT after receiving the well-known blood thinner heparin may suffer a cascade of blood clots, amputations, and death if left untreated. Prior to the Food and Drug Administration’s (“FDA”) approval of Argatroban Injection in 2000, doctors had few options for HIT patients other than to cease heparin and hope that clotting did not occur.
Generic drug manufacturers Barr Laboratories, Inc. and Pliva-Hrvatska d.o.o., a wholly owned subsidiary of Barr Laboratories, Inc., (collectively “the defendants” or “Barr”) now seek to market a generic copy of the FDA-approved product known as Argatroban Injection pursuant to Abbreviated New Drug Application (“ANDA”) No. 79-238, which was filed by Barr Laboratories, Inc., as agent for Pliva. Mitsubishi Chemical Corporation (“MCC”), Mitsubishi Tanabe Pharma Corporation, Encysive Pharmaceuticals Inc., SmithKline Beech-man PLC, SmithKline Beecham Corporation, doing business as GlaxoSmithKline, and Glaxo Group Limited (collectively “the plaintiffs” or “Mitsubishi”) have brought the current action against Barr. MCC is the assignee of United States Patent No. 5,214,052, entitled “Method of Dissolving Arginineamides and Pharmaceutical Compositions Containing Them” (“the '052 patent”). Encysive is the holder of the approved New Drug Application (“NDA”) for Argatroban Injection.
Argatroban (also known as argipidine), the active ingredient in Argatroban Injection, was known years before the development of a marketable formulation. The argatroban molecule, however, is poorly soluble in water alone, and pharmaceutical formulators tried for years without success to develop an injectible argatroban product at a concentration sufficient to treat effectively severely ill patients who were under fluid restrictions. The problem of determining an acceptable formulation of an injectible argatroban product remained unresolved until Mitsubishi employees discovered that a co-solvent system comprising ethanol, water, and sorbitol would greatly enhance the solubility of argatroban. Dr. Timothy Kogan, who had attempted to develop a high-concentration argatroban product for 7 years, found this result extremely surprising.
The '052 patent claims a method for dissolving argabtroban in ethanol, water, and a saccharide, and a pharmaceutical composition for injection comprising argatroban along with ethanol, water, and a saccharide. The plaintiffs Argatroban Injection product is covered by the '052 patent.
The '052 patent was issued on May 25, 1993 and expires on June 30, 2014 as a result of a patent term extension pursuant to 35 U.S.C. § 156. Barr filed ANDA No. 79-238 with the FDA pursuant to the Hatch-Waxman Act, 21 U.S.C. § 355(j), seeking to market a generic copy of Argatroban Injection prior to the expiration of the '052 patent.
On December 26, 2007, the plaintiffs filed this suit under the Hatch-Waxman Act, alleging that Barr’s making, using, selling, or importing its proposed argatroban product would infringe, induce infringement of, or contribute to the infringement of the '052 patent. All parties in this case have stipulated that Barr’s argatroban product described in ANDA No. 79-238 is either a direct infringement of claims 1-4 of the '052 patent pursuant to 35 U.S.C. § 271(a) or an indirect infringement of the '052 patent claims 1-4 pursuant to 35 U.S.C. § 271(b) or (c), unless the '052 patent is found to be invalid.
Barr alleges that claims 1-4 of the '052 patent are invalid because they are anticipated pursuant to 35 U.S.C. § 102 or obvious under 35 U.S.C. § 103. The '052 patent was issued as a continuation of a patent application that the plaintiffs represent without opposition was filed on July 28, 1988. Thus, for purposes of analyzing the prior art that could disqualify the patent for anticipation or obviousness, the Court should look to prior art that existed one year before that date, namely before July 28, 1987.
Barr’s anticipation defense rests entirely on one prior art reference, an article written by Mitsubishi employee Toshihiro Yamamoto and his co-authors publishing the results of a preclinical study of the effect of argatroban on rats. See Toshihiro Yamamoto, et al., Effect of Argipidine (MD-805) on Cerebral Microcirculation After Cerebral Ischemic Rats, 14 (Supp.5) Japanese Pharmacology & Therapeutics 25 (1986). During the study, the investigators compared the blood flow after induced stroke in the brains of rats that had received an intraperitoneal injection of a highly acidic argipidine solution with the -blood flow in the brain of rats after stroke that had not received such an injection. In one sentence, whose translation is hotly disputed by the parties, Yamamoto states that a solution was prepared containing argipidine, ethanol, sorbitol, water, and hydrochloric acid. Barr alleges that, under its various translations, this sentence discloses the '052 patent’s invention. Mitsubishi offers a competing translation, and disputes Barr’s contention that the Yamamoto article would enable one skilled in the art to create the '052 invention.
Barr also argues that the claims of the '052 patent would have been obvious to one skilled in the art in 1987, based upon references in the literature other than the Yamamoto article. Mitsubishi responds that the invention was not obvious, and that the commercial success of Argatroban Injection, long felt need, the failure of others to discover the invention, and other objective factors point to nonobviousness.
The Court conducted a non-jury trial from January 26, 2010 through February 10, 2010. The Court makes now the following findings of fact and reaches the following conclusions of law.
LEGAL BACKGROUND AND FINDINGS OF FACT
1. To the extent that any of the findings of fact below is a conclusion of law, it is hereby adopted as a conclusion of law.
2. This case arises under the patent laws of the United States and the Drug Price Competition and Patent Term Restoration Act of 1984, Publ. L. No. 98-417, 98 Stat. 1585, as amended (“the Hatch-Wax-man Act”). The defendants filed an ANDA with the FDA, seeking to market a generic copy of the plaintiffs’ FDA-approved product known as Argatroban Injection. The defendants concede that their proposed generic product is covered by and would infringe all four claims of the '052 patent. Having conceded infringement, the defendants bear the burden of proving, by clear and convincing evidence, that the '052 patent is invalid. Whether the defendants have met their burden is the only issue before this Court.
I. Jurisdiction
3. The Court has subject matter jurisdiction over this case pursuant to 28 U.S.C. §§ 1331 and 1338(a). (Joint PreTrial Order (“JPTO”) ¶ 2.)
II. Relevant Statutory and Regulatory Provisions
4. To market a drug in interstate commerce, a drug manufacturer must obtain approval from the United States Food and Drug Administration (“FDA”) through the submission of an NDA. The NDA includes the results of extensive testing to determine that a drug product is both safe and effective. 21 U.S.C. § 355(b).
5. The filing of an NDA represents an enormous expenditure of time, money, and human resources, particularly when the drug product is a pioneering one, requiring years of research involving animal and human studies, including clinical trials.
6. The pharmaceutical at issue here, marketed under the name Argatroban Injection, is just such a pioneering drug product. Its active ingredient is argatroban.
7. As discussed below, Argatroban Injection is used for the prophylaxis or treatment of thrombosis in patients with HIT, and for use in patients with or at risk for HIT undergoing percutaneous coronary intervention (“PCI”).
8. An ANDA permits an applicant seeking approval of a generic version of a pioneering drug to avoid the costly and time-consuming studies required for the pioneer to demonstrate safety and effectiveness. Instead, the ANDA filer may avoid those requirements through the ANDA process, so long as the ANDA filer is able to establish that its generic version of the drug is “bioequivalent” to the drug for which approval has already been obtained. 21 U.S.C. § 355(j).
III. The Presumption of Validity and the Standard of Proof
9. By express Congressional declaration, patents are presumed valid. Each patent claim is independently presumed valid. 35 U.S.C. § 282.
10. The burden of proving invalidity rests on the patent challenger, who must do so by clear and convincing evidence. Id.; Schumer v. Lab. Computer Sys., Inc., 308 F.3d 1304, 1315 (Fed.Cir. 2002).
11. “The ‘clear and convincing’ standard of proof of facts is an intermediate standard which lies somewhere between ‘beyond a reasonable doubt’ and a ‘preponderance of the evidence’ ” and 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 Inc. v. Kason Indus., Inc., 849 F.2d 1461, 1463 (Fed.Cir.1988) (alteration in original) (internal quotation marks omitted).
12. The burden is “constant” and “remains throughout the suit on the challenger” and “does not shift at any time to the patent owner.” TP Labs., Inc. v. Prof'l Positioners, Inc., 724 F.2d 965, 971 (Fed. Cir.1984).
IV. The Parties
13. Mitsubishi Chemical Corporation (“MCC”) is a Japanese corporation having its corporate headquarters and principal place of business in Tokyo, Japan. (JPTO ¶ 17.) MCC is engaged in the business of employing the science of chemistry to create, develop, and improve products.
14. Mitsubishi Tanabe Pharma Corporation (“MTPC”) is a Japanese corporation having its corporate headquarters and principal place of business in Osaka, Japan. (JPTO ¶ 18.) MTPC is a pharmaceutical company engaged in the business of the development, manufacture, and marketing of a broad spectrum of pharmaceutical products. (MCC and MTPC will sometimes be referred to collectively as “Mitsubishi.”)
15. Encysive Pharmaceuticals Inc. (“Encysive”), formerly known as Texas Biotechnology Corporation (“TBC”), is a Delaware corporation having its corporate headquarters and principal place of business in New York, New York. (JPTO ¶ 19.) Encysive is also the holder of the approved NDA for Argatroban Injection. (Pis.’ Ex. (“PX”) 31; PX 116; PX 119.)
16. Glaxo Group Limited (“GGL”) is a company organized and existing under the laws of England and Wales having its registered office in Greenford, England. (JPTO ¶ 20.)
17. SmithKline Beecham pic e/k/a SmithKline Beecham Limited (“SKB Ltd.”) is a company organized and existing under the laws of England and Wales having its registered office in Brentford, England. (JPTO ¶ 21.)
18. SmithKline Beecham Corporation c/k/a GSK LLC (“GSK LLC”) is a Pennsylvania corporation having a principal place of business at One Franklin Plaza, Philadelphia, Pennsylvania. (JPTO ¶ 22.) GSK LLC sells Argatroban Injection in the United States pursuant to the FDA’s approval of NDA No. 20-883 on June 30, 2000.
19. Defendant Barr Laboratories, Inc. (“Barr”) is a Delaware corporation with corporate headquarters in Pomona, New York. (JPTO ¶ 23.) Barr is in the business of manufacturing and marketing generic pharmaceuticals. On or about December 23, 2008, Barr was acquired by Teva Pharmaceuticals Industries Ltd. (JPTO ¶ 25.)
20. Defendant Pliva-Hrvatska d.o.o. (“Pliva”) is a European generic pharmaceutical company with a principal place of business in Zagreb, Croatia. Pliva is a wholly-owned subsidiary of Defendant Barr. (JPTO ¶ 24.)
21. The patent at issue in this suit is United States Patent No. 5,214,052, entitled “Method for Dissolving Arginineamides and Pharmaceutical Compositions Containing Them,” which was issued on May 25,1993, to inventors Kunihiko Ofuchi and Tatsuo Nomura, and assigned to the plaintiff MCC (then known as Mitsubishi Kasei Corporation). (Defs.’ Ex. (“DX”) 1; JPTO ¶ 37.)
22. MCC is the assignee of record of the '052 patent, which expires on June 30, 2014, as a result of a patent term extension MCC received pursuant to 35 U.S.C. § 156. (JPTO ¶¶ 37-38.)
23. Barr filed ANDA No. 79-238 with the FDA under 21 U.S.C. § 355(j), seeking approval to market generic Argatroban Injection prior to the expiration of the '052 patent. (JPTO ¶ 32.)
24. On December 26, 2007, the plaintiffs filed a complaint in this Court, alleging that the defendants’ making, using, selling, or importing its proposed argatroban product under ANDA No. 79-238 would infringe, induce infringement of, or contribute to the infringement of the '052 patent.
25. The plaintiffs filed the First Amended Complaint on February 21, 2008 and the Second Amended Complaint on March 25, 2008 alleging that the defendants’ making, using, selling, and importing its proposed argatroban product under ANDA No. 79-238 would infringe, induce infringement, or contribute to the infringement of the '052 patent.
26. On April 24, 2009 the parties stipulated that the commercial manufacture, use, importation, sale, or offer for sale within the United States of the pharmaceutical product described in ANDA No. 79-238 would be a direct infringement under 35 U.S.C. § 271(a) or an indirect infringement under 35 U.S.C. § 271(b) or (c) of claims 1-4 of the '052 patent, provided that such claims are not found to be invalid. (JPTO ¶ 3.)
27. Therefore, the only issue before the Court is the defendants’ allegation that claims 1-4 of the '052 patent are invalid. (JPTO ¶ 4).
V. Background of the '052 Patent
28. The '052 patent sought to solve the following problem, as stated in the patent specification:
Arginineamides are known to have anti-thrombotic activities and are expected to be used as anti-thrombotic agents.... However, it is very difficult to obtain a solution containing any of [the] arginineamides at high concentration due to poor solubility in water and therefore any of these compounds [are] not suitable for applying as the injection containing it at high concentration.
An object of the invention is to provide a method for improving the solubilities of arginineamides so as to apply as the injections containing them at high concentration.
(DX 1 at Col. 1, 11. 17-28.) In the terminology of the '052 patent, “high concentration” means a broad range of concentrations above the solubility of the arginineamide in water. (DX 1 at Col. 4, 11. 22-27.)
29. The claims of the '052 patent are directed to improvements in solubility of argatroban. Argatroban was discovered by at least 1979, and was patented under United States Patent No. 4,258,192 (“the '192 patent”) in 1981. (DX 51.) Although argatroban was considered to have promise as an inhibitor of thrombosis, that promise never came to fruition in the United States during the term of the '192 patent, which expired in 1995. Despite the fact that MCC licensed the argatroban compound to Genentech for pharmaceutical development in 1987 (DX 100), it was not until the technology of the '052 patent permitted the preparation of high concentration pharmaceutical compositions of argatroban for injection that a commercially viable product, namely Argatroban Injection, was approved by the FDA in 2000. (JPTO ¶ 28.)
30. Because argatroban is poorly water-soluble, the concentration of argatroban that could be given to patients prior to the discovery of the '052 technology was severely limited. The maximum solubility of argatroban in water is about 1.0 mg/mL. Therefore the actual concentration of a pharmaceutical composition of argatroban in a water-based system would be substantially less than 1.0 mg/mL if that compound is to remain stable in solution and not precipitate before it gets to the patient. (See generally Tr. 267:24-268:25.) Prior to the invention of the '052 technology, both MCC and Daiichi Pharma were trying to make a high concentration argatroban solution. (Tr. 1314:12-24.)
31. Surprisingly, the inventors of the '052 patent found that when argatroban was dissolved in combinations of ethanol, water, and sorbitol (or other saccharide), its solubility increased substantially over its solubility in water alone or in mixtures of water with sorbitol. (Compare DX 1, Figs. 3 & 4, with DX 1, Fig. 2.) This result was directly contrary to the expectations of those skilled in the art. Barr’s expert Dr. Thomas E. Needham, retired professor of pharmaceutics from the University of Rhode Island College of Pharmacy, admitted that argatroban is the only exception to the general principle that the solubility of zwitterions, molecules with both a positive and negative charge, is reduced by the introduction of ethanol. (Tr. 54:14-18, 219:7-220:11; see also PX 252.)
32. Moreover, as Dr. Needham acknowledged, the introduction of a material that was less polar than water, or lacking a plus and minus part of the molecule, such as sorbitol or ethanol, would be expected to lower the solubility of a zwitterion such as argatroban, and Figures 1 and 2 of the '052 patent confirmed that expectation. (DX 1, Figs. 1 & 2; Tr. 66:12-15, 294:1-296:6.) Therefore the fact that the addition of ethanol and sorbitol (or other saccharide) drastically increased the solubility of argatroban in the aqueous mixture was contrary to the expectations of those skilled in the art.
33.The '052 patent has four claims: claims 1 and 2 claim a method of dissolving argatroban; claims 3 and 4 claim a pharmaceutical composition for injection containing argatroban. The invalidity of all four claims is at issue in this case. Indeed, because it is undisputed that the defendants’ product infringes all four claims of the '052 patent, the defendants must establish by clear and convincing evidence that each of the four claims in the '052 patent is invalid.
34.Claim 1 of the '052 patent claims: “A method for dissolving an arginineamide comprising: dissolving N2-arylsulfonyl-Largininamide represented by formula (I):
and/or its salt in a solvent containing ethanol, water and a saccharide.” (DX 1 at Col. 6,11. 23-39.)
35.The parties agree that the compound represented by formula (I) in the claim is known by the names “argipidine” and “argatroban.” Accordingly, claim 1 may be restated as:
Claim 1: A method for dissolving an arginineamide, comprising: dissolving [argatroban] and/or its salt in a solvent containing ethanol, water and a saccharide.
36. Claim 2 is dependent on claim 1, and adds the limitation that “the saccahride is at least one member selected from the group consisting of sorbitol, glucose, glycerin and sucrose.” (DX 1 at Col. 6, 11. 41-44.)
37. Claim 3 of the '052 patent recites: “A pharmaceutical composition for injection, comprising: N2-arylsulfonyl-L-argininamide represented by formula (I):
and/or its salt together with ethanol, water and a saccharide.” (DX 1 at Col. 6, 11. 45-53.)
38. As noted, the parties agree that the compound represented by formula (I) is known by the names “argipidine” and “argatroban.”
39. Accordingly, claim 3 can be restated as:
Claim 3: A pharmaceutical composition for injection, comprising: [argatroban] and/or its salt together with ethanol, water and a saccharide.
40. Claim 4 is dependent on claim 3, and adds the limitation that “the saccharide is at least one member selected from the group consisting of sorbitol, glucose, glycerin and sucrose.” (DX 1 at Col. 4, 11. 4-7.)
41. The saccharide used in the Argatroban Injection product is sorbitol. (DX 568 at 1.)
A. The '052 Patent Technology Permits Injection of Argatroban With Less Fluid Volume
42. Argatroban Injection is supplied at the “high concentration” of 100 mg/mL. The benefits from that aspect of the invention are described below.
43. More important to the patients, however, is the fact that the '052 patent technology allows argatroban to be injected into the patient at the high concentration of 1.0 mg/mL, twice the concentration of Novastan, a prior Japanese 0.5 mg/mL formulation where the solvent was water containing a small amount of sorbitol as a tonicity modifier. (DX 376.) This allows the physician using argatroban to manage the fluid load on the patient much more effectively than could be the case with aqueous argatroban at a 0.5 mg/mL concentration.
44. In determining whether and how to launch argatroban as a product, both Dr. John Plachetka, the head of clinical development programs at TBC from 1993 to 1995, and Dr. Richard Dixon, head of research at TBC from 1990 through 2008, focused on the importance of the clinical benefit obtained by using a higher concentration to minimize fluid load on the patient. (PX 199 at 29:21-23; see, e.g., PX 12). Dr. Plachetka pointed out his deep interest in the '052 technology: “this formulation could help us overcome some of our potential problems with volume issues in the clinic.” (PX 12). Dr. Plachetka explained that this meant that their issues involved the volume load on the patient. (PX 200 at 210:22-211:15.) Dr. Plachetka pointed out to TBC President David McWilliams that the more concentrated formula using the '052 technology “will allow us to reduce the volume load given to patients versus the old formulation by at least one-half....” (PX 9 at GNE-ARG 624; see PX 200 at 212:1-15, 214:18-216-21, 218:24-221:21 (Dr. Plachetka’s deposition); see also PX 199 at 59:2-59:11, 74:23-75:18, 96:16-97:14, 114:13-115:7 (Dr. Dixon’s deposition).)
45. The importance of fluid volume control in HIT patients is typical of the importance of fluid volume control in a variety of different indications. The benefits of the high concentration formulation are clinically significant in the treatment of HIT patients. (Tr. 827:12-17.) If a 0.5 mg/mL formulation were available in the United States along with the Argatroban Injection 1.0 mg/mL formulation, clinicians would not prescribe the 0.5 mg/mL formulation. (Tr. 828:3-14.) Even Dr. Charles Eby, the defendants’ medical expert and associate professor at the Washington University School of Medicine in St. Louis, testified to the superiority of the high concentration formulation of Argatroban Injection, conceding that “if you have got the choice of having a drug that’s in a smaller volume and it makes no difference about the activity or the performance of that drug, sure, take it.” (Tr. 479:20-23; see also Tr. 352:9-10, 479:10-14, 834:11-19, 399:19-24, 441:9-15.)
46. A significant number of HIT patients are subject to fluid restrictions. Dr. Lewis, a principal investigator on the clinical trials that led to the approval of Argatroban Injection in the United States and an expert for the plaintiffs, testified that “the heart failure patients, the renal failure patients, the dialysis patients all are very obvious groups that require fluid restrictions. The pulmonary patients are another obvious group. And, you know, if I were to put a number, certainly that’s over half the patients.” (Tr. 834:14-19.) Dr. Eby conceded that there are at least some HIT patients requiring careful fluid management, who therefore benefit from the high concentration of Argatroban Injection. (See Tr. 441:12-15 (“It’s like an iceberg. There’s a tip of the iceberg of patients who are indeed — where fluid management is critical. I think we’re arguing over the size of the iceberg and how much of it’s above the water.”))
47. As Dr. Lewis testified: “The '052 patent and the [claimed] formulation provides a huge advantage to these patients. We’re able to deliver the compound through a pharmaceutical agent and an amount of fluid that our patients can tolerate and we can affect the outcome of that horrific course of disease.” (Tr. 760:4-8; see also Tr. 826:12-828:6, 837:7-840:13.)
48. The ability to use small amounts of ethanol and sorbitol to hold 1.0 mg/mL of argatroban in solution as a pharmaceutical composition for injection, contrary to the expectation of those skilled in the art, is a great boon to patients, and a great advantage over the 0.5 mg/mL product.
B. The Ability to Supply Argatroban in 2.5 ml 100 mg/mL Vials Provides Substantial Advantages
49. Other significant advantages achieved by use of the high concentration Argatroban Injection include the benefits of storage, dilution, and other benefits appreciated by pharmacists. For example, prior to discovery of the availability of the '052 technology, TBC was faced with the choice of using a 0.5 mg/mL solution comprising 10 mg in 20 mL ampoules. These were highly impractical. For the indications under consideration at TBC when it licensed argatroban, a “typical patient might require 2,000 milliliters of fluid in a day of the [a]rgatroban solution, and that would require breaking a hundred of these glass amp[o]ules, filtering the contents, [and] putting it into an IV bag under sterile conditions, which would be quite difficult to do for most hospitals.” (PX 200 at 48:18-23; see also PX 200 at 50:17-51:6.) Dr. Sophia Pasedis, an expert pharmacist with over twenty years of experience as a hospital pharmacy director, testified that breaking the 20 ml/0.5 mg/mL ampules of argatroban to administer a day’s dosage for an average-sized patient would be “an immense burden” on a hospital pharmacy. (Tr. 1331:16-19, 1345:8.) Dr. Plachetka testified at his deposition: “Well, that was a nonstarter from day one. I mean, that was commercially a killer. That product in 20 milliliter amp[o]ules for any of the indications that Texas considered would be a nonstarter.” (PX 200 at 70:19-22; see also PX 200 at 49:16-51:6.)
50. TBC’s other alternative was to fill 500 mL glass bottles with 0.5 mg/mL argatroban solution. (Cf Tr. 654:7-9 (0.5 mg/mL argatroban solution was available in 500 mL glass bottles).) However, the larger glass bottles also had very significant drawbacks in terms of higher storage and shipping costs, as compared to the 2.5 mL vials in which Argatroban Injection is supplied. (See PX 200 at 68:17-69:3.)
51. When the members of TBC found out about the fact that the '052 technology allowed the provision of 250 mg of argatroban in only a 2.5 mL container, “it was almost beyond belief.... It was startling and completely unexpected from [Dr. Plachetcka’s] perspective.” (PX 200 at 62:6-10; see also PX 200 at 74:7-12.)
52. The '052 technology made it possible to make highly concentrated, highly stable solutions of argatroban, which meant that the Argatroban Injection could be packaged and stored at very high concentrations and very low volumes, and simply diluted to the desired dosage just prior to being injected into the patient. (DX 1 at Col. 4, 11. 42-51.) The benefits of that aspect of the invention are significant, to patients, physicians, pharmacists, hospitals and to the manufacturer of Argatroban Injection. Argatroban Injection can be provided at a concentration of 100 mg/mL in a 2.5 mL vial, which can be simply and accurately diluted with the diluent of choice (e.g., dextrose solution, saline or Ringers solution) by putting it into a 250 mL IV bag, and filling the bag with diluent. The ability to supply it in a small vial avoids the costs of large bottles, shipping charges, the necessity of breaking multitudes of ampoules, and is not a burden on space in hospital pharmacies, where space is at a premium. (Tr. 1334:10-13,1338:23-1345:8.) It also relieves pharmacists from having to use lengthy filtration steps to remove any glass shards that would come from the required breaking of the ampoules. (Tr. 1340:22-1342:19.)
53. This increase in solubility of argatroban in ethanol and a saccharide was surprising to everyone, including the defendants’ expert Dr. Needham. (Tr. 311:3-5.)
C. Clinical Background Relevant to the '052 Patent
1. HIT
54. Argatroban Injection is an anticoagulant indicated for prophylaxis or treatment of thrombosis in patients with heparin-induced thrombocytopenia, and for use in patients with or at risk for heparin-induced thrombocytopenia undergoing PCI. (DX 568 at 10.)
55. According to Dr. Lewis, heparin is “one of the most commonly prescribed drugs in the hospital setting at this point in time, and has been for decades.” (Tr. 758:3-5.) As acknowledged by Dr. Eby, heparin is administered to many hospitalized patients because many of them are at risk of forming blood clots, for example, patients who have sustained serious trauma, either accidentally or postoperatively, are at high risk for forming blood clots, especially in the veins in their legs. (Tr. 371:7-14.) In a significant number of patients treated with heparin, however, it triggers an immune response called HIT, which, paradoxically, promotes blood clotting. (Tr. 758:2-11.)
56. Any patient exposed to heparin is at risk for developing HIT. (Tr. 372:13-14.) HIT is considered to be the most potent hypercoagulable state in medicine, and is one of the most serious and potentially catastrophic blood-related complications of drug therapy. (Tr. 758:11-13, 758:24-759:4.) The blood clots associated with HIT can occur anywhere in the body, leading to the possibility of stroke, heart attack, and death of the affected portion of the bowel, and clots can also occur in the adrenal glands, kidneys and limbs. (Tr. 774:4-22.) HIT is the most serious disease process that Dr. Lewis has encountered in his years of clinical experience. (Tr. 774:24-775:1.)
57. The marked increase in clotting activity caused by HIT results in clinically relevant blood clots in approximately 50% of untreated HIT patients. (Tr. 773:2-9.) About 10-50% of untreated HIT patients require amputation (Tr. 773:21-774:1) and about 30% die. (Tr. 773:15-17.)
58. HIT patients typically have multiple medical or system failures that result from HIT and underlying disease. (Tr. 827:12-16.) It is not unusual for these patients to require intravenous medications for one or more of the following: support of blood pressure, treatment for a failing heart, or antibiotics for concomitant medical problems. (Tr. 790:12-791:2.) Each of these therapies adds fluid volume to the patient’s daily requirement in a situation where clinicians are trying to restrict fluid intake. (See Tr. 790:12-791:2.) Dr. Eby acknowledged that if a patient is on fluid restriction, the only way to implement this is by restricting the fluids administered to the patient. (Tr. 487:22-25.) As explained by Dr. Lewis, in such patients it is recommended that fluids be restricted to 1500 to 2000 mL per day, depending on the patient’s size and condition. (Tr. 762:22-24.) “That includes all fluids, whether it be intravenous or oral intake,” and “that can be very challenging.” (Tr. 762:24-763:1.) Fluid load was a significant concern in the development and commercialization of Argatroban Injection. (PX 9; PX 13; PX 199 at 74-75, 97; PX 200 at 210-16, 219-21.)
59. According to Dr. Plachetka, HIT presented a “very significant unmet medical need.” (PX 200 at 18-19, 41; see also PX 50 at 1839.)
60. In the early 1990s, the primary treatment for HIT was limited to discontinuation of heparin. This was not a successful strategy, because many patients require anticoagulation for underlying medical conditions, and approximately 40-50% of untreated HIT patients suffered a thrombotic event after heparin was discontinued. (Tr. 776:1-777:12 (discussing PX 50 at 1839).) At that time, the only treatment for a HIT patient with a thrombosis (known as heparin-induced thrombocytopenia with thrombosis syndrome, or “HITTS”) was “surgical removal of the clot with an attempt to rapidly anticoagulate the patient with an oral drug, which usually failed.” (PX 200 at 41:14-17.) “The choices a physician had when this occurred were extremely dire ... a good physician, could try and extract a clot and hope that it wouldn’t reoccur. But more [often] than not, it resulted in amputation and then slowly spun down to death.” (PX 200 at 43:3-9.)
61. Other anticoagulant therapies available at the time, including warfarin, ancrod, low-molecular weight heparin, danaproid, and lepirudin, had disadvantages and were generally unsuccessful. (PX 50 at 1839; see generally Tr. 775-785.) For example, physicians treating HIT patients were so “very desperate” that, ancrod, an unapproved drug derived from pit viper venom (of which the entire United States supply was locked in a single refrigerator in Connecticut), was used through the FDA’s compassionate use mechanism. (Tr. 781:3-4; see generally Tr. 779-81.)
62. In a 1996 meeting with TBC representatives, Stephen Fredd, M.D., Director of FDA’s Division of Gastrointestinal and Coagulation Drug Products, characterized HIT and HITTS patients “as a class of subjects with a life-threatening condition for which there is no available therapy.” (PX 199 at 262:10-19 (discussing PX 23 at ENCY 10511); see PX 42 at ENCY 246682.) According to Dr. Lewis, “there was no existing therapy and ... this was a catastrophic problem....” (Tr. 804:19-20.) Argatroban Injection “satisfied a very long-felt need and did a very nice job of satisfying that need.” (Tr. 787:1-2.)
63. The patient population receiving Argatroban Injection for HIT is generally a population of very sick people who, beyond suffering from HIT, present with one or more indications giving rise to their need for heparin anticoagulation in the first place, including cardiac-related diagnoses, cardiac surgery, cardiac interventional procedure(s), other surgery, or prevention or treatment of deep vein thrombosis. (Tr. 827:12-14.) Additionally, because many patients receiving Argatroban Injection have other serious problems such as cardiovascular surgery, congestive heart failure, or kidney impairment, they require restriction of fluid loads. (Tr. 793:3-9.) In fact, there is a correlation between the conditions that require a higher dose of Argatroban Injection and those that require fluid restrictions due to the large background of heparin treatment by the time these patients develop HIT. (Tr. 851:9-19.) By the time such patients develop HIT, they have likely lost some cardiac function and, as a consequence, are in advanced stages of heart failure or decline in kidney function or pulmonary function. (Tr. 851:19-24.) Accordingly, the HIT subgroup is an extremely sick group of patients. (Tr. 851:24-852:1.)
2. Treatment of HIT
64. Two direct thrombin inhibitors (“DTIs”) are presently approved for use in the United States for treating HIT, namely, Argatroban Injection (first approved in 2000) and Refludan® (first approved in 1998). (Tr. 375:15-19, 376:11-16, 382:5-6.)
65. As its FDA-approved label shows, Argatroban Injection is indicated as an anticoagulant for prophylaxis or treatment of thrombosis in patients with HIT and HITTS, and as an anticoagulant in patients with or at risk for HIT or HITTS undergoing PCI. (Tr. 376:11-16; DX 568 at 10.)
66. Refludan® (lepirudin) is indicated for anticoagulation in patients with HIT and associated thromboembolic disease in order to prevent further thromboembolic complications. (DX 482.) Refludan® does not have approval for use with HIT patients undergoing PCI. (DX 482 at 2; Tr. 848:10-11.)
67. Angiomax® (bivalirudin) is a DTI approved in 2000 for use in the United States in patients with or at risk for HIT who are undergoing PCI, but Angiomax® is not approved for use for treating HIT in other patients. (DX 603 at B-ARG-112873.)
68. Dr. Lewis testified that Argatroban Injection has clear clinical advantages over Refludan®, including reduced fluid administration. (Tr. 829:13-18 (discussing DX 758).) Barr’s expert Dr. Eby testified that the clinical advantages of Argatroban Injection over Refludan® are due to the active ingredient argatroban, but also acknowledged that reduced fluid load is an advantage for Argatroban Injection. (■Compare Tr. 384:7-15, with Tr. 384:2-4, and 386: 18-19. See generally Tr. 383-86.) The high concentration at which Argatroban Injection can be administered to HIT patients results in a clinically significant two-thirds reduction in infusion volume as compared to Refludan®. (Tr. 828:15-829:18 (discussing DX 758); see also Tr. 386:18-19 (Dr. Eby noting that “fluid volume would favor argatroban [over Refludan®]”).)
69. Unlike Argatroban Injection, Refludan® and Angiomax® are immunogenic compounds, and carry the risk of a secondary anaphylactic response. (Tr. 785:3-10, Tr. 383:15-23.) Argatroban Injection also carries a lower (and shorter) risk of bleeding compared to Refludan® because the anticoagulant effect of Argatroban Injection has a much shorter half-life. (Tr. 383:24-384:1.) Argatroban is preferable in renally-impaired patients. (Tr. 860:2-11; see generally Tr. 383:3-384:1 (discussing DX 758).)
70. Argatroban Injection quickly became the most frequently prescribed treatment for HIT, even though Refludan® was on the market as a treatment for HIT prior to approval of Argatroban Injection. (Tr. 663:8-21.)
71. Argatroban Injection, prescribed in terms of mcg/kg/min (micrograms of drug per kilogram of patient weight per minute) at the approved concentration of 1.0 mg/mL would require double the obligatory infusion volume if administered at a 0.5 mg/mL concentration. (Tr. 822:11-823:9 (discussing PX 175).)
72. “The recommended initial dose of Argatroban for adult patients without hepatic impairment is 2 mcg/kg/min, administered as a continuous infusion.” (DX 568 at 19; see Tr. 378:10-12 (discussing DX 568).) Dosing requirements can, however, vary substantially both with the underlying medical condition and with concomitant medical therapies. {See Tr. 825:5 (noting that “[e]ach patient is different.”).) In cases of severe liver disease, Argatroban Injection,may be started at a lower dose, while medical HIT patients on circulatory assist devices may require dosing “in the range of at least 10 and oftentimes 25 mies per kilo per minute” on a 24-hour basis. (Tr. 821:5-13, 824:12-826:10; see also PX 175.)
73. Angioplasty patients are maintained on even higher doses of Argatroban Injection and require a 250-350 meg/kg bolus and maintenance infusions of 25-30 mcg/kg/min. {See generally Tr. 814:3-817:10.) Angioplasty procedures in HIT patients can last up to seven hours. (Tr. 817:15-18.) HIT patients undergoing a PCI procedure usually do not just stop receiving Argatroban Injection after the PCI procedure is completed; they continue in their treatment with Argatroban Injection at their resumed regular dose for HIT treatment “until the HIT process is controlled.” (Tr. 820:8, see generally Tr. 817:11-820:8.)
74. Dr. Lewis summarized the treatment of HIT with Argatroban Injection as follows: “The '052 patent and the [claimed] formulation provides a huge advantage to these patients. We’re able to deliver the compound through a pharmaceutical agent and an amount of fluid that our patients can tolerate and we can affect the outcome of that horrific course of disease.” (Tr. 760:4-8.)
D. Background on Pharmaceutical Development and Formulation in the Prior Art Period
75. Both the plaintiffs’ drug formulation expert, Dr. Stephen Byrn, and the defendants’ drug formulation expert, Dr. Thomas Needham, agreed in large part on the propositions set forth in this section.
76. Drug formulation is a difficult and frequently unpredictable science. “The bottom line is,” Dr. Needham testified, “you have to do the work, meaning go to the lab and do empirical testing of the solubility of the compound.” (Tr. 212:19-23.)
77. It takes months, and often years, of time and effort to develop a formulation of a drug compound that is suitable for use in patients. As Dr. Needham testified, “[fit’s always a struggle to get a formulation that’s stable, efficacious, and nontoxic.” (Tr. 269:7-8.)
78. The solubility of a given compound to be administered via intravenous injection is often very difficult to predict. (Tr. 212:12-213:3.)
79. In addition to solubility, the pH of the solution to be administered via intravenous injection is extremely important. The pH of human blood is approximately 7.4. (PX 107 at 155; Tr. 1131:16-1132:1.) It is important that injectables be as compatible with blood as possible, including with respect to pH. (PX 107 at 155; Tr. 255:3-8.) As Dr. Needham testified, “what you want to do when you have an injectable solution is, you want it to be as compatible with the body fluids in the cells as you can have it.” (Tr. 103:9-11.) As a consequence, a solution designed for injection should not be below pH 3.0 nor above pH 10.5. (PX 107 at 155; Tr. 1130:4-1132:12.)
80. Tonicity is also an important consideration for an injectable formulation. (Tr. 103:8-18.) Tonicity is a measure of a solution’s ability to exert osmotic pressure on a cell membrane. (Tr. 103:8-18, 1229:2 — 4, 1229:14-16.) Tonicity is affected by the nature of solute particles in an aqueous solution: in particular, whether they can cross the cell membrane freely or not. (Tr. 1408:14-1409:25.) An “isotonic” solution has the same tonicity as human blood. (Tr. 1228:13-19.) If an injection of improper tonicity is administered to a patient, blood cells can either burst or shrink to death. (Tr. 1229:5-23.)
81. The stability of an injectable is also extremely important to the formulator. (Tr. 267:22-23.) The stability of a given drug will vary depending upon the solution in which the drug is dissolved. (Tr. 268:19-21.) Additionally, the stability profile of a drug at different pHs is important to know when developing a formulation of that drug. (Tr. 268:22-25.) Dr. Needham took the position at his deposition that a composition prepared by Iida by dissolving argatroban in acid and then neutralizing it to a pH of 7 “required a good bit more work” because 4 mg/mL of aqueous argatroban at a pH of 7 would be unstable and would be expected to form a precipitate. (PX 174 at 140; see also Tr. 272:6-273:17.) As of 1987 or before there was no stability profile available for argatroban. (Tr. 269:1-3.)
82. An injectable must also be safe, i.e., non-toxic, to administer to patients. This is why a person of ordinary skill in the art would always want to make a dosage form “as simple as possible” and “as compatible with the body fluids in the cells as you can have it.” (Tr. 65:7-8,103:9-11.)
E. Development of Argatroban Injection
1. The Surprising Nature of the Discoveries Claimed in the '052 Patent
83. Scientists who have worked with argatroban agree that the molecule has “rather unusual solubility characteristics.” (PX 22 at ENCY 262046.)
84. Despite many attempts, Mitsubishi and Daiichi Pharma failed to develop an acceptable high concentration injectable formulation until Mitsubishi ultimately invented the ethanol-water-sorbitol formulation covered by the '052 patent. Even in the late 1980s and 1990s, Genentech, TBC and others, not knowing of the '052 technology, tried and failed to develop an injectable argatroban pharmaceutical composition with improved solubility. (See infra.)
85. Ethanol, water, and sorbitol, individually, can hardly dissolve argatroban (water and sorbitol to only about 1.0 mg/ mL, and ethanol to only about 4 mg/mL). Mitsubishi researchers eventually made the surprising discovery that adding sorbitol to ethanol-water mixtures yielded improved argatroban solubilities, some approaching 300 mg/mL, despite the fact that simply adding sorbitol to water generally decreased the solubility of argatroban in the mixture. (DX 1, Figs. 1-3.) The defendants’ expert Dr. Needham admitted at trial that these results were “surprising and unexpected,” and that it is unusual to achieve an increase in solubility of 300-fold, or even 100-fold. (Tr. 310:19-311:11.)
86. Mitsubishi researchers also discovered that similarly high solubilities of argatroban could be achieved in mixtures of ethanol, water, and certain saccharides other than sorbitol, including glucose, glycerin and sucrose. (DX 1, Fig. 4.)
87. The '052 patent, which discloses these results, was duly issued by the United States Patent and Trademark Office (“PTO”) on May 25,1993. (DX 1.)
2. Concurrent and Subsequent Failures of Others
88. In the late 1980s and early 1990s, Mitsubishi sought out partners to help develop and market an approved argatroban injectable for use in both Europe and the United States. As of that time, the maximum concentration argatroban solution was a 0.5 mg/mL formulation. (PX 8 at M 52330; PX 200 at 155-56.)
89. In the United States, Mitsubishi initially licensed its rights in argatroban to Genentech, Inc.; it was Genentech that filed the first Investigational New Drug Application (“IND”) for argatroban with the FDA. (DX 100; DX 111; DX 705.)
90. Genentech later sublicensed its development rights in the United States to TBC. (DX 146.)
91. In 1997, TBC began collaborating on argatroban with SmithKline Beecham (later GlaxoSmithKline, or “GSK”). (DX 308.)
92. All of Mitsubishi’s collaborators were intensely interested in developing a high concentration formulation of argatroban as a needed step in the development of argatroban as an approvable drug. For example, Genentech was looking into high concentration formulations of argatroban at least as early as 1992. (See PX 22 at ENCY 262047, 262060-64.) TBC, on the very day it signed its license agreement in 1993, made a presentation in which it noted the need to develop a high concentration formulation of argatroban. (See PX 19 at M 52153.)
93. Genentech experimented with dozens of formulations of argatroban. (PX 22 at ENCY 262047, 262060-64.) Yet all of those turned out to be either toxic, unstable, or only achieved argatroban solubilities of approximately 100 fold less than those disclosed in the '052 patent. (PX 22 at ENCY 262047, 262060-64.) As a result of these toxicity concerns, Genentech reported that it had “dropped [its] efforts to increase the solubility of Argatroban.” (PX 22 at ENCY 262060.)
94. TBC, in conjunction with researchers at the University of Iowa, also conducted extensive solubility studies of argatroban, using many different solvent systems. High solubilities of argatroban were only achieved in solutions that were not pharmaceutically acceptable for injection. (PX 22 at ENCY 262046-47, ENCY 262065-66.) When TBC learned that Mitsubishi had developed a high concentration formulation, it switched its development efforts to that formulation. (See, e.g., PX 8; PX 9; PX 12; PX 13.)
95. Timothy P. Kogan, Ph.D., then head of TBC’s chemistry department, ultimately concluded that “I am absolutely confident that it is not possible to formulate [argatroban] at 100 mg/mL outside the claims of U.S. 5,214,052” using generally-recognized-as-safe (“GRAS”) ingredients for intravenous injection. (PX 22 at ENCY 262047; see PX 199 at 254-57.) Dr. Kogan offered: “If anyone at SKB would like to investigate this further, I have bulk [argatroban] available, and that person can either come here to try, or we can transfer material to SKB for investigation.” (PX 22 at ENCY 262047.)
96. That all of this effort met with no success is evidence of the uniqueness of the ethanol-water-sorbitol formulation and the '052 patent. In short, as Dr. Kogan, the TBC (and former Genentech) researcher who was familiar with much of these data and failed efforts reported, the degree of solubility achieved by the water-ethanol-sorbitol formulation developed by Mitsubishi was an “extremely surprising result!” (PX 22 at ENCY 262047, Tr. 316:9-14.)
97. In 2000, upon receiving FDA approval, TBC and GSK began selling the 100 mg/mL Argatroban Injection that is still on the market today, using Mitsubishi’s patented ethanol-water-sorbitol formulation. (Tr. 663:4-5.)
F. The '052 Patent Claims
98. As explained above, the '052 patent has four claims, each of which is asserted in this case. The claims, with argatroban substituted for its recited structure, read as follows:
1. A method for dissolving an arginineamide, comprising: dissolving argatroban and/or its salt in a solvent containing ethanol, water and a saccharide.
2. The method according to claim 1, wherein the saccharide is at least one member selected from the group consisting of sorbitol, glucose, glycerin and sucrose.
3. pharmaceutical composition for injection, comprising: argatroban and/or its salt together with ethanol, water and a saccharide.
4. The composition according to claim 3, wherein the saccharide is at least one member selected from the group consisting of sorbitol, glucose, glycerin and sucrose.
(DX 1 at Col. 6,11. 23-67.)
99. With respect to both anticipation and obviousness arguments in this case, the parties agree that the prior art consists of information in the public domain prior to July 28,1987, the filing date of the '052 patent Japanese priority application.
YI. The Prior Art
A. Ordinary Skill in the Art
100. The parties agree that a person of ordinary skill in the art relevant to the '052 patent is a person who, at the time of the invention, had (1) a Ph.D. in a field related to pharmaceutical formulation and processing (such as physical chemistry, medicinal chemistry, or pharmaceutics) and at least one year of experience in the area of pharmaceutical formulation, (2) a similar master’s degree and at least two to three years experience in pharmaceutical formulation, or (3) a similar undergraduate degree and at least five years of experience in pharmaceutical formulation. (Tr. 61:15-25, 1075:23-1076:9; see also DX 700.)
101. The plaintiffs’ expert, Dr. Stephen R. Byrn, is personally familiar, through extensive experience, with the science and practice of pharmaceutical formulation, the relevant scope and content of the prior art, and the capabilities of a person of ordinary skill in the art.
102. Dr. Byrn currently holds the title of Charles B. Jordan Professor of Medicinal Chemistry at Purdue University. He is an elected member of the United States Pharmacopia Revision Committee, its Council of Experts, and its Dissolution Subcommittee. He has extensive knowledge of, and experience in, pharmaceutical formulation, chemistry, and solubility. (Tr. 1069:1-1075:15; see generally PX 100 (Dr. Byrn’s curriculum vitae).)
103. Dr. Byrn is qualified to express expert opinions on organic chemistry, medicinal chemistry, formulation science, and solubility. (Tr. 1075:16-22.)
104. As noted above, the defendants’ expert, Dr. Thomas E. Needham, is a retired professor of pharmaceutics from the Rhode Island College of Medicine. He is also qualified as an expert witness to offer opinions with respect to the relevant prior art for the '052 patent.
B. Relevance of the Chemical Structure of Argatroban
105. The chemical structure of argatroban was known by at least March 24, 1981, the issue date of the '192 patent, which claimed a variety of N2-arylsulfonyl-Larginineamides, including argatroban. (DX 51.)
106. The argatroban molecule is composed of three distinct chemical moieties, as depicted in the structure below:
(Tr. 1080:20-1081:42.)
107.A person of ordinary skill in the art at the relevant time would have noticed that one portion of the argatroban molecule is derived from the amino acid arginine, which has a three-carbon chain ending in a guanidino group that will be positively charged at physiological pH. (Tr. 1081:3-7, 1082:12-14.)
108.A person of ordinary skill in the art would have noticed that another portion of the argatroban molecule is derived from a piperidine carboxylic acid (specifically, a 4-methyl-2-piperidine carboxylic acid), and expected it to have a negative charge at physiological pH. (Tr. 1081:13— 19,1082:12-16.)
109. A person of ordinary skill in the art would have known that the third portion of the argatroban molecule contains an arylsulfonyl group (or more specifically, a tetrahydroquinolinesulfonyl group). (Tr. 1081:21-24.)
110. A zwitterion is an internally dissociated molecule with both positive and negative charges. (PX 252). Zwitterions are also referred to synonymously as “emphoteric electrolytes,” “ampholytes,” and “dipolar ions.” (Tr. 222:12-25, 223:11-17; see also PX 103 at 241-42.) Argatroban, containing a functional group with a positive charge and a functional group with a negative charge, is a zwitterion. (Tr. 1080:6-11; see also PX 103 at 241-42.) Argatroban was readily recognizable as a zwitterions to a person of ordinary skill in the art in 1987. (Tr. 216:10-14; see also Tr. 1078:25-1079:4.)
111. The Court credits Dr. Byrn’s testimony that if a person of ordinary skill were to have focused on any structural feature of argatroban, it would have been its zwitterionic character, and its zwitterionic character would have guided the formulator’s approach to addressing argatroban’s poor aqueous solubility. (Tr. 1078:17-24,1079:15-21.)
112. The evidence establishes that, based on argatroban’s structure and zwitterionic character, a person of ordinary skill in the art as of 1987 or before could not have predicted argatroban’s solubility in any particular solvent or solvent mixtures. But such a person would have had the following general expectations about argatroban’s solubility: (1) acid would increase its aqueous solubility, (2) ethanol would decrease its aqueous solubility, and (3) saccharides (including sorbitol) would decrease its aqueous solubility.
113. One property that was known to be shared by all zwitterions is that their solubility increases at both ends of the acid/base (pH) spectrum, regardless of their baseline solubility. (PX 105 at 1511, Fig. 1; PX 111 at 566, Fig. 2; Tr. 216:19-217:3.) This property results in a “u”shaped solubility curve when a zwitterion’s solubility is measured as a function of pH. (Tr. 216:1