Citations
- 956 F. Supp. 2d 429
Full opinion text
FINDINGS OF FACT AND CONCLUSIONS OF LAW
PAUL A. CROTTY, District Judge:
TABLE OF CONTENTS
FINDINGS OF FACT...........................................................434
I. THE PARTIES.........................................................434
II. II. RHEUMATOID ARTHRITIS AND ITS TREATMENT ..................434
A. Rheumatoid Arthritis................................................434
B. Treatment of Rheumatoid Arthritis....................................435
C. Methotrexate.......................................................435
D. Treatment of Rheumatoid Arthritis with Combination Therapy............436
E. Anti-Tumor Necrosis Factor Alpha Antibodies..........................437
III. KENNEDY’S DISCOVERIES............................................438
A. Kennedy’s Early Work with cA2.......................................438
B. Kennedy’s Open Label eA2 Study......................................440
C. Kennedy’s Anti-CD4 and Anti-TNFa Combination Study.................440
D. Kennedy’s Extension Study of cA2 in Humans...........................441
E. The Double-Blind Placebo-Controlled Trials of cA2......................442
IV. OTHER RESEARCH AND PUBLICATIONS..............................442
A. Schwieterman Discussion of Combination Treatment.....................442
B. The Rankin CDP571 Trial............................................444
C. Higgins Report on CDP571 and Methotrexate Combination Treatment.....444
V. THE T-14 STUDY......................................................445
VI. KENNEDY’S PATENTS.................................................448
A. The '248 Application.................................................448
B. The'766 Patent.....................................................449
C. The Claims of the'766 Patent.........................................449
D. The Specification of the '766 Patent....................................450
E. Prosecution History of the '766 Patent.................................454
F. The '004 Application.................................................461
G. The '631 Application.................................................463
H. The '442 Patent and Specification......................................470
I. The Claims of the '442 Patent.........................................470
VII. THE INSTANT DISPUTE...............................................472
A. Humira ............................................................472
B. Abbott’s Sublicenses to Kennedy’s Patents..............................472
CONCLUSIONS OF LAW.......................................................473
I. JURISDICTION........................................................473
II. OBVIOUSNESS-TYPE DOUBLE PATENTING...........................473
A. The Doctrine of Obviousness-Type Double Patenting......................473
B. Claim Construction....................................................474
C. Patentably Distinct Claims.............................................476
III. THE PERSON OF ORDINARY SKILL IN THE ART......................477
IV THE SIMILARITIES AND DIFFERENCES BETWEEN THE CLAIMS OF THE '766 AND '442 PATENTS .....................................478
A. Construction of Claims 8 through 14 of the '766 Patent...................478
B. Construction of Claims 1 through 7, 13, 14, and 17 through 20 of the '442 Patent.......................................................482
C. The Differences Between Claims 8 through 14 of the '766 Patent and Claims 1 and 2 of the '442 Patent....................................484
D. The Differences Between Claims 8 through 14 of the '766 Patent and Claims 3 through 7, and 13 of the '442 Patent.........................488
E. The Differences Between Claims 8 through 14 of the '766 Patent and Claims 14 and 17 through 20 of the '442 Patent........................491
CONCLUSION.......................... .....................................493
Plaintiffs-Counterclaim-Defendants Abbvie Inc. and Abbvie Biotechnology Limited (collectively, “Abbott”) bring this action against Defendant-Counterclaim-Plaintiff The Mathilda and Terence Kennedy Institute of Rheumatology Trust (“Kennedy”) for a declaratory judgment that each of claims 1 through 7, 13, 14, and 17 through 20 of Kennedy’s U.S. Patent No. 7,846,442 (the “'442 patent”) is invalid for obviousness-type double patenting over claims 8 through 14 of U.S. Patent No. 6,270,766 (the “'766 patent”). Kennedy denies that these claims of the '442 patent are invalid for obviousness-type double patenting and counterclaims for a declaratory judgment that each of these claims of the '442 patent is not invalid. The Court held a four-day bench trial in this action from September 18 through September 21, 2012. After considering the parties’ arguments, pretrial memoranda of law, and proposed findings of fact and conclusions of law, and evaluating the evidence produced at trial, including the documentary record and the testimony of the witnesses, the Court sets forth its Findings of Fact and Conclusions of Law pursuant to Federal Rule of Civil Procedure 52(a). For the following reasons, the Court concludes that each of claims 1 through 7, 13, 14, and 17 through 20 of the '442 patent is invalid for obviousness-type double patenting and that Kennedy has failed to prove its counterclaim that these claims of the '442 patent are not invalid.
FINDINGS OF FACT
I. THE PARTIES
1. As of the initiation of this action, Abbott Laboratories was an Illinois corporation with a principal place of business in Illinois and conducted business in this District. (Compl. ¶ 2, ECF No. 1.) Pursuant to Federal Rule of Civil Procedure 25 and a Stipulation and Order Substituting Parties entered on January 11, 2013, Abbvie Inc. was substituted for Abbott Laboratories for all purposes with respect to Plaintiffs’ claims and Defendant’s counterclaims in this action. (ECF No. 119.) Abbvie Biotechnology Limited (formerly named Abbott Biotechnology Limited) is a corporation organized under the laws of Bermuda, with a place of business in Hamilton, Bermuda. Through intermediate organizations, Abbott Biotechnology Limited was formerly owned by Abbott Laboratories. (ComplJ 3.) The Court refers to the Plaintiffs-Counterclaim-Defendants collectively as “Abbott” throughout these Findings of Fact and Conclusions of Law. At all relevant times, Abbott was engaged in the development, sale, and distribution of a broad range of pharmaceuticals and other health-care products. (Id. ¶ 2.)
2. The Mathilda and Terence Kennedy Institute of Rheumatology Trust is organized and exists under the laws of the United Kingdom, with a place of business in London, England. Kennedy is the owner of certain United States patents, including the '766 patent and the '442 patent. (Id. ¶ 5; Am. Answer ¶ 5, ECF No. 40.)
II. RHEUMATOID ARTHRITIS AND ITS TREATMENT
A. Rheumatoid Arthritis
3. Rheumatoid arthritis is an autoimmune disease characterized by inflammation of the joints. This inflammation, if left untreated, may result in joint pain and swelling, cartilage and bone destruction, deformity, incapacity, and potentially life-threatening complications. It may reduce life expectancy by up to a decade. At present, there is no cure for rheumatoid arthritis. Rheumatoid arthritis is estimated to affect approximately 0.6 to 1% of the U.S. population. (Tr. at 136:23-137:13, 137:16-18, 138:18-19; Ex. 1408.1, Mark J. Borigini & Harold E. Paulus, “Rheumatoid Arthritis,” in Treatment of the Rheumatic Diseases (Michael Weismann & Michael Weinblatt eds., 1995), at ABTKEN00444893-94.)
4. Physicians identify rheumatoid arthritis and measure its severity based on the presence of a variety of signs and symptoms, including morning stiffness, fatigue, pain, and tenderness and swelling of the joints. (Tr. at 138:2-7, 140:17-22, 456:22-457:20.)
B. Treatment of Rheumatoid Arthritis
5. Historically, the treatment of rheumatoid arthritis would begin with nonsteroidal anti-inflammatory drugs (“NSAIDs”), such as ibuprofen and aspirin, to reduce the pain and swelling caused by the disease. While treating symptoms, these medications do not stop or impede the progression of the disease or the damage it causes to the body. (Tr. at 138:20-23, 164:7-13, 164:20-165:1; Ex. 1408.1 at ABTKEN00444895-98.)
6. For patients for whom NSAID treatment did not work, rheumatologists would frequently prescribe cortisone or corticosteroids to reduce pain and swelling. These medications serve as anti-inflammatories, but can have negative side effects. (Tr. at 164:14-16, 165:5-14; Ex. 1408.1 at ABTKEN00444903-06.)
7. Beyond these treatments are disease-modifying antirheumatic drugs, or “DMARDS.” DMARDs are more effective than NSAIDs in reducing the inflammation associated with rheumatoid arthritis, but can produce more serious side effects than the above treatments. Drugs classified as DMARDs include methotrexate, gold compounds, azathioprine, hydroxychloroquine, and sulfasalazine. (Tr. at 165:15-166:18; Ex. 1408.1 at ABTKEN00444898-03.)
C. Methotrexate
8. Methotrexate is a drug that inhibits folic acid metabolism and was originally developed in the late 1940s for the treatment of childhood leukemia. Reports of methotrexate’s positive effects in rheumatoid arthritis patients were published in the 1950s, but methotrexate was not adopted as a common treatment for this disease until much later. (Tr. at 166:23-167:14.)
9. By 1985, Dr. Michael Weinblatt and others were studying the use of methotrexate to treat rheumatoid arthritis. A 1985 Weinblatt study reported on the first randomized, placebo-controlled trials of short-term methotrexate treatment for this purpose and provided evidence of the short-term efficacy of methotrexate in the treatment of rheumatoid arthritis. (Id. at 169:2-170:12; Ex. FD, Michael Weinblatt et al., “Efficacy of Low-Dose Methotrexate in Rheumatoid Arthritis,” New Eng. J. Med. 312:818 (1985).)
10. In 1988, the Food and Drug Administration (“FDA”) approved methotrexate for the treatment of rheumatoid arthritis. (Tr. at 170:24-25.)
11. Subsequent long-term, controlled trials established that methotrexate remained effective for treating rheumatoid arthritis over many years of therapy with acceptable toxicity levels. (Id. at 171:12-172:11; Ex. 1497, Michael Weinblatt et al., “Methotrexate in Rheumatoid Arthritis,” Arth. & Rheum. 37:1492 (1994).)
12. By 1994, studies and trials “ha[d] documented the efficacy of methotrexate and ha[d] indicated that its onset of action is more rapid than other DMARDs, and patients tend[ed] to remain on therapy with methotrexate longer than they remained] on other DMARDs because of better clinical responses and less toxicity.” Additionally, “[b]ecause of its therapeutic benefit and toxicity profile, methotrexate [was] used before other second-line drugs by many rheumatologists.” (Ex. 1403, Peter Lipsky, “Rheumatoid Arthritis,” in Harrison's Principles of Internal Medicine (Kurt Isselbacher et al., eds., 13th ed.1994), at 1654-55; Tr. at 173:8-19; see Ex. 1475, Marc Feldmann & Ravinder N. Maini, “Anti-TNF Therapy, from Rationale to Standard of Care: What Lessons Has It Taught Us?,” J. Immunology 185:791, 792 (2010) (“By the time the extensive, longer trials designed for drug registration were being planned (1994), the work of Michael Weinblatt and others had led to low-dose methotrexate (MTX) being widely used for the treatment of [rheumatoid arthritis] as the gold standard.” (citing Ex. 1497)); cf. Ex. IB, Michael M. Ward, “Trends in the Use of Disease Modifying Antirheumatic Medications in Rheumatoid Arthritis, 1980-1995: Results from the National Ambulatory Medical Care Surveys,” J. Rheumatology 26:546, 547-48 (1999) (stating that methotrexate was prescribed in 27% of rheumatoid arthritis patient visits from 1993 to 1995); Tr. at 592:2-16; see also Tr. at 354:2-360:22, 390:22-392:8 (noting that of patients in the Ward survey who were on DMARDs, almost half were receiving methotrexate, and percentage of rheumatoid arthritis patients on methotrexate was likely an underrepresentation because many patients were being treated by primary care physicians without expertise in rheumatology); Tr. at 719:17-722:18.)
13. By August 1, 1995, published studies had reported that methotrexate was at least no more toxic than other DMARDs and had fewer side effects than other DMARDs. (Tr. at 172:12-18; Ex. 1497; see also Tr. at 349:11-16, 350:15-351:16 (comparing methotrexate to other DMARDs).)
14. By this time, rheumatologists treated rheumatoid arthritis patients with doses of methotrexate ranging from 7.5 to 25 mg per week. While methotrexate may be administered either as a tablet or an injection, by the mid-1990s, methotrexate was more frequently administered in tablet form. Furthermore, by this time, it was only given on a weekly basis because more frequent administration was associated with greater toxicity risks. (Tr. at 167:23-168:13; Ex. FF, Michael Weinblatt, “Methotrexate,” in Textbook of Rheumatology (4th ed., William N. Kelley et al., eds., 1993), at ABTKEN00444963.)
15. Although many patients responded favorably to methotrexate treatment for their rheumatoid arthritis, many still experienced symptoms of the disease despite methotrexate’s benefits. The range of responses to methotrexate by itself ran from a significant reduction in painful and swollen joints and an improvement in function, to variable responses showing mediocre improvement, to no response at all. (Tr. at 174:7-14; see id. at 592:17-593:19.)
D. Treatment of Rheumatoid Arthritis with Combination Therapy
16. By 1995, rheumatologists often would administer another drug in combination with the underlying methotrexate a patient was already receiving to patients who were not responding completely to methotrexate treatment alone. Although not universally accepted, the treatment of rheumatoid arthritis with a combination of drugs (e.g., NSAIDs, corticosteroids, and DMARDs) was an established practice among rheumatologists by 1995. (Tr. at 174:25-180:2; e.g., Ex. 1408.1 at ABTKEN00444895, -00444909.)
17. By August 1, 1995, several studies had indicated that methotrexate could be more effective when used in combination with other DMARDs, as compared to methotrexate treatment alone, or methotrexate “monotherapy.” (Tr. at 180:22-186:17; Ex. FA, Peter Tugwell et al., “Combination Therapy with Cyclosporine and Methotrexate in Severe Rheumatoid Arthritis,” New Eng. J. Med. 333:137 (1995); Ex. DB, William Bensen et al.,
“Combination Therapy of Cyclosporine with Methotrexate and Gold in Rheumatoid Arthritis,” J. of Rheumatology 21:2034 (1994); see also Ex. 1409, Rita Jain & Peter Lipsky, “Treatment of Rheumatoid Arthritis,” Med. Clinics of N. Am. 81:57 (1997) (citing Exs. FA, DB); cf. Tr. at 364:24-367:9 (noting that of the many possible combinations of DMARDs being studied in the early 1990s, some were more successful than others).)
18. Physicians in the mid-1990s who were treating rheumatoid arthritis patients with methotrexate would often continue this treatment, even if it did not provide complete relief to patients, but add another treatment on top of the background methotrexate in order to prevent losing the benefits the methotrexate was providing and in an effort to prevent flares in patients’ symptoms that could arise from stopping methotrexate. (Tr. at 180:3-21; e.g., Ex. 1408.1 at ABTKEN00444909.)
E. Anti-Tumor Necrosis Factor Alpha Antibodies
19. In the 1980s, researchers began to study the use of a class of therapeutics known as biologies for the treatment of rheumatoid arthritis, including the use of antibodies. Antibodies are produced naturally in the body, for example, in response to an infection, and regulate the body’s immune response. (Tr. at 140:3-8, 144:8-13, 458:11-460:18.)
20. Beginning in the mid-1980s, Professors Ravinder Máini and Marc Feldmann, the named co-inventors of the '766 and '442 patents, began research on the role in rheumatoid arthritis of a group of proteins called cytokines. Their research led to the discovery of the role of a protein called Tumor Necrosis Factor Alpha, or “TNFa.” (Id. at 451:10-454:8, 461:2-464:6.)
21. Professors Maini and Feldmann determined that TNFa is directly involved in the inflammatory effects of rheumatoid arthritis. In rheumatoid arthritis, TNFa present in the joints will bind to receptors on the surface of cells in the joint, which triggers an inflammatory immune response that leads to the joint damage and related signs and symptoms that are characteristic of the disease. (Id. at 143:1-24, 461:2-464:6.)
22. Through their research, Professors Maini and Feldmann discovered that blocking TNFa with a “monoclonal” antibody that specifically binds to it had positive therapeutic effects in rheumatoid arthritis patients. Anti-TNFa antibodies function by binding to TNFa, thereby preventing the TNFa from binding to the cell-surface receptors. By preventing the TNFa from binding to the cell-surface receptors, the immune-mediated processes associated with the disease are blocked. (Id. at 143:25-144:18, 145:7-146:17.)
23. The human body makes antibodies in response to foreign invaders, but typically will not make antibodies against its own proteins, such as TNFa. Accordingly, such antibodies must be manufactured for administration to patients. (Id. at 144:19-145:6, 187:9-190:24.)
24. Antibodies that bind specifically to TNFa differ in composition and construction, and thus trigger varying responses in the human body. For example, a monoclonal antibody constructed completely from underlying mouse elements will be recognized as foreign in the human body, and the body will develop a response against it, known as a Human Anti-Mouse Antibody, or “HAMA,” response. (Id. at 146:18-147:9.)
25. To overcome the problem of an immune reaction to the antibody used for treatment, genetic engineering techniques are used to replace much of the mouse protein in manufactured anti-TNFa antibodies with human protein, creating what is known as a “chimeric” antibody. In chimeric antibodies, the part of the antibody that binds to the TNFa originates from a mouse antibody while the portion of the antibody that does not bind to the target originates from a human antibody. (Id. at 147:10-148:2.)
26. Monoclonal antibody cÁ2, which binds specifically to human TNFa, is an example of a chimeric antibody. The part of the antibody that binds to the TNFa is from mouse' monoclonal antibody A2, and the rest of the antibody is from a human antibody. (Id. at 147:13-148:2; Ex. 78, Michael J. Elliott, Ravinder N. Maini, Marc Feldmann et al., “Treatment of Rheumatoid Arthritis with Chimeric Monoclonal Antibodies to Tumor Necrosis Factor a,” Arth. & Rheum. 36:1681 (1993), at KEN00349043.)
27. Although the human part of a chimeric antibody makes it appear less foreign to the body when administered to a human patient, the body may still recognize the chimeric antibody as foreign and develop an immune response to it. This is referred to as a Human Anti-Chimeric Antibody, or “HACA,” response. (Tr. at 148:3-9; see Ex. 79, Michael J. Elliott, Ravinder N. Maini, Marc Feldmann et al., “Repeated Therapy with Monoclonal Antibody to Tumor Necrosis Factor a (cA2) in Patients with Rheumatoid Arthritis,” The Lancet 344:1125 (1994), at KEN00267406.)
28. Antibodies that are comprised of fully human constituents are designed to have a low potential for detection and immune responses from the body, but some patients still develop a Human Anti-Human Antibody, or “HAHA,” response to such antibodies. Humira®, which is marketed by Abbott for the treatment a number of conditions, is an example of a fully human antibody that specifically binds to TNFa. (Tr. at 148:10-25.)
III. KENNEDY’S DISCOVERIES
A. Kennedy’s Early Work with cA2
29. Professor Maini became affiliated with Kennedy in 1979 and became its scientific director in 1990. Professors Maini and Feldmann began collaborating in 1985 on research into rheumatoid arthritis. (Tr. at 447:1-451:19; Ex. HA, Professor Sir Ravinder Maini Curriculum Vitae.)
30. In the mid-1980s, Professors Maini and Feldmann researched cytokines in the joints of patients with rheumatoid arthritis and, by the late 1980s, they developed the hypothesis that blocking TNFa would yield therapeutic benefits in the treatment of rheumatoid arthritis. Professors Maini and Feldmann performed experiments to test their hypothesis and, in 1990, began a trial of a hamster monoclonal anti-TNFa antibody in mice with an induced rheumatoid arthritis-like illness. (Tr. at 458:11-468:6.)
31. The results of this study, ultimately published in 1992, demonstrated a clear amelioration of the inflammation and bone and cartilage damage in the mice that were treated with the anti-TNFa antibody. (Id. at 466:14-16; Ex. JQ, Richard O. Williams, Marc Feldmann & Ravinder N. Maini, “Anti-Tumor Necrosis Factor Ameliorates Joint Disease in Murine Collagen-Induced Arthritis,” Proc. Nat’l. Acad. Sci 89:9784 (1992).)
32. Professors Maini and Feldmann then pursued similar experiments in humans suffering from rheumatoid arthritis, by working with companies that were making monoclonal anti-TNFa antibodies for use in human trials for other diseases. By 1991, Professors Maini and Feldmann had discussions with the company Centoeor regarding the use of Centocor’s anti-TNFa antibody, cA2. (Tr. at 473:10-15, 474:3-476:9.)
33. Centoeor had previously developed cA2 to treat a condition known as septic shock, but Centocor’s clinical trials for this use in humans were not successful. Centocor agreed to allow Professors Maini and Feldmann to use cA2 in their rheumatoid arthritis trials. (Id. at 477:3-478:1.)
34. Centoeor and Kennedy entered into a research and licensing agreement, dated January 1, 1992, under which Centoeor provided funding and material support for Professors Maini and Feldmann’s research in return for licensing rights to any intellectual property that would result from this research. (Ex. AX, Research and Licensing Agreement.)
35. Professors Maini and Feldmann thereafter performed a study of cA2 in human rheumatoid arthritis patients in an “open label” format, in which both the physicians and patients knew that the patients were being administered cA2. This clinical investigation took place from April to June 1992, and the results were announced in September 1992 at a scientific conference organized by Professor Feldmann. These results were ultimately published in 1993. (Tr. at 478:9-481:22; Ex. 78; Ex. 1588, Dep. of Prof. Marc Feldmann at 28:14-19 (Mar. 15, 2012).)
36. This open label study showed positive results, with patients describing significant physical improvement and Professors Maini and Feldmann observing improvements in joint swelling and tenderness. (Tr. at 478:9-481:22; Ex. 78.)
37. At the same time Professors Maini and Feldmann were performing the open label study, they were also following up on their first trial of hamster monoclonal antiTNFa antibody in mice. The first study had shown that over time the mice developed an immune response to the hamster antibody similar to the HAMA response (see supra ¶ 24), which resulted in decreased efficacy of the anti-TNFa antibody. (Tr. at 468:9-19.)
38. Professors Maini and Feldmann devised a second mouse trial to test whether the use of another antibody (“anti-CD4”) in combination with an anti-TNFa antibody would yield longer-term benefits by suppressing the HAMA-like response in mice. This second study, ultimately published in 1994, showed that the combination of the anti-TNFa antibody and anti-CD4- antibody yielded superior benefits over the use of the anti-TNFa antibody alone. (Id. at 468:20-473:5; Ex. JR, Richard O. Williams, Lesley J. Mason, Marc Feldmann & Ravinder N. Maini, “Synergy between Anti-CD4 and Anti-Tumor Necrosis Factor in the Amelioration of Established Collagen-Induced Arthritis,” Proc. Nat’l. Acad. Sci 91:2762 (1994).)
B. Kennedy’s Open Label cA2 Study
39. In December 1993, Professors Maini and Feldmann published the final results of their initial open label clinical study involving the administration of Centocor’s anti-TNFa chimeric antibody, cA2, for the treatment of rheumatoid arthritis. (Ex. 78; Tr. at 187:9-19, 481:16-22.)
40. The objective of the open label study was to evaluate the safety and efficacy of a chimeric anti-TNFa antibody in the treatment of patients with rheumatoid arthritis. (Ex. 78 at KEN00349041.)
41. The patients who participated in the open label trial were, by design, those who had failed the standard treatments of the time, including having failed a median of four different DMARDs before enrolling in the trial, with a significant percentage having received methotrexate in the past. Of the twenty patients enrolled in the trial, all had active rheumatoid arthritis, despite prior treatment with multiple DMARDs; fourteen of the twenty patients had not completely responded to prior treatment with methotrexate. (Id. at KEN0034904243; Tr. at 189:3-15, 483:2-25.)
42. The patients in the open label trial were administered cA2 by itself, after a period of at least one month in which they ceased receiving their previous DMARD treatment, including methotrexate. Such a break in treatments is known as a “washout” period. (Ex. 78 at KEN00349043; Tr. at 189:16-21, 482:3-483:1.)
43. The patients received administrations of eA2 as infusions over staggered weeks, either in doses of 10 mg/kg of body weight over two weeks or 5 mg/kg over four weeks, but in all instances totaling 20 mg/kg. (Ex. 78 at KEN00349043; Tr. at 478:23-479:22.)
44. The open label cA2 study concluded:
Treatment with anti-TNFa was safe and well tolerated and resulted in significant clinical and laboratory improvements. These preliminary results support the hypothesis that TNFa is an important regulator in [rheumatoid arthritis], and suggest that it may be a useful new therapeutic target in this disease. (Ex. 78 at KEN00349041; Tr. at 484:1-12.)
45. Due to the “open label” design of the study, however, Professors Maini and Feldmann could not confirm that the clinical efficacy observed was due to cA2, and not to a placebo effect in the subject patients. (Tr. at 480:5-21; see id. at 188:19—189:2.)
C. Kennedy’s Anti-CD4 and AntiTNFa Combination Study
46. In March 1994, Professors Maini and Feldmann published the final results of their study to test whether the combination of anti-CD4 with an anti-TNFa antibody would lead to longer-term benefits by suppressing the HAMA-like response in mice. (Ex. JR; Tr. 471:24-472:3.)
47. This study concluded:
[Ojptimal anti-TNF combined with antiCD4 caused significantly greater reductions in paw swelling and joint erosion than those achieved by optimal anti-TNF alone. Coadministration of antiCD4 was also effective in preventing an antibody response to the hamster anti-TNF antibody, which may have implications for long-term therapy in human disease. Thus anti-CD4 acts synergistieally with anti-TNF in ameliorating established collagen-induced arthritis and this combined therapeutic approach may provide effective long-term control of rheumatoid arthritis. (Ex. JR at KEN00356475; Tr. at 472:4-473:5.)
D. Kennedy’s Extension Study of cA2 in Humans
48. Although the open label study of the use of cA2 in rheumatoid arthritis patients showed successful results for a short time period (see supra ¶¶ 39-44), continued evaluation showed that after a predictable period of time, the open label patients’ rheumatoid arthritis returned. Professors Maini and Feldmann thus continued to treat a subset of the patients in the open label study for a prolonged period of time to determine the long-term effects of cA2 treatment. (Tr. at 484:15-485:13; see id. at 196:22-197:10; Ex. 79.)
49. In this subsequent “extension” study, patients received multiple doses of cA2 as infusions in response to flares of rheumatoid arthritis. The first dose of cA2 the extension study patients received was 20 mg/kg, while the second dose was 10 mg/kg. (Ex. 79; Tr. at 485:15-20, 489:4-22; see Tr. at 197:6-14.)
50. This study demonstrated that when rheumatoid arthritis reappeared in patients after the initial dose of cA2, subsequent doses of cA2 produced the same level of reduction in signs and symptoms of the disease, but with each successive subsequent dose, the duration of the benefits produced shortened significantly. (Ex. 79; Tr. at 485:21-489:22; see 198:18-199:5.)
51. The extension study paper, published in October 1994, stated that the “success in demonstrating repeated responses in the same individuals suggests that regular treatment with cA2 may achieve long-term disease suppression,” indicating that the antibody was an effective treatment approach for chronic rheumatoid arthritis. (Ex. 79 at KEN00267407; Tr. at 198:1-7.)
52. Professors Maini and Feldmann also observed from the extension study that the shortened duration of response to each successive treatment of cA2 appeared to be due to the patients’ developing a HACA response to the chimeric antiTNFa antibody, cA2. (Ex. 79 at KEN00267407; Tr. 486:4-12; see Tr. at 198:18-199:5.)
53. Professors Maini and Feldmann suggested that “[s]everal strategies could be adopted to prevent the development of antiglobulin responses to cA2, including combination therapy with traditional immunosuppressive drugs or the co-administration of specific, T-cell-directed monoclonal antibodies with the aim of inducing tolerance.” The purpose of these strategies was to reduce the human body’s immune (HACA) response to the anti-TNFa antibody in order to produce a longer duration of the benefits of the cA2 administrations. (Ex. 79 at KEN00267407; Tr. at 199:6-24, 491:4-494:4.)
54. As of October 1994, when the extension study was published, methotrexate was a drug known to have immunosuppressive properties. (Tr. at 199:25-201:10; Ex. 1403 at 1654; see also Tr. at 392:9-393:11; cf. Tr. at 501:24-504:20, 557:10-561:21 (discussing immunosuppressive properties of methotrexate when administered in high doses).)
55. The extension study also cited Professors Maini and Feldmann’s combination study of both anti-TNF and anti-CD4 antibodies in mice, and noted these two antibodies “were synergistic in the control of murine collagen-induced arthritis, and antiglobulin responses to the TNF blocking antibody were reduced. The application of such combination immunotherapy deserves further investigation in man.” (Ex. 79 at KEN00267407 (citing Ex. JR).)
E. The Double-Blind Placebo-Controlled Trials of cA2
56. Following the success of the open label cA2 study, Professors Maini and Feldmann sought to confirm its results in a double-blind, placebo-controlled trial undertaken in several separate research centers in Europe. (Tr. at 494:6-495:6; see id. at 190:9-16.)
57. As in the open label study, the double-blind study involved patients with rheumatoid arthritis who “had a history of failed treatment with at least one disease-modifying anti-rheumatic drug.” Also, the patients were withdrawn from their DMARD therapies for at least four weeks before entering into the double-blind trial. (Ex. 80, Michael J. Elliott, Ravinder N. Maini, Marc Feldmann et ah, “Randomised Double-Blind Comparison of Chimeric Monoclonal Antibody to Tumour Necrosis Factor a (cA2) Versus Placebo in Rheumatoid Arthritis,” The Lancet 344:1105 (1994), at KEN00355972-73; Tr. at 495:7-496:9; see Tr. at 190:17-24.)
58. Participants in the double-blind study received either an infusion of placebo or cA2 antibody and were monitored for four weeks. The cA2 was administered in doses of either 1 mg/kg or 10 mg/kg. (Ex. 80 at KEN00355973; Tr. at 496:13-22.)
59. The results of the double-blind study, published in October 1994, “confirm[ed] the findings of [Professors Maini and Feldmann’s] open-label trial of cA2 in a similar patient group.” (Ex. 80 at KEN00355976; see Tr. at 496:17-18.)
60. As in the case of the open label study, Professors Maini and Feldmann reported that “cA2 infusions were well tolerated and few adverse events were recorded in any group.” The duration of the benefits produced continued longer with the higher (10 mg/kg) dose of cA2. (Ex. 80 at KEN00355976.)
61. The double-blind study concluded that the “results show that blockade of TNFa with cA2 was highly effective and safe in the short term treatment of rheumatoid arthritis.” Professors Maini and Feldmann also cited their long-term extension study results and stated that “[w]ith our' accompanying results, which demonstrate repeated beneficial responses to cycles of cA2, the data define a major new direction for rational therapy in this disease.” (Id. at KEN00355976 (citing Ex. 79); see id. at KEN00355972; Tr. at 498:7-17.)
IV. OTHER RESEARCH AND PUBLICATIONS
A. Schwieterman Discussion of Combination Treatment
62. At a conference in March 1995, leading rheumatologists and FDA representatives discussed the use of biologic agents, including anti-TNFa antibodies, in the treatment of rheumatoid arthritis. (Tr. at 206:6-207:13; Ex. 73, William Schwieterman, “Immunosuppression in Combination with Monoclonal Antibodies,” in Proceedings: Early Decisions in DMARD Development IV: Biologic Agents in Autoimmune Diseases (1996).)
63. By March 1995, Professors Maini and Feldmann had published three studies on the safety and efficacy of using antiTNFa antibodies to treat rheumatoid arthritis. (See Exs. 78, 79, 80; supra ¶¶ 39, 51, 57.)
64. Professors Maini and Feldmann had also observed the synergistic benefits in the treatment of rheumatoid arthritis with anti-CD4 in combination with an antiTNFa antibody, specifically the prevention of an immune response to the anti-TNFa antibody. (Ex. JR; see supra ¶¶ 46, 47.)
65. In addition, Professors Maini and Feldmann had suggested research into the suppression of the human immune response to anti-TNFa antibodies, including “combination therapy [of cA2] with traditional immunosuppressive drugs.” (Ex. 79 at KEN00267407; see supra ¶ 53.)
66. At the March 1995 conference, Dr. William Schwieterman, from the FDA, discussed the use of biologies for the treatment of rheumatoid arthritis, and particularly the safety of combination treatments involving immunosuppressives or DMARDs and biologies such as anti-TNFa antibodies. Dr. Schwieterman stated that in such research, patient safety was the paramount concern, and cautioned that the safety of the biologic must be established first, in the “Phase I” of any study. As such, he. noted that the use of “immunosuppressive agents and DMARDs should usually be minimized, if not eliminated, in Phase I studies.” Dr. Schwieterman acknowledged, however, that “[t]here are cases to be made for initially studying patients who are also treated with methotrexate background therapy.” (Ex. 73 at ABTKEN00445120.)
67. In response to Dr. Schwieterman, Dr. Weinblatt raised “the issue of withdrawing people from methotrexate” before enrolling in studies of biologic therapies, stating that “[t]here are some real ethical issues ... in asking patients to get worse in order to enroll in studies.” Instead, Dr. Weinblatt suggested that “[b]ecause methotrexate is such a dominant drug in the U.S., ... a likely study population will be patients that are incomplete responders on methotrexate. That is the population, from both a practical and commercial standpoint, that we would be interested in looking at: not patients withdrawn from methotrexate, but rather, incomplete responders on it.” (Id. at ABTKEN00445122.)
68. Dr. Weinblatt’s question addressed the situation in which rheumatoid arthritis patients who were receiving methotrexate, even if they did not respond completely to this treatment, would experience flares in their disease activity when taken off of methotrexate, including when enrolling in trials of other therapies. (Tr. at 208:1-209:6.)
69. Dr. Weinblatt’s suggestion was that after a biologic was shown to be safe, it should then be tested in patients who were receiving, and would continue with, methotrexate treatment. As of March 1995, companies did not follow this practice in testing their treatments. (Id. at 210:2-16.)
70. Indeed, at the time of- this convention, the FDA required that patients be withdrawn from methotrexate treatment before trials with biologies could bégin. Dr. Weinblatt sought to allow clinical studies with patients who remained on methotrexate treatment. (Id. at 312:25-317:17.)
71. Dr. Schwieterman agreed with Dr. Weinblatt’s suggestion and responded that if the studies of the biologic agent' alone (without methotrexate) were shown to be sáfe, then it would be “perfectly appropriate to go into a methotrexaté treated population.” (Ex. 73 at ABTKEN00445123; see Tr. at 210:17-211:12.)
72. In discussing the structure of such trials, Dr. Weinblatt asked-Dr. -Schwieterman whether, after the “Phase I” to determine the safety of the biologic alone, it would make sense “instead of going into' a Phase II background on methotrexate; you would repeat those [Phase I] studies in [rheumatoid arthritis] patients on methotrexate.” (Ex. 73 at ABTKEN00445123; see Tr. at 211:21-25.)
. 73. Dr. Schwieterman responded that the -FDA had “recommended the design that you mentioned to several sponsors, and it has become standard to go first alone [with the biologic] and then go with methotrexate.” (Ex. 73 at ABTKEN00445123; see Tr. at 212:1-213:1.)
B. The Rankin CDP571 Trial
74. While Professors Maini and Feldmann were advancing their research with cA2, other researchers and institutions were also studying and experimenting with other anti-TNFa antibodies. (Tr. at 192:20-193:2.)
75. In April 1995, Professor E.C.C. Rankin and colleagues published the results of a placebo-controlled trial of a monoclonal anti-TNFa antibody known as CDP571 in patients with rheumatoid arthritis. (Ex. 1412, E.C.C. Rankin et al., “The Therapeutic Effects of an Engineered Human Anti-Tumour Necrosis Factor Alpha Antibody (CDP571) in Rheumatoid Arthritis,” British J. of Rheumatology 34:334 (1995); Tr. at 193:6-16.)
76. The CDP571 was administered intravenously as an infusion in doses of 0.1, 1.0, or 10 mg/kg of body weight to patients suffering from rheumatoid arthritis. The CDP571 study also included a washout period where patients stopped their prior DMARD treatment before receiving any antibody. (Ex. 1412; Tr. at 193:18-194:2.)
77. The study concluded that “CDP571, an engineered human anti-TNF antibody, is well tolerated, and, after a single dose of 10 mg/kg, provides improvements in symptoms, signs, and serological markers of disease activity in patients with active [rheumatoid arthritis].” (Ex. 1412 at ABTKEN00445106, Tr. 193:12-17.)
78. Similar to the extension work that Professors Maini and Feldmann continued after the positive results of the open label study- of cA2 (see supra ¶ 48), the authors of the CDP571 study continued their research after the initial results with a second infusion of the antibody in order to determine the safety and longer-term benefits of CDP571. The authors concluded that “[t]he continuation phase, although open, confirmed both the safety and beneficial effects of CDP571 in active [rheumatoid arthritis].” (Ex. 1412 at ABTKEN00445106.)
C. Higgins Report on CDP571 and Methotrexate Combination Treatment
79. In July 1995, a medical news publication, reporting on recent developments in rheumatology research, stated that researchers were focusing on the method of treatment Drs. Weinblatt and Schwieterman discussed at the March 1995 conference — where patients receiving methotrexate, but still experiencing signs and symptoms of rheumatoid arthritis, would receive treatment of an anti-TNFa antibody on top of their background methotrexate. (Ex. 1575, Gill Higgins, “Cytokine Antagonism: Still A Main Attraction in Rheumatology R & D,” Inpharma (Jul. 8, 1995); see Tr. at 215:3-24.)
80. This article stated that “the greatest potential [for developing cytokine antagonists as therapy for autoimmune diseases] appears to lie with antibodies to tumour necrosis factor-a (TNF-a) and the use of soluble receptors for TNF-a and interleukin-1 (IL-1).” (Ex. 1575 at 9.)
81. The article, covered the human cA2 studies published by Professors Maini and Feldmann and the positive results shown in each. (Id. at 9-10 (citing Exs. 79, 80); see Tr. at 213:24-214:13.)
82. In addressing future studies being planned by researchers in the field, -the article stated:
The development of CDP-571 will be pursued by Bayer following its recent acquisition of the drug from Celltech. One of the key studies to be conducted will look at the possibility of combining CDP-571 with methotrexate in patients with rheumatoid arthritis who do not respond to methotrexate alone. (Ex. 1575 at 10.)
Y. THE T-14 STUDY
83. In September 1994, Professors Maini and Feldmann began a study of rheumatoid arthritis patients where antiTNFa antibody was given, over a period of time, either alone or in combination with methotrexate, to patients who had not responded completely to previous methotrexate treatment alone. This was known as the “T-14 study.” The results of the study were ultimately published in September 1998. (Ex. 1025, Ravinder N. Maini et al., “Therapeutic Efficacy of Multiple Intravenous Infusions of Anti-Tumor Necrosis Factor a Monoclonal Antibody Combined with Low-Dose Weekly Methotrexate in Rheumatoid Arthritis,” Arth. & Rheum. 41(9):1552 (1998); Tr. at 508:10-509:8, 564:14-18; see Tr. at 231:6-17; Ex. 1051, Martin Page, “Chimeric (Human, Murine) Monoclonal Antibody (cA2) to Tumor Necrosis Factor, Methotrexate” (May 29, 1996); Ex. 1571, R.N. Maini, “Phase II Multicenter Study of Chimeric Anti-TNF Monoclonal Antibody (cA2) in Adjunct to Methotrexate Treatment in Patients With Rheumatoid Arthritis” (Sept. 16, 1999).)
84. The T-14 study was designed to evaluate the efficacy, safety, and immunogenicity (the human body’s rejection of the mouse component of the chimeric antibody, or HACA response (see supra ¶ 27)) of multiple doses of the anti-TNFa antibody cA2 (at 1, 3, or 10 mg per dose) administered as infusions to patients at weeks 0, 2, 6,10, and 14 of a 26-week trial, either with or without weekly methotrexate doses (at 7.5 mg/kg) as well. (Ex. 1025 at 1553; Tr. at 231:6-232:3; see Tr. 492:18-493:3, 527:16-19.)
85. The patients enrolled in the T-14 trial had each been treated with weekly methotrexate for at least six months prior to the trial. Before receiving any cA2 in the T-14 trial, the patients were “stabilized” on a fixed weekly dose of 7.5 mg/kg of methotrexate for four weeks. (Ex. 1025 at 1553; Tr. at 519:6-16; see Tr. at 291:8— 292:2.)
86. The T-14 study was the first successful study of an anti-TNFa antibody that did not include a washout period of prior DMARD therapies. (Tr. at 311:18-312:24.)
87. The patients in the T-14 study were organized into three overarching groups—(1) patients who received methotrexate as a tablet and infusions of a placebo (instead of cA2) throughout the trial (the “control” group), (2) patients who received methotrexate as a tablet and infusions of cA2 throughout the trial, and (3) patients who received a placebo as a tablet (instead of methotrexate) and infusions of cA2 throughout the trial. Among these three overarching groups, the patients in the T-14 study were further organized into seven separate “arms.” Within the control group, there was only one “arm,” in which patients received weekly doses of 7.5 mg/kg of methotrexate as a tablet, while receiving infusions of placebo at the designated weeks of the trial. Within the group who received methotrexate and cA2 throughout the trial, there were three arms, in which the patients received weekly doses of 7.5 mg/kg of methotrexate as a tablet, while receiving infusions of cA2 at the designated weeks in doses of either 1, 3, or 10 mg/kg, respectively. Within the group who received placebo and cA2 throughout the trial, there were also three arms, in which the patients received weekly placebo tablets while receiving infusions of cA2 at the designated weeks in doses of either 1, 3, or 10 mg/kg, respectively. The designated weeks of the trial during which the infusions of either cA2 or placebo were administered were weeks 0, 2, 6, 10, and 14. (Ex. 1025 at 1553; Tr. at 514:6-515:15.)
88. The published article on the T-14 study visualized the administration groups and arms in Table 1, with the three arms for patients who received methotrexate and each respective dose of cA2 throughout the trial being indicated as “MTX + ” and the three arms for patients who received placebo and each respective dose of cA2 throughout the trial being indicated as “MTX-”:
(Ex. 1025 at 1555.)
89. The T-14 study results showed that patients in the group who continued to receive the weekly methotrexate while also receiving infusions of cA2 (for each cA2 dose) showed longer lasting results than those patients in the group who only received cA2 (and not methotrexate) throughout the trial. (Id. at 1552; Tr. at 525:18-527:5.)
90. The T-14 study results also showed that for the patients who continued to receive the weekly methotrexate during the trial, in addition to the duration of response, the magnitude of the body’s response to the cA2 treatment was increased as well. (Tr. at 527:6-15.)
91. Professors Maini and Feldmann further confirmed their hypothesis from their earlier studies with mice that the immunogenicity of cA2 (the body’s HACA response) was dramatically reduced by administration in combination with methotrexate. (Id. at 527:16-19.)
92. Specifically, Professors Maini and Feldmann noted that “coadministration of cA2 at 1 mg/kg with MTX [methotrexate] appeared to be synergistic, prolonging the duration” of the body’s positive response to cA2, and that this increased durational response was due to methotrexate reducing the body’s immune response to the chimeric antibody. (Ex. 1025 at 1552; see id. at 1561 (observing that “[t]he difference in pharmacokinetics of cA2 at 1 mg/kg very likely reflects the immunogenicity of cA2, since the incidence of HACA was 53% in the group not receiving MTX and only 15% when MTX was administered concomitantly. Based on these data, we suggest that the apparent synergy of the action of cA2 plus MTX is based in part on the decreased immunogenicity of cA2 given simultaneously with MTX”); Tr. at 283:22-284:25.)
93. Professors Maini and Feldmann summarized the conclusions of the T-14 study in a 1997 abstract titled “Low Dose Methotrexate Suppresses Antiglobulin Responses and Potentiates Efficacy of a Chimeric Monoclonal Anti-TNF Antibody Given Repeatedly in Rheumatoid Arthritis,” Arth. & Rheum. 40(9 Suppl.):A571 (1997). (Ex. 1023; see Tr. at 576:21-577:6, 579:2-20.) This abstract stated:
In this multicentre, placebo-controlled trial of cA2 (Centocor Inc.), given as a monotherapy or combined with MTX, we sought to establish whether the regimen we used a) induced immunological tolerance to cA2; and b) was effective therapy during and beyond the period of cA2 administration.
[...]
The frequency of human anti-cA2-antibody (HACA) responses in patients receiving cA2 as monotherapy at 1, 3 and 10 mg/kg was 53%, 21 % and 7% respectively, and in cA2 plus MTX treated groups was 17%, 7% and 0% respectively. (Ex. 1023.)
94. In the published article on the T-14 study in the peer-reviewed journal Arthritis and Rheumatism, Professors Maini and Feldmann described the treatment given to the overarching group of patients who had been receiving methotrexate prior to the trial, had been stabilized on a weekly methotrexate dose of 7.5 mg/kg for four weeks before receiving infusions of cA2, had stopped receiving methotrexate at the beginning of the infusion treatment, and had received infusions of cA2 at weeks 0, 2, 6,10, and 14 of the trial as cA2 “monotherapy” or “without methotrexate.” (Ex. 1025 at 1553, 1560; Tr. at 232:4-18; see Tr. at 564:14-576:8.)
95. In the same, article, Professors Maini and Feldmann described the treatment given to the overarching group of patients who had been receiving methotrexate prior to the trial, had been stabilized on a weekly methotrexate dose of 7.5 mg/kg for four weeks before receiving infusions of cA2, had continued receiving the same weekly methotrexate throughout the infusion treatment, and had received infusions of cA2 at weeks 0, 2, 6, 10, and 14 of the trial as “combination therapy when coadministered” or “combination therapy.” (Ex. 1025 at 1553, 1560; Tr. at 232:19-233:3; see Tr. at 564:14-576:8.)
96. Professors Maini and Feldmann distinguished in this published study between these two overarching sets of patient groups as receiving either cA2 “alone or in combination with” methotrexate. (Ex. 1025 at 1552; see id. (distinguishing between patients receiving cA2 “with or without MTX [methotrexate]”); id. (noting that “[w]hen cA2 at 1 mg/kg was given with low-dose MTX, synergy was observed”); see also Tr. at 564:14-576:8.)
97. Similarly, in the abstract of the T-14 study, Professors Maini and Feldmann identified these two sets of patient groups as having received either cA2 “monotherapy” or “combined with [methotrexate].” (Ex. 1023; Tr. at 578:20-579:20.)
98. In a January 1997 letter to the New England Journal of Medicine, enclosing a manuscript on the T-14 study, Professor Maini summarized the manuscript by stating that “[fit describes the control of symptoms of rheumatoid arthritis by repeated intravenous monoclonal anti-TNFa antibody alone, and in combination with low-dose weekly methotrexate, in a randomized placebo-controlled trial.” (Ex. 1052, Letter from R.N. Maini to Jerome P. Kassierer, Editor-in-Chief, New Eng. J. Med. (Jan. 29, 1997), at KEN00042592; Tr. at 582:6-21.)
99. In an October 1997 letter to the journal that published the T-14 study, Professor Maini submitted a manuscript and described the protocols of the T-14 study: “Treatment was with cA2 alone or in combination with methotrexate while the placebo group continued to receive methotrexate.” (Ex. 1603, Letter from R.N. Maini to William P. Arend, Editor, Arth. & Rheum. (Oct. 28, 1997), at KEN00362659; Tr. at 579:21-581:13; see also Ex. 1602, R.N. Maini, Abstract, “Interference with the Cytokine Cascade via Monoclonal Anti-TNFa Antibody,” EULAR (1997) (“In this presentation, the results of a multi-centre European trial in which infusions of anti-TNF antibody are given at monthly intervals either as monotherapy, or in combination with low dose methotrexate (MTX) once a week, over a period of 14 weeks, is presented.”); Tr. at 581:15-582:4.)
100. In a January 2003 email from Professor Feldmann to Professor Maini, concerning their joint research on rheumatoid arthritis and treatment with anti-TNFa antibodies for submission for the Lasker Prize, Professor Feldmann described the results of the T-14 study as showing that “the efficacy of anti-TNF antibody is shown to be more durable when coadministered with methotrexate.” (Ex. 1036, Email from Marc Feldmann to Ravinder Maini (Jan. 13, 2003), at KEN00219466, Tr. 535:8-537:21; see also Ex. GX (inscription on Albert Lasker Clinical Research Award “for discovery of anti-TNF therapy as an effective treatment for rheumatoid arthritis and other autoimmune diseases”); Tr. at 537:22-539:2.)
101. In all these materials, Professors Maini and Feldmann used the same language as that of the T-14 study and distinguished between cA2 “alone” and “in combination with” methotrexate. (Tr. at 582:22-24.)
102. Excluding the materials submitted in support of the '442 and '766 patents, Professors Maini and Feldmann never referred to the group of patients who had been receiving methotrexate prior to the trial, had been stabilized on a weekly methotrexate dose of 7.5 mg/kg for four weeks before receiving infusions of antibody, had stopped receiving methotrexate at the beginning of the infusion treatment, and had received only infusions of cA2 at weeks 0, 2, 6, 10, and 14 of the trial as having received either “co-administration” or “sequential co-administration” treatment. (Id. at 569:13-570:4.)
103. On the contrary, in their published works in peer-reviewed journals and their communications with the editorial staff of several peer-reviewed journals and each other, Professors Maini and Feldmann identified those patients who did not receive weekly methotrexate throughout the T-14 trial as having received cA2 “alone” or cA2 “monotherapy.”
104. Furthermore, in these same materials and communications, Professors Maini and Feldmann identified those patients who did receive weekly methotrexate throughout the T-14 trial as having received cA2 in “co-administration with” methotrexate, or in “combination with” methotrexate, or as “combination therapy” with methotrexate.
VI. KENNEDY’S PATENTS
A. The '248 Application
105. On October 8, 1992, Kennedy filed U.S. Patent Application No. 07/958,248 (“the '248 application”), which lists Marc Feldmann, Ravinder Maini, and Richard Williams as inventors and is entitled “Treatment of Autoimmune and Inflammatory Disorders.” (Ex. 1068.1 at ABTKEN00008981, -00009002; Tr. at 539:8-25.)
106. The “Summary of the Invention” in the '248 application states that the invention “pertains to the discovery that combination therapy, involving the use of anti-CD4 antibodies in conjunction with anti-TNF antibodies, produces markedly superior results than the use of each agent alone in the treatment of autoimmune or inflammatory disease, particularly in rheumatoid arthritis.” (Ex. 1068.1 at ABTKEN00008985.)
107. The '248 application primarily discusses combination therapy involving an anti-CD4 antibody and an anti-TNF antibody, but the “Detailed Description of the Invention” section of the '248 application further states that “[o]ther anti-inflammatory drugs, such as the anti-rheumatic drugs methotrexate or cyclosporin A, can be administered in conjunction with the anti-CD4 antibody or the anti-TNF antibody.” (Id. at ABTKEN00008991.)
B. The '766 Patent
108. The United States Patent and Trademark Office (“PTO”) issued the '766 patent on August 7, 2001. The '766 patent names Marc Feldmann and Ravinder Maini as inventors and is entitled “Anti-TNF Antibodies and Methotrexate in the Treatment of Arthritis and Crohn’s Disease.” The assignee of the patent is the Kennedy Institute of Rheumatology. (Ex. 1, Ex. 1419.1 at ABTKEN00000077; Tr. at 107:21-108:7, 152:18-153:10.)
109. Kennedy had filed the underlying application that led to the '766 patent, U.S. Patent Application No. 08/690,775 (the “'775 application”), on August 1, 1996. (Ex. 1, Ex. 1419.1 at ABTKEN00000068, - 00000078; Tr. at 153:2-10.)
110. The '766 patent is part of a family of related patent applications traceable to the filing of the '248 application on October 8, 1992. Through several intervening applications, the '766 patent has an effective filing date of October 8, 1992. (Ex. 1; Ex. 1419.1 at ABTKEN00000077.) By statute, the '766 patent expired twenty years from this date, on October 8, 2012. See 35 U.S.C. § 154(a)(2).
C. The Claims of the '766 Patent
111. Claim 8 of the '766 patent, an independent claim, recites:
A method of treating rheumatoid arthritis in an individual in need thereof comprising co-administering methotrexate and an anti-tumor necrosis factor alpha antibody or an antigen-binding fragment thereof to the individual, in therapeutically effective amounts. (Ex. 1 at col. 35, lines 59-63.)
112. Claims 9 through 14 of the '766 patent each depend, either directly or indirectly, on claim 8 and add additional limitations to the method of treating rheumatoid arthritis recited in claim 8. (Id. at col. 35, line 64-col. 36, line 51.)
113. Specifically, claims 9 through 14 of the '766 patent recite:
9. A method of claim 8 wherein the anti-tumor necrosis factor alpha antibody or antigen-binding fragment is administered in a series of doses separated by intervals of days or weeks.
10. A method of claim 8 wherein the anti-tumor necrosis factor alpha antibody or antigen-binding fragment is a chimeric antibody or chimeric fragment, wherein said chimeric antibody or chimeric fragment comprises a non-human variable region specific for tumor necrosis factor alpha or an antigen-binding portion thereof and a human constant region.
11. A method of claim 10 wherein the chimeric antibody binds to one or more epitopes included in amino acid residues set forth in SEQ ID NO:l or SEQ ID NO:2.
12. A method of claim 10 wherein the chimeric antibody competitively inhibits binding of TNFa to monoclonal antibody cA2.
13. A method of claim 12 wherein the chimeric antibody is monoclonal antibody cA2.
14. A method of claim 8 wherein the anti-TNFa antibody or antigen-binding fragment is a humanized anti-TNFa antibody or antigen-binding fragment thereof. (Id.)
D. The Specification of the '766 Patent
114. The specification of the '766 patent states that
[t]he present invention is based on the discovery that treatment of patients suffering from a TNF-mediated disease with a tumor necrosis factor antagonist, such as an anti-tumor necrosis factor antibody, as adjunctive and/or concomitant therapy to methotrexate therapy produces a rapid and sustained reduction in the clinical signs and symptoms of the disease. (Ex. 1 at col. 2, line 33-39.)
115. The specification also states that the invention “relates to a method of treating and/or preventing rheumatoid arthritis in an individual comprising co-administering an anti-TNF antibody or a fragment thereof and methotrexate to the individual in therapeutically effective amounts.” (Id. at col. 2, line 66-col. 3, line 3.) The specification continues that the invention relates “to the discovery that tumor necrosis factor antagonists can be administered to patients suffering from TNF-mediated disease as adjunctive and/or concomitant therapy to methotrexate therapy, with good to excellent alleviation of the signs and symptoms of the disease.” (Id. at col. 4, lines 31-36.)
116. According to the specification,
an “anti-tumor necrosis factor antibody” decreases, blocks, inhibits, abrogates or interferes with TNF activity in vivo. Anti-TNF antibodies useful in the methods and compositions of the present invention include monoclonal, chimeric, humanized, resurfaced and recombinant antibodies and fragments thereof which are characterized by high affinity binding to TNF and low toxicity (including human anti-murine antibody (HAMA) and/or human anti-chimeric antibody (HACA) response). (Id. at col. 7, lines 26-34.)
117. The specification discloses the chimeric antibody cA2, which has since been designated as “infliximab” and marketed under the brand name Remicade®. (Id. at col. 9, lines 50-64; see Tr. at 147:19-20.)
118. The specification lays out several possible routes of administration (Ex. 1 at col. 18, lines 36-48), and states that the two therapies can be administered at different frequencies from each other: “TNF antagonists can be administered prior to, simultaneously with (in the same or different compositions) or sequentially with the administration of methotrexate. For example, TNF antagonists can be administered as adjunctive and/or concomitant therapy to methotrexate therapy.” (Id. at col. 18, lines 58-62.)
119. The specification provides that the antibody and methotrexate are each administered in a “therapeutically effective amount,” which* means “that administration of TNF antagonist and methotrexate, or administration of a composition of the present invention, results in inhibition of the biological activity of TNF relative to the biological activity of TNF when therapeutically effective amounts of antagonist and methotrexate are not administered, or relative to the biological activity of TNF when a therapeutically effective amount of the composition is not administered.” (Id. at col. 19, lines 18-26.)
120. The specification further explains that “[a] therapeutically effective amount is preferably an amount of TNF antagonist and methotrexate necessary to significantly reduce or eliminate signs and symptoms' associa