# Abbvie Inc. v. Mathilda & Terence Kennedy Institute of Rheumatology Trust

> District Court, S.D. New York · June 20, 2013 · 956 F. Supp. 2d 429

URL: https://www.frixlaw.com/law-library/cases/8709810

## Case

- **Full name:** ABBVIE INC. and Abbvie Biotechnology Limited, Plaintiffs-Counterclaim-Defendants v. The MATHILDA AND TERENCE KENNEDY INSTITUTE OF RHEUMATOLOGY TRUST, Defendant-Counterclaim-Plaintiff
- **Court:** District Court, S.D. New York
- **Decided:** June 20, 2013
- **Citations:** 956 F. Supp. 2d 429; 2013 U.S. Dist. LEXIS 106463; 2013 WL 3853149
- **Precedential status:** Published
- **Opinion:** Opinion of the court by Crotty
- **Judges:** Crotty
- **Cited by:** 0 later opinions in the Frix Law Library

## Citator (automated)

- No negative treatment found by the automated citator. That is not the same as a confirmation that the case is good law; read the citing cases.
- Full citator and citing cases: https://www.frixlaw.com/law-library/cases/8709810

## How later opinions describe it (automated extraction)

- noting that while board certification- in rheumatology would be ideal, approximately half of the physicians treating rheumatoid arthritis patients at the time did not háve such certification

## 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
*433 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. 1 The Court held a four-day bench trial in this action from September 18 through September 21, 2012. 2 After considering the parties’ argu *434 ments, 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. 3 (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. 4 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. 5 )
*435 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 *436 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, 6 the treatment of rheumatoid arthritis with a combination of *437 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.)
*438 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 rheuma *439 toid 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. 7 (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 Feld *440 mann & 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 *441 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. 8 (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 *442 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 *443 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 *444 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. *445 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. 9 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 *446 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-”:
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(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:
*447 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. 10 )
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. *448 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 *449 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.
*450 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 11
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 *451 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' associated with a particular TNF-mediated disease.” (Id. at col. 19, lines 26-30.)
121. The specification of the '766 patent contains three examples. (Id. at col. 20, line 37-col. 34, line 49.) The examples are based on human clinical trials involving rheumatoid arthritis patients. (Id.; Tr. at 155:10-156:5.)
122. These three examples were included in the '775 application. (Ex. 1419.1 at ABTKEN00000118-47.)
123. Example 1 of the '766 patent is drawn from the T-14 study undertaken by Professors Maini and Feldmann. (Tr. at 155:10-20; see id. at 508:10-13 ; see also ¶¶ 83-92.) This study was designed to evaluate the safety and efficacy of chimeric anti-TNFa antibody cA2 in multiple infusions, alone or in combination with methotrexate, in the treatment of rheumatoid arthritis patients. (Ex. 1 at col. 20, lines 43-9; see Ex. 1025 at 1552.)
124. The specification of the '766 patent notes that the patients enrolled in the T-14 study had been previously treated with methotrexate for at least six months, although they still had “active disease.” (Ex. 1 at col. 20, lines 51-56; see also supra ¶ 85.) A patient had “active disease,” as used in Example 1, if he or she had six or more swollen joints plus as least three of four secondary conditions,'such as prolonged morning stiffness or tender or painful joints. (Ex. 1 at col. 20, lines 56-61; see Tr. at 158:5-8.)
125. Although the patients in the T-14 study were taking methotrexate and still had active disease, that does not mean the patients were necessarily receiving no benefit from the methotrexate treatment. By August 1995, it was understood that rheumatoid arthritis, patients treated with methotrexate might, exhibit partial relief of their symptoms, but still have active disease. (See, e.g., Ex. FF at ABTKEN00444962; Ex. 1408.1 at ABTKEN00444909; Tr. at 174:25-177:3.) As described in the '766 patent, there is no way to determine if the T-14 study participants were partial responders to chronic methotrexate treatment or complete non-responders.
126. The specification of the '766 patent recounts, as described above (see supra ¶ 87), that the T-14 study was designed with- separate “arms” to compare the effect of various doses of an anti-TNFa antibody alone of in combination with methotrexate. (Ex. 1 at col. 20, lines 43-49; id. at col. 21, lines 13-24.)
127. The specification also states that the anti-TNFa chimeric antibody cA2 was administered to study participants by intravenous infusion. (Id. at col. 21, lines 2-12.)
128. As the specification notes, the patients were randomly' placed into one of seven treatment arms. The patients in the control arm received methotrexate tablets and infusions of a placebo throughout the trial. The patients in the three arms that received methotrexate tablets and antibody infusions throughout the trial received methotrexate at 7.5 mg a week and either 1, 3, or 10 mg/kg of cA2, respectively. The patients in the three arms that received placebo tablets and cA2 infusions throughout the trial received weekly placebo instead of methotrexate and received either 1, 3, or 10 mg/kg of cA2, respectively. (Id. at Table 1.) Patients received antibody (or placebo) infusions at weeks 0, 2, *452 6, 10, and 14 of the trial. (Id. at col. 21, lines 15-18.) There was no washout period between the last dose of “stabilizing” methotrexate and the assignment of patients to their treatment arm for the trial. (Tr. at 521:4-7.)
129. The specification 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-”:
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(Ex. 1 at col. 21-22.)
130. The specification explains that patients in the study were evaluated- at various intervals for 26 weeks using six primary disease-activity assessments and the Paulus index, which is used by rheumatologists to measure the clinical response to drugs in clinical trials. (Id: at col. 21, line 24-col. 22, line 23; Tr. at 142:3-22.)
131. The specification of the '766 patent further recounts that in the T-14 study, high clinical response rates were obtained with a multiple dose regimen of 3 mg/kg of cA2 in combination with weekly doses of 7.5 mg of methotrexate. Similar results were also obtained at the higher dose of 10 mg/kg of cA2 with weekly doses of 7.5 mg of methotrexate. The specification states that the 3 mg/kg dose of cA2 is “preferable to the 1 mg/kg plus methotrexate regimen because better pharmacokinetics are obtained, virtually no immune response was detected and the clinical response is better sustained following the last treatment with cA2.” (Ex. 1 at col. 31, lines 23-34.).
132. The- specification states that “the results of this study indicate that treatment with multiple infusions of cA2 as adjunctive and/or concomitant therapy to • methotrexate therapy is an important and efficacious therapeutic approach for treating [rheumatoid arthritis] in patients.” (Id. at col. 31, lines 44-48.)
133. Tables 2 through 5 of the specification of the '766 patent tabulate the results of the T-14 study, and, like Table 1, identify the treatment the groups of patients received as either “MTX+” or “MTX-” depending on whether during the infusion period of the trial they received cA2 and methotrexate or cA2 alone, respectively. (See id. Tables 2-5.)
134. The specification of the '766 patent summarized the T-14 study, stating that “the results of this study indicate that treatment with a multiple dose regimen of cA2 as adjunctive and/or concomitant therapy to methotrexate therapy, in [rheumatoid arthritis] patients whose disease is incompletely controlled by methotrexate, produces a highly beneficial or synergistic clinical response that can be sustained through 26 weeks.” (Id. at col. 31, lines 35-40.)
135. The synergy reported in the T-14 study, as submitted in the '775-application and recited in the '766 patent specification, is- based on a comparison of the results of co-administration of both drugs to the re- *453 suits of the administration of either drug alone. (Ex. 1419.1 at ABTKEN0000123537; Tr. at 237:17-243:12.)
136. Example 2 of the '766 patent reported a clinical study in which rheumatoid arthritis patients with active disease despite receiving chronic methotrexate treatment were given either the anti-TNFa antibody cA2 or a placebo. (Ex. 1 at col. 31, line 60-col. 32, line 3; Tr. at 155:21-25.)
137. “Active disease” for Example 2 is defined the same as in Example 1. (Ex. 1 at col. 31, line 65-col. 32, line 3.)
138. In this study, the patients received a weekly dose of 10 mg of methotrexate for at least four weeks prior to the study and then received a single administration of either the antibody cA2 or a placebo at a dose of 5, 10, or 20 mg/kg. (Id. at col. 31, line 54-65, Table 7; Tr. at 237:17-243:12.)
139. All of the patients in the study continued to receive a weekly dose of 10 mg of methotrexate throughout the duration of the twelve week trial. No patients in this study received antibody alone without methotrexate. (Ex. 1 at col. 32, lines 22-24.)
140. The specification of the '766 patent explains a single dose of antibody cA2, particularly at the 10 mg/kg and 20 mg/kg doses, produced a clinical response that was sustained for as long as twelve weeks after a single treatment. (Id. at col. 32, line 67-col. 33, line 4.)
141. The specification states that “the results of this study indicate that treatment with cA2 as adjunctive and/or concomitant therapy to methotrexate therapy is effective in the reduction of the signs and symptoms of rheumatoid arthritis in patients whose disease is incompletely controlled by methotrexate.” (Id. at col. 33, lines 19-23.)
142. Example 3 of the '766 patent specification is a continuation of the clinical trial described in Example 2. Twenty-three patients from the study were administered 10 mg/kg of antibody cA2 in an open label format at weeks 12, 20, and 28. During this period of the extension study, the patients continued to receive methotrexate administered at a dose of 10 mg/week. (Id. at col. 33, lines 35-50; Tr. at 156:1-5.)
143. As in Example 2, none of the patients in Example 3 received antibody alone. (Ex. 1 at col. 33, lines 35-49.)
144. In all three examples in the '766 patent specification, the clinical studies involved “adjunctive” therapy, wherein patients who had active rheumatoid arthritis, despite receiving methotrexate, continued to receive weekly methotrexate, and infusions of anti-TNFa antibody (at some interval) were added to this treatment. (Tr. at 159:6-9; see id. at 515:20-25; see generally Test, of Dr. Michael Weinblatt (describing and defining “adjunctive” therapy as adding one therapy to another, ongoing treatment). 12 )
145. The adjunctive therapy shown in the three examples of the '766 patent specification is one of three possible methods of “co-administration” of methotrexate and *454 an anti-TNFa antibody. In the parlance of “genus” and “species,” “co-administration” is the “genus” under which there are three “species,” or possible methods of co-administration, or ways to give two drugs to a patient: (1) treatment with methotrexate and antibody is started at the same time; (2) treatment with antibody is begun first and treatment with methotrexate is then added later while treatment with antibody continues; or (3) treatment with methotrexate is begun first and treatment with antibody is then added later while treatment with methotrexate continues. The latter two methods of co-administration constitute “adjunctive” therapy. (Tr. at 224:1-19.)
146. The '766 patent only provides examples where patients received adjunctive anti-TNFa antibody therapy with continuing methotrexate treatment. The examples do not include any situations in which patients began both drugs at the same time or started antibody first and added methotrexate; such treatment scenarios were (and are) unlikely because patients frequently were put on methotrexate treatment first and their responses evaluated to such treatment alone, before antibody treatment was considered, due to both the heightened intensity and expense of antibody treatment. (Id. at 224:20-225:11.)
E. Prosecution History of the '766 Patent
147. The original'775 application, filed on August 1, 1996, from which the '766 patent issued, included a total of 31 claims. (Ex. 1419.1 at ABTKE N00000068, - 00000154-57.)
148. Claim 1 in the'775 application was directed toward “[a] method for treating or preventing a tumor necrosis factor-mediated disease in an individual in need thereof comprising co-administering methotrexate and an anti-tumor necrosis factor antibody or fragment thereof to the individual, in therapeutically effective amounts.” (Id. at ABTKEN00000154.)
149. Claim 10 in the'775 application was directed toward “[a] method for treating or preventing rheumátoid arthritis in an individual in need thereof comprising eo-administering methotrexate and an anti-tumor necrosis factor antibody to the individual, in therapeutically effective amounts.” (Id. at ABTKEN00000155.)
150. Claims 11 and 12, which were dependent on Claim 10, referred to methods in which the anti-TNFa antibody and methotrexate were administered “simultaneously” and “sequentially,” respectively. (Id.)
151. Through several intermediate steps, Kennedy in the '755 application claimed priority back to the '248 application and its filing date of October 8, 1992. (Id. at ABTKEN00000079.)
152. On March 3, 1997, in the first “Office action,” the PTO rejected the pending claims. (Id. at ABTKEN00000587-95.) The PTO examiner denied the claimed priority date of the '248 application, stating that certain of the claims were not supported by the earlier applications that related back, and deemed the filing date of the claims to be August 1, 1996. (Id. at ABTKE N00000588.) The examiner also rejected the claims under 35 U.S.C. §§ 103 and 112. (Id. at ABTKEN00000588-94.)
153. Kennedy filed a response on September 3, 1997, “Amendment A,” which included amendments to the specification and claims, arguments responding to the objections and rejections set forth by the examiner in the first Office action, and Kennedy’s reply to the examiner’s denial of a priority date for the'775 application back to the earlier filed applications. (Id. at ABTKEN00000620-45, -00000656-57.)
*455 154. In Amendment A, Kennedy argued against the examiner’s rejections under 35 U.S.C. §§ 103 and 112, referring to the claimed invention as “co-administration” or “coadministering” of methotrexate and anti-TNFa antibody (or antagonist). (Id. at ABTKEN00000627, -00000630, - 100000644-45.)
155. Kennedy stated, “Applicants have exemplified the claimed methods using monoclonal anti-TNFa antibody cA2 in patients with active rheumatoid arthritis (see specification, e.g., Examples 1-3).” (Id. at ABTKEN00000628.)
156. Kennedy responded to the examiner’s rejections under 35 U.S.C. § 103 by arguing that the claimed co-administration methods resulted in unexpected results. Specifically, Kennedy argued that it had
demonstrated the unexpected result that combination therapy with methotrexate and an anti-TNFa antibody produced a rapid and sustained reduction in the clinical signs and symptoms of the treated autoimmune disease (see specification, e.g., page 4, lines 2-8; and Example 2). Applicants also demonstrated the unexpected and dramatic result that combination therapy with methotrexate and a multiple dose regimen of an antiTNFa antibody produced markedly superior results than the results obtained with each agent alone, particularly at low doses of methotrexate (see specification, e.g., page 4, lines 9-19 [ 13 ]; Examples 1-3). The magnitude of these results in the treatment of autoimmune or inflammatory disease could not have been reasonably predicted from the cited references, as illustrated in, for example, Figures 1A, 2A, 3A, 4A, 5A and Figure 7 of the specification. (Id. at ABTKEN00000644.)
' 157. The data that Kennedy relied' on to establish unexpected results of the claimed co-administration methods included Examples 1, 2, and 3 of the specification. (Id.)
158. In referring to the unexpected results that “combination therapy” produced, as compared to “each agent alone,” this latter designation covered both the group of patients in Example 1 who received methotrexate and infusions of placebo (instead of antibody) throughout the T-14 study, as well as the group of patients who stopped receiving methotrexate at the beginning of the infusion treatment and received infusions of antibody throughout the trial. Kennedy’s description of these two groups in Amendment A as having received “each agent alone” corresponds to what Professors Maini and Feldmann referred to as “monotherapy” in their published article on the T-14 study. (Tr. at 234:5-235:1; Ex. 1025 at 1553, 1560.)
159. On December 9, 1997, the PTO mailed a second Office action, again rejecting all of the pending claims. (Ex. 1419.1 at ABTKEN00000659-66.) In this action, the examiner again denied Kennedy’s claim for priority, stating that Kennedy hád not provided adequate support for the priority of the asserted claims, and as a result, the effective filing date of the '755 application remained August 1, 1996. (Id. at ABTKEN00000660.)
*456 160. In rejecting Kennedy’s unexpected results argument, the examiner noted, with respect to Example 1, that
the instant specification discloses that: the results of the study indicate that treatment with a multiple dose regimen of cA2 as adjunctive and/or concomitant therapy to methotrexate therapy, in [rheumatoid arthritis] patients whose disease is incompletely controlled by methotrexate, produces a highly beneficial or synergistic clinical response that can be sustained through 26 weeks.... Accordingly, the results of this study indicate that treatment with multiple infusions of cA2 as adjunctive and/or concomitant therapy to methotrexate therapy is an important and efficacious therapeutic approach for treating [rheumatoid arthritis] in patients. (Id. at ABTKEN00000663.)
161. With regards to Example 2, the examiner stated that
the instant specification discloses that: the results of the study indicate that treatment with cA2 as adjunctive and/or concomitant therapy to methotrexate therapy is effective in the reduction of the signs and symptoms of rheumatoid arthritis in patients whose disease is incompletely controlled by methotrexate.... Accordingly, the results of this study indicate that treatment with cA2 as adjunctive and/or concomitant therapy to methotrexate therapy is an important and efficacious therapeutic approach for treating [rheumatoid arthritis] in patients. (Id.)
162. The examiner rejected the pending claims, despite recognizing that Examples 1 and 2 — demonstrating adjunctive therapy — showed improved treatment results. (Id.)
163. On June 8, 1998, Kennedy responded to the second Office action with “Amendment B.” (Id. at ABTKEN00000997-1016.) Kennedy argued that the'775 application was entitled to the priority filing date of the '248 application, stating that “[a]t page 10, lines 6-9, the '248 application specifically recites the use of methotrexate in conjunction with an anti-TNF antibody.” (Id. at ABTKEN00000998.) As such, Kennedy argued that “the '248 specification provides support for these claims” and “[a]ccordingly, the claims are entitled to a priority date of October 8, 1992, the filing date of the '248 application.” (Id. at ABTKEN00000999. 14 )
164. In response to the examiner’s rejection under 35 U.S.C. § 112 , first paragraph, that the specification did not sufficiently enable the claimed methods, Kennedy argued that “the present specification provides human clinical data of the claimed co-administration.” (Id. at ABTKEN00001001 (emphasis omitted).)
165. In Amendment B, Kennedy responded to the examiner’s rejection under 35 U.S.C. § 103 by noting first that “Applicants’ invention relates to methods of ’ treating ... rheumatoid arthritis (claims 10-17) ... in an individual comprising co-administering methotrexate and an antiTNFa antibody[.]” (Id. at ABTKEN00001004.)
166. In response to the examiner’s rejection for obviousness and the examiner’s *457 comments in the second Office action with regard to Examples 1 and 2 of the specification, Kennedy repeated its argument that those examples demonstrated unexpected results of combination therapy with methotrexate and a TNFa antagonist, stating:
the Examiner’s summary of the results disclosed in Example 1 is consistent with Applicants’ assertions relating to the same example: that combination therapy with methotrexate and anti-TNFa produced markedly superior results than the results obtained with each reagent alone, particularly at low doses of methotrexate and that significant improvement of the combination therapy was observed even in comparison to where optimal dosages of anti-TNFa antibody were administered alone (see Amendment A at page 25). The Examiner’s summary of the results disclosed in Example 2 is also consistent with Applicants’ assertion relating to the same example: that combination therapy with methotrexate and anti-TNFa antibody produced a rapid and sustained reduction in the signs and symptoms of the treated autoimmune disease (see Amendment A at page 25). (Id. at ABTKEN00001006-07.)
167. On September 1, 1998, the PTO mailed an Office action rejecting the pending claims for the third time and denying Kennedy’s request for the priority date of the '248 application. (Id. at ABTKEN00001124-28.)
168. In denying Kennedy’s asserted priority to the '248 application, the examiner stated that the'775 application’s “limitations drawn to modes of administration encompassing ‘simultaneously,’ ‘sequentially’ and ‘multiple doses’ do not appear to receive written support or priority to” the '248 application, and “it does not appear that these various modes of administration as they encompass the instant combination of anti-TNF antibodies (or TNF antagonists) and methotrexate are supported in” the '248 application. (Id. at ABTKEN00001125.)
169. The examiner again rejected Kennedy’s claims as being obvious under 35 U.S.C. § 103 in view of several references in the prior art. (Id. at ABTKEN00001126-28.) Responding to Kennedy’s argument that the combination of methotrexate and an anti-TNFa antibody showed unexpected results, the examiner explained that
applicant’s arguments rely, in large part, to asserted synergistic effects disclosed in the instant examples, however it is noted that such effects were observed with certain patient populations with certain dosing. Such particular patient populations and particular dosing regimens are not claimed. (Id. at ABTKEN00001127 (emphasis added).)
170. After the third Office action was made final (see id. at ABTKEN00001128), Kennedy filed a Notice of Appeal on March 1, 1999, and an Appeal Brief on September 3, 1999, appealing the rejection of all the claims remaining in the application. (Id. at ABTKEN00001131-82.)
171. The Appeal Brief argued that
[t]he present invention relates to the discovery that a TNFa antagonist can be administered to patients suffering from a TNF-mediated disease (such as an autoimmune or inflammatory disease) as adjuvant or concomitant therapy to methotrexate therapy, with a rapid and sustained reduction in the clinical signs and symptoms of the disease. The present invention also relates to the unexpected discovery that a multiple dose regimen of a TNFa antagonist can be administered to patients suffering from a TNF-mediated disease as adjuvant or concomitant therapy to methotrexate *458 therapy, with a highly beneficial or synergistic clinical response for a significantly-longer duration compared to that obtained with a single or multiple dose regimen of the antagonist administered alone or that obtained with methotrexate administered alone. (Id. at ABTKEN00001137.)
172. Kennedy also argued “that the pending claims are entitled to a priority date of October 8, 1992, the filing date of the '248 application,” again relying, inter alia, on “page 10, lines 6-9, [of] the '248 application[, which] specifically recites the use of methotrexate in conjunction with an anti-TNF antibody.” (Id. at AJBT-KEN00001139.)
173. Kennedy further contested the examiner’s rejections for obviousness under 35 U.S.C. § 103 , again relying on Examples 1, 2, and 3 of the specification as evidence of the unexpected results of combination therapy, stating that
Appellants demonstrated the unexpected result that combination therapy with methotrexate and a TNFa antagonist produced unexpected synergistic effects between methotrexate and the TNFa antagonist (see, e.g., Figures 1A, 2A, 3A, 4A, 5A and Table 4 of the specification). Appellants also demonstrated the unexpected result that significantly reduced immunogenicity of anti-TNFa antibodies was obtained with combination therapy with methotrexate (see, e.g., page 57, line 30 to page 60, line 4, including Table 6, of the specification). Appellants further demonstrated the unexpected result that combination therapy with methotrexate and a TNFa antagonist produced high clinical response rates for significantly longer durations in comparison with that obtained with treatment with each therapeutic modality separately (see specification, e.g., page 4, lines 8-18; Examples 1-3 ...). (Id. at ABTKEN00001154.)
174. On November 23, 1999, the PTO examiner reopened prosecution by issuing a fourth Office action. (Id. at ABTKEN00001183-98.) The examiner determined that the '248 application did support certain claims of the'775 application, including claim 10, which was directed to treating rheumatoid arthritis, and granted these claims an effective filing date of October 8, 1992. (Id. at ABTKEN00001184.) The examiner maintained the rejection of certain claims under 35 U.S.C. § 112 , first paragraph, for lack of enablement. (Id. at ABTKEN00001187-88.) The examiner also rejected all of the claims under 35 U.S.C. § 102 (e) as being anticipated by several references, as well as under 35 U.S.C. § 103 . (Id. at ABTKEN0000118997.)
175. In response to Kennedy’s arguments regarding the asserted synergistic benefits disclosed in Examples 1, 2, and 3, the examiner elaborated on one of the bases for the previous rejections and stated in the fourth Office action that
[A]pplicant[s’] arguments rely, in large part, to the asserted synergistic effects disclosed in the instant examples. Applicants’] asserted synergistic effects are based on the comparison of each therapeutic modality used separately. Also, it has been noted that such effects were observed with certain patient populations with certain dosing. The putative synergistic effects relate to a particular multiple dose regiment of [sic] based upon cA2 and methotrexate therapy in rheumatoid arthritis patients whose disease is incompletely controlled by methotrexate (see page 62, paragraph 3 and page 66, paragraph 3 of the specification). Such particular patient populations, and particular dosing regimens are not claimed. *459 Also, it is noted that such effects observed with certain patient populations with certain dosing regimens does not discount the well known use and expectation of success in combining therapeutic agents to treat diseases. (Id. at ABTKEN00001196 (emphasis added).)
176. The examiner thus noted that of the three overarching treatment groups of patients — those who entered the study on methotrexate and continued receiving methotrexate and placebo, those who entered the study on methotrexate, continued to receive methotrexate, and also received antibody, and those who were receiving methotrexate, ceased receiving methotrexate at entry, but received antibody during the study — the putative synergistic benefits were experienced by the second (i.e., the group who stayed on methotrexate and received adjunctive cA2 treatment). The examiner explained that the unexpected results did not extend to the more broadly claimed “co-administration” methods generally (i.e., the evidence of unexpected results proffered only supported claims for the cA2 adjunctive therapy “species,” not the entire “genus” of co-administration). (Tr. at 239:7-241:4.) As such, the examiner refused to allow a broader claim to all ways of co-administering methotrexate and anti-TNFa antibody, as the evidence in Examples 1, 2, and 3 were not necessarily representative of the broader coverage sought, but merely of the cA2 adjunctive therapy.
177. The examiner continued:
The nonobviousness of a broader claim can be supported by evidence based on unexpected results from testing a species contained within the claim if one of ordinary skill in the art would be able to determine a trend • in the exemplified data which would allow the artisan to reasonably extend the probative value thereof to the broader claim.... Here, however, ... it does not appear that the specification provides sufficient objective evidence to extend unexpected results showing contained herein based upon the asserted synergistic effects of this .combination therapy in rheumatoid arthritis patients who were resistant to conventional therapy with methotrexate. (Ex. 1419.1 at ABTKEN00001197 (citations omitted).)
178. The examiner highlighted this distinction in comparing the scope of the methods claimed in the '248 application and the '775 application:
[A]pplicant[s’] assertion of synergistic results based upon by [sic] the limited clinical results [in] rheumatoid arthritis patients who were resistant to conventional therapy with methotrexate in the instant application appears inconsistent with applicants’] assertion of priority; wherein [the '248 application] simply disclosed that other anti-inflammatory agents such as methotrexate can be administered in conjunction with anti-TNF antibodies. (Id.)
179. On May 23, 2000, Kennedy mailed a response, “Amendment C,” to the fourth Office action, in which it amended two claims and argued that all the claims in the subject application should be entitled to the same benefit of a priority date of the '248 application. Kennedy also continued to argue against the 35 U.S.C. § 112 , first paragraph, rejection based on lack of an enabling disclosure. (Id. at ABTKEN00001216-39.)
180. In response to the examiner’s rejections for obviousness under 35 U.S.C. § 103 , Kennedy asserted that the clinical data in the specification evidenced that
Applicants demonstrated the unexpected result that combination therapy with methotrexate and a TNFa antagonist produced unexpected synergistic effects between methotrexate and the TNFa *460 antagonist (see, e.g., Figures 1A, 2A, 3A, 4A, 5A and Table 4 of the specification) .... Applicants further demonstrated the unexpected result that combination therapy with methotrexate and a TNFa antagonist produced high clinical response rates for significantly longer durations in comparison with that obtained with treatment with each therapeutic modality separately (see specification, e.g., page 4, lines 8-18; Examples 1-3 ...). (Id. at ABTKEN00001235.)
181. Kennedy’s argument compared the group of patients who received methotrexate and placebo and the group who stopped receiving methotrexate at entry but received infusions of antibody throughout the study, to the group of patients who continued to receive methotrexate and also received antibody infusions, and asserted that there was an unexpected synergistic response when the two drugs were combined. (Tr. at 237:17-239:6.)
182, Responding to the examiner’s statements in the fourth Office action that the synergistic effects were observed only with “certain patient populations with certain dosing,” and that “[s]uch particular patient populations and particular dosing regimens are not claimed,” Kennedy argued that
[t]here is no technical reason to believe that the synergistic effects exemplified in the specification by combination therapy with methotrexate and a TNFa antagonist is limited to a certain patient population. That is, there is no technical reason to believe that treatment with a combination of methotrexate and a TNFa antagonist, in accordance with Applicants’ teachings, would not yield the superior therapeutic effects described in the subject application. The superior therapeutic effects are due to co-administration of methotrexate and a TNFa antagonist functionally limited to therapeutically effective amounts, as described in the specification. (Ex. 1419.1 at ABTKEN00001236 (emphasis added).)
183. Thus, Kennedy, drawing supporting data from the clinical trials in Examples 1, 2, and 3, in which a TNFa antagonist was administered as adjunctive therapy to patients with an inadequate response to ongoing methotrexate treatment, argued that these data were representative of the broader genus of “co-administration” of methotrexate and a TNFa antagonist to treat patients with rheumatoid arthritis (i.e., Kennedy argued that the results observed in the cA2 adjunctive treatment group were representative of what one would expect when co-administering methotrexate and anti-TNFa antibody generally). (Tr. at 241:5-242:13.)
184. In its prosecution of the'775 application, Kennedy did not distinguish between the antibody adjunctive treatment group, in which patients on continuing methotrexate were given infusions of cA2, and either of the other-possible methods of co-administration — starting patients on both antibody and methotrexate at the same time or starting patients on antibody first then adding methotrexate treatment later — because the T-14 trial did not study either of these methods. {Id. at 242:14-23.)
185. Furthermore, in the entirety of the '766 patent file history, Kennedy never suggested that there was an additional form of co-administration — distinct from one in which antibody was administered as adjunctive therapy to ongoing methotrexate — in which antibody was administered as “sequential co-administration” to the methotrexate therapy. (Id. at 242:24-243:4; see also id. at 564:1-13 .)
186. As Professor Maini testified at trial, this is consistent with the subsequently *461 published article on the T-14 study, in which the patients who received infusions of cA2 were described as being given antibody either “alone or in combination with” methotrexate, and where “co-administration” referred to the group who had received cA2 adjunctive therapy added to ongoing methotrexate treatment. Professor Maini testified that the patients who stopped receiving methotrexate upon entry to the T-14 trial at week 0 and received infusions of cA2 throughout the trial were not referred to in the published study as having received “sequential coadministration” because the phenomenon of these patients experiencing superior results at the beginning of the trial was not “scientifically proven to be due to sequential co-administration ... [and] because it was not scientifically proven, as a scientist, I did not think it was appropriate to draw attention to a phenomenon that I could not scientifically support, and therefore, I haven’t referred to it.” Professor Maini explained that this phenomenon “wasn’t the subject of what I believed that our study had proven conclusively, which was adjunctive therapy.” (Id. at 564:14-570:24; see id. at 523:9-525:15 .)
187. After a June 13, 2000 interview between the examiner, Kennedy’s counsel, Professor Feldmann, and others, Kennedy filed a Supplemental Amendment on August 7, 2000, and indicated that at the interview Kennedy and the PTO examiner had agreed that each of the pending claims was entitled to a priority date of October 8, 1992, the filing date of the '248 application. 15 (Ex. 1419.1 at ABTKEN0000124253.)
188. On October 25, 2000, the examiner issued a Notice of Allowability indicating that the application, and all the claims therein, were allowable. (Id. at ABTKEN00001288.) The examiner’s reasons for allowance indicated that the pending claims were deemed allowable upon reconsideration of Kennedy’s amended claims and arguments, and in view of the unexpected results. (Id. at ABTKEN00001290.)
189. On August 7, 2001, the PTO issued the '766 patent. (Ex. 1.)
F. The '004 Application
190. Shortly after the Notice of Allowability of the '766 patent, on January 3„ 2001, Kennedy filed Application No. 09/754,004 (the “'004 application”) as a continuation application of the'775 application. The '004 application named Professors Maini and Feldmann as inventors and the Kennedy Institute of Rheumatology Trust as assignee. (Ex. 1423.1 at ABTKEN00032566-32710.)
191. The'004 application claimed priority to the '248 application through the same series of applications as the'775 application. (Id. at ABTKEN00032646.)
192. Original claim 1 was directed to “[a] method for treating or preventing a tumor necrosis factor-mediated disease in an individual in need thereof comprising co-administering methotrexate and a TNFa antagonist to said individual, in therapeutically effective amounts.” (Id. at ABTKEN00032701.)
193. Original claim 29 was directed to “[a] method for treating or preventing rheumatoid arthritis in an individual in *462 need thereof comprising co-administering methotrexate and a TNFa antagonist to said individual, in therapeutically effective amounts.” (Id. at ABTKEN00032703.) •
194. Original claims 30 and 31 were directed to methods of claim 29 wherein the TNFa antagonist and methotrexate were administered “simultaneously” and “sequentially,” respectively. (Id. at ABTKEN00032703-04.)
195. In an Office action mailed December 9, 2002, the examiner rejected all of the pending claims. (Id. at ABTKEN00033087-88.) The examiner did not grant the'004 application the benefit of the October 8, 1992 filing date of the '248 application, explaining that the priority applications did not support the pending claims. Accordingly, the filing date of the'004 application was deemed to be August 1, 1996. (Id. at ABTKEN00033090.)
196. The examiner also rejected the pending claims on several grounds under 35 U.S.C. §§ 101 , 102, 103, 112 and under the judicially-created doctrine of obviousness-type double patenting over claims the '766 patent. (Id. at ABTKEN0003309195.)
197. On June 17, 2003, Kennedy submitted an amendment in response to the December 9, 2002 Office action. Kennedy amended its claims and the first paragraph of the specification and maintained the asserted priority date of the-'248 application. (Id. at ABTKEN00033122-23, -00033098, - 00033111-12, -00033099.) Kennedy characterized the invention as “methods for treating or preventing an inflammatory disease in an individual in need thereof comprising co-administering methotrexate and a TNFa antagonist to said individual, in therapeutically effective amounts.” (Id. at ABTKEN00033100.)
198. Kennedy argued that its invention was not obvious under 35 U.S.C. § 103 by, in part, highlighting the claimed
unexpected results of treating an inflammatory disorder with a combination of methotrexate and a TNF antagonist. These results are exemplified by the data set forth in Figures 1A, 2A, 3A, 4A, 5A and Table 4 of the specification. [Kennedy also draws] the Examiner’s attention to the unexpected result that combination therapy with methotrexate and a TNF antagonist produced high clinical response rates for significantly longer durations in comparison with that obtained with treatment with each therapeutic modality separately (see, e.g., page 3, linés 18-24, Examples 1-3; particularly, page 35, lines 5-8, page 37, lines 1-3, pages 36-37 (Table 3), pages 38-39 (Table 4), page 46, line 24 through page 47, line 8 of Example 1; page 48, line 20 through page 50, line 8 of Example 2; and page 51, lines 8-32 of Example 3). (Id. at ABTKEN00033105.)
199. The June 17, 2003 amendment did not respond to-the examiner’s obviousness-type double patenting rejection. (Id. at ABTKEN00033098-33112,-0033122-23.)
200. On November 4, 2003, the examiner mailed another Office action rejecting the pending claims. (Id. at ABTKEN00033334-41.) The examiner stated that while Kennedy’s amendment again sought the- October 8, 1992 priority date of the '248 application, it “did not address” the examiner’s -position that the pending claims were not supported by the earlier application; accordingly, the examiner maintained the August 1, 1996 effective filing date. (Id. at ABTKEN00033336.) The examiner also rejected Kennedy’s arguments in response to the rejections under 35 U.S.C. §§ 102 and 103. (Id. at ABTKEN00033337-40.)
*463 201. In the November 4, 2003 Office action, the examiner also stated that in the absence of any rebuttal from Kennedy to the examiner’s rejection under the doctrine of obviousness-type double patenting, “[i]t appears that applicant has acquiesced to the double patenting rejection of record.” (Id. at ABTKEN00033340.)
202. On February 4, 2004, Kennedy sent its response to the November 4, 2003 Office action, again repeating the argument that the'004 application was entitled to the 1992 priority date of the '248 application, and specifically argued that “[a]t page 10, lines 6-9, the '248 Application specifically teaches the use of methotrexate in conjunction with an anti-TNF antibody.” (Id. at ABTKE N00033345.)
203. In responding to the rejections for obviousness under 35 U.S.C. § 103 , Kennedy relied on the same evidence of unexpected results as in the prior amendment. (Id. at ABTKEN00033351-52; see supra ¶ 198.)
204. Kennedy also stated that it inadvertently failed to respond to the examiner’s obviousness-type double patenting rejection. Kennedy stated that it intended to file a terminal disclaimer with regards to the '766 patent “once the claims are otherwise in condition for allowance.” (Ex. 1423.1 at ABTKEN00033355.)
205. On March 26, 2004, the examiner mailed an Advisory Action maintaining the prior rejections (id. at ABTKEN0003335759), to which Kennedy responded in a supplemental amendment on August 6, 2004 (id. at ABTKEN00033366-402). The supplemental amendment referenced a May 4, 2004 notice of appeal and a July 27, 2004 interview with the examiner. (Id. at ABTKEN00033401.)
206. The August 6, 2004 supplemental amendment included a chart in furtherance of Kennedy’s argument that each of the pending claims in the '004 application was supported by the 1992 '248 application through intermediate patents and applications. (Id. at ABTKEN00033372-73.)
207. In response to the examiner’s rejection under 35 U.S.C. § Í03, Kennedy again argued that the claimed co-administration methods showed unexpected results, relying on the same clinical data as before. (Id. at ABTKEN00033378-83.)
208. Kennedy responded to the obviousness-type double patenting rejection based on the '766 patent by arguing that the rejection was moot as to the canceled claims and that with respect to the other claims, Kennedy intended to file a terminal disclaimer for the '766 patent. (Id. at ABTKEN00033383-84.)
209. On March 11, 2005, the examiner mailed an Office action rejecting all of the pending claims. (Id. at ABTKEN00033455-64.) Kennedy did not respond to this Office action, and the'004 application was abandoned. (Id. at ABTKEN00033475-76.)
G. The '631 Application
210. On September 12, 2005, Kennedy filed U.S. Patent Application No. 11/225,-631 (the “'631 application”). The '631 application named Professors Maini and Feldmann as inventors. (Ex. 1420.1 at ABTKEN00001307-11.)
211. The original '631 application included 38 claims (id. at ABTKEN00001364-67), but a concurrently filed preliminary amendment canceled all the claims except for independent claim 1 (id. at ABTKEN00001386-89.) Claim 1 was directed to “[a] method for treating or preventing a tumor necrosis factor-mediated disease in an individual in need thereof comprising co-administering methotrexate and a TNFa antagonist to said individual, *464 in therapeutically effective amounts.” (Id. at ABTKEN00001388.)
212. The original'631 application claimed benefit to the '248 application, filed October 8, 1992, through the same series of applications as the'775 and'004 applications. (Id. at ABTKEN00001387.)
213. Kennedy filed a second preliminary amendment on January 12, 2006, and revised the first paragraph of the specification, while still asserting the benefit of the October 8, 1992 date. (Id. at ABTKEN00001392-94.)
214. On January 18, 2007, Kennedy filed a third preliminary amendment, which canceled claim 1 (in addition to previously canceled claims 2 through 38), and added 33 new claims, which were all method claims. (Id. at ABTKEN00001414-27.)
215. The new claims began at claim 39, which was directed toward:
[a] method of treating an individual suffering from a human tumor necrosis factor-mediated disease comprising adjunctively administering with methotrexate an anti-human tumor necrosis factor-a antibody or a fragment thereof to the individual, wherein the anti-human tumor necrosis factor-a antibody or a fragment thereof (a) binds to an epitope on human tumor necrosis factor-a, (b) inhibits binding of human tumor necrosis factor-a to human tumor necrosis factor-a cell surface receptors and (c) is administered at a dosage of 0.01-100 mg/ kg/day. (Id. at ABTKEN00001419.)
216. Similarly, claim 41 of the amended'631 application was directed toward:
[a] method for adjunctive treatment of an individual suffering from rheumatoid arthritis who is already being treated with methotrexate weekly comprising administering an anti-tumor necrosis factor-a antibody or a fragment thereof to the individual, wherein the anti-human tumor necrosis factor-a antibody or fragment thereof is administered to the individual multiple times, each such administration (i) being separated by an interval of weeks from the prior administration, and (ii) delivering 0.01-100 mg/ kg/day of the anti-human tumor necrosis factor-a antibody or fragment thereof. (Id. at AJBTKEN00001420.)
217. In response to a December 21, 2007 Office action requiring restriction of the claimed invention pursuant to 35 U.S.C. § 121 (see id. at ABTKEN00001430-35), on June 23, 2008, Kennedy filed an amendment, which, in part, amended the first paragraph of the specification setting forth the claimed priority to the '248 application and deleted the four oldest prior applications. As so amended, the'631 application claimed the benefit of the August 1, 1996 priority date of the'775 application instead of the October 8, 1992 priority date of the '248 application. 16 (Id. at ABTKEN00004539.)
218. On April 15, 2009, the examiner mailed an Office action, in which the examiner acknowledged the amended claim to a priority date and rejected or withdrew all the pending claims on various grounds, including under 35 U.S.C. § 103 , and for obviousness-type double patenting over claims 1 through 14 of the '766 patent. (Id. at ABTKEN00006935-46.)
219. In explaining the rejection for obviousness-type double patenting, the examiner stated:
Although the conflicting claims are not identical, they are not patentably distinct from each other because the pat *465 ented claims anticipate or render obvious the instant claimed methods, as-the instant and patented claims are drawn to the same or nearly the same methods of treating arthritis with the anti-TNFa antibodies and methotrexate to meet the needs of the patient.
It is well settled that discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art....
As manipulating combination therapy was known and readily practiced by the ordinary artisan at the time the invention was made, it would have been obvious to optimize the dosing and dosing regimens of both the conventional methotrexate treatment as a disease modifying anti-rheumatic disease drug treatment (e.g., DMARDs) as well as the anti-TNFa antibodies in the treatment of rheumatoid arthritis. (Id. at ABTKEN00006945-46 (internal citations and quotations omitted).)
220. On August 5, 2009, the examiner held an interview with Professor Feldmann and Kennedy’s representatives. (Id. at ABTKEN00007107.)
221. On September 15, 2009, Kennedy filed a response to the April 15, 2009 Office action, including amendments to the claims and remarks, and a summary of the interview held on August 5, 2009. (Id. at ABTKEN00007108-77.) In the interview summary, Kennedy stated that its proposed amendments to the claims were being made to
make clear that the present invention involved the treatment of patients with active arthritis whose disease is incompletely controlled despite already receiving methotrexate by adjunctively administering with methotrexate therapy a different composition comprising an anti-human tumor necrosis factor a antibody or a fragment thereof to the individual. (Id. at ABTKEN00007110 (emphasis added).)
222. In addition, Kennedy’s summary of the interview recounted that, with respect to the obviousness-type double patenting rejection over the '766 patent, “Applicants noted that claims 1-14 of the ['766] patent ... are not directed to the same patient population as is claimed in the present application and are not directed to adjunctive therapy.” Kennedy further recounted that “Applicants also noted that their claimed present invention provides unexpected results that demonstrate that the claimed invention is not obvious over claims 1-14 of the '766 Patent.” (Id. at ABTKEN00007117.)
223. .Kennedy responded to the rejections under 35 U.S.C. § 103 by arguing that the prior art combinations of methotrexate with other arthritis therapies did not provide the benefits obtained by adjunctively administering an anti-TNFa antibody to a patient already receiving methotrexate. Specifically, Kennedy stated that
[a]s discussed above, combination therapy includes numerous different types of associations such as simultaneous, sequential, separate, parallel, or intermittent administration of two or more therapeutic agents. The choice of a TNF-antagonist in adjunctive therapy was not obvious over the cited references. The advantages obtained using the claimed adjunctive therapy are NOT obtained with other types of combination. (Id. at ABTKEN00007138 (emphasis added).)
224. Kennedy’s statement that the “advantages obtained using the claimed adjunctive therapy are NOT obtained with other types of combination” is inconsistent with prior statements Kennedy made during the prosecution of the '766 patent, *466 where Kennedy asserted that the adjunctive therapy results in Examples 1, 2, and 3 of the specification were representative of broader co-administration of methotrexate and a TNFa antagonist to treat patients with rheumatoid arthritis (i.e., that the results of adjunctive treatment group were representative of what one would expect from co-administering methotrexate and anti-TNFa antibody generally). (Ex. 1419.1 at ABTKEN00001235-36; Tr. at 241:5-242:13; see supra ¶¶ 182,183.)
225. ,.I-n responding to,the examiner’s obviousness rejection, Kennedy also relied on the alleged unexpected results obtained by. adjunctively administering antiTNFa antibody to a patient population already receiving, but failing to respond to, methotrexate' therapy. (Ex. 1420.1 at ABTKEN00007143-44; see id'. at ABTKÉN00001346-50.) In taking this position, Kenhedy relied on the same data from the T-14 study as it had in the prosecution of the '766 patent. (Compare id. at ABTKEN00007143-44 (citing underlying data at page 35, lines 1 through 8, and Tables 3 and 4 of specification) and - 00001346-50 (containing underlying data at page'35, lines 1 through 8, and Tables 3 and 4 of specification), with Ex. 1419.1 at ABTKEN00001235-36 (citing, inter alia, same' underlying data at page 48, lines 6 through 11, and Tables 3 and 4 of specification) and -00000126-31 (containing same underlying data at page 48, lines 6 through 11, and Tables 3 and 4 of specification); see Tr. at 155:10-20; see also supra ¶¶ 184, 185, 186.)
22’6. With regard to the examiner’s obviousness-type double patenting rejection based on the '766 patent, Kennedy attempted to distinguish claims 1 through 14 of the '766 patent directed to co-administration from those in the pending application directed to adjunctive therapy. Specifically, Kennedy stated that
Applicants note that, in contrast to claims 1-14 of the '766 Patent, the individuals are already receiving methotrexate therapy in all of the pending claims. Additionally, the individuals still have active disease in the pending claims, despite having undergone methotrexate therapy. Claims 1-14 of the '766 Patent are generic with respect to these claim elements. For instance, the '766 Patent claims include individuals who did and . who. did not receive methotrexate. Likewise, they include individuals who are and who are not receiving benefit from methotrexate.
Applicants also note that the pending claims also differ from the '766 Patent claims in that the pending claims are directed to adjunctive therapy, a particular type of combination therapy. In contrast, the '766 Patent claims include adjunctive, sequential and simultaneous therapy.
Applicants further note that, in further contrast to the '766 Patent claims, the pending claims are limited to administration of anti-TNFa antibody in a separate composition from methotrexate. The '766 Patent claims include administration of anti-TNFa antibody and methotrexate in the same or separate compositions. (Ex. 1420.1 at ABTKEN00007151.)
227. Although Kennedy’s September 15, 2009 filing stated that the pending claims covered only administration of the antibody and methotrexate in separate compositions while the '766 patent claims administration of the antibody and methotrexate in the same or separate compositions, it was well known by the August 1995 that methotrexate was more frequently administered in tablet form, while anti-TNFa antibody was administered "via infusion (i.e., in separate compositions). *467 (See Tr. at 150:8-12, 167:15-168:18; see also supra ¶ 14.)
228. Kennedy also argued that the claimed invention was not obvious to try because “it is well known that methotrexate is toxic.... As the patients had already failed treatment with methotrexate, it would not be obvious to try to continue methotrexate therapy, given its known toxicity, while commencing anti-TNFa antibody therapy.” (Ex. 1420.1 at ABTKEN00007151-52.) By August 1995, however, it was a well-established practice to continue treating with methotrexate rheumatoid arthritis patients who had not completely responded to such treatment (in order to prevent flares), while adding another therapeutic agent to the methotrexate treatment. (See, e.g., supra ¶¶ 16, 17, 18.)
229. To buttress the argument that the claimed invention was not obvious, Kennedy claimed there was no reasonable probability of success because “in patients who are not responding to methotrexate, there is no basis to expect them to respond to treatment with an anti-TNFa antibody administered adjunctively with methotrexate as opposed to anti-TNFa antibody monotherapy.” (Ex. 1420.1 at ABTKEN00007153.) By August 1995, however, rheumatoid arthritis patients who had not responded completely to methotrexate alone were often treated with a second therapy in combination with continuing methotrexate treatment. (See, e.g., supra ¶¶ 16, 17, 18.)
230. Kennedy again claimed the unexpected results of “adjunctive” therapy over purported “sequential” therapy methods in arguing against the examiner’s obviousness-type double patenting rejection. (Ex. 1420.1 at ABTKEN00007153-55.) As noted above (see supra ¶¶ 224, 225), however, the data Kennedy cited to support these alleged unexpected results were the same data it had previously cited in support of its argument that the results of adjunctive therapy were representative of the results of co-administration generally. (Compare Ex. 1420.1 at ABTKEN00007154 (citing underlying data at page 35, lines 1 through 8, and Tables 3 and 4 of specification) and -00001346-50 (containing underlying data at page 35, lines 1 through 8, and Tables 3 and 4 of specification), with Ex. 1419,1 at ABTKEN00001235-36 (citing, inter alia, same underlying data at page 48, lines 6 through 11, and Tables 3 and 4 of specification) and -00000126-31 (containing same underlying data at page 48, lines 6 through 11, and Tables 3 and 4 of specification).) Furthermore, as Professor Maini testified at trial, these data did not support Kennedy’s assertion of unexpected results because “sequential co-administration” was not a subject of the relevant research, which instead had focused on adjunctive therapy. (See, e.g., supra ¶ 186.)
231. In addition, Kennedy argued that the results from the claimed invention were unexpected because the “efficacy of the adjunctive therapy is clearly unrelated to any reduction in the development of an antiglobulin response to the anti-TNFa antibody in the patient, i.e. a HACA response, because the antibody is no longer present at therapeutic levels.” (Ex. 1420.1 at ABTKEN00007154.)' Kennedy stated that “it is again clear that a reduced HACA response cannot be the basis for the improvement in methotrexate therapy.” (Id. at ABTKEN00007154-55.)
232. This assertion contradicts, inter alia, Kennedy’s prior arguments to the PTO, Professor Maini and Feldmann’s scientific articles, the '766 patent, and Professor Maini’s testimony at trial, all of which identified reduction in immunogenicity (i.e., reduction in the HACA response) as one of the benefits of co-administration of anti-TNFa antibody and methotrexate. *468 (See, e.g., supra ¶¶ 84, 91, 92, 93, 116, 173 & n. 10.)
233. Furthermore, the studies and data that Kennedy cited as support for these alleged unexpected results (and which Kennedy cited in the prosecution of the '776 patent) did not compare adjunctive with co-administration therapy; these materials only included situations where patients received adjunctive anti-TNFa antibody therapy to continuing methotrexate treatment. As such, these materials provide no basis to conclude that adjunctive administration of an anti-TNFa antibody to methotrexate therapy provides unexpectedly better results compared to other forms of co-administration of methotrexate and an anti-TNFa antibody. (See, e.g., supra ¶¶ 146,184,186.)
234. On December 24, 2009, the PTO mailed a third Office action, in which the examiner responded to Kennedy’s September 15, 2009 filing by withdrawing the previous grounds for rejection of the claimed invention in the'631 application. (Ex. 1420.1 at ABTKEN00008453, -00008456.)
235. The examiner rejected, however, the asserted claims under, inter alia, 35 U.S.C. §§ 102 and 103. (Id. at ABTKEN00008456-64.)
236. The examiner also maintained the obviousness-type double patenting rejection of the claims over claims 1 through 14 of the '766 patent, stating:
Although the conflicting claims are not identical, they are not patentably distinct from each other because the patented claims anticipate or render obvious the instant claimed methods, as the instant and patented claims are drawn to the same or nearly the same methods of treating arthritis with the anti-TNFa antibodies and methotrexate to meet the needs of the patient. (Id. at AJ3T-KEN00008465.)
237. The examiner also stated that
it would have been obvious to optimize the dosing and dosing regimens of both the conventional methotrexate treatment in the treatment of arthritis as well as the anti-TNFa antibodies in the treatment of diseases/conditions associated with arthritis. (Id. 17 )
238. On May 7, 2010, Kennedy mailed a response amending certain claims, canceling certain claims, responding to the examiner’s rejections, and; summarizing a February 23, 2010 interview with the examiner. (Id. at ABTKEN000084748526, -00008761-64, -00008935-36.)
239. In its summary of the February 23, 2010 interview, Kennedy stated that the claimed invention of adjunctive therapy was “an unobvious species of claims 1-14 of the '766 Patent.” (Id. at ABTKEN00008483.)
240. Kennedy’s assertion contradicted its prior argument tó the PTO,’ made during the prosecution of the '766 patent, that the adjunctive species was representative of the broader co-administration genus. (See, e.g., supra ¶¶ 182,183.)
241. In responding to the examiner’s rejection under 35 U.S.C. § 103 , Kennedy repeated the argument it made in its prior response to the PTO and stated that “the advantages obtained by adjunctively administering with methotrexate therapy anti-human tumor necrosis faetor-a antibodies are not obtained with other types of combination therapy.” (Ex. 1420.1 at ABTKEN00008495.) This is also inconsistent with Kennedy’s prior argument to the PTO during the prosecution of the '766 *469 patent, when — in order to get the examiner to allow broader claims 1 through 14 of the '766 patent related to the genus of co-administration — Kennedy asserted that adjunctive therapy was representative of combination therapy. (See, e.g., supra ¶¶ 182, 183; see also Ex. 1419.1 at ABTKEN00001235-36.)
242. Kennedy also stated that “Applicants discovered the unexpected result that patients who failed to respond to methotrexate therapy showed a remarkably high response rate when they were adjunctively administered methotrexate therapy with an anti-human tumor necrosis factored antibody therapy, even after disappearance of therapeutic levels of antibody.” (Ex. 1420.1 at ABTKEN00008508 (emphasis omitted).) Once again, however, the studies and data on which Kennedy relied in making this assertion were the same as those Kennedy had cited in support of the asserted unexpected benefits of co-administration generally during the prosecution of the '766 patent. (Compare id. at ABTKEN00008508-09 (citing underlyi

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Source: Frix Law Library, https://www.frixlaw.com/law-library/cases/8709810. Public record. Not legal advice.