Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 1 of 77 PageID #: 10732
`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF DELA WARE
`
`
`THE RESEARCH FOUNDATION OF
`
`STATE UNIVERSITY OF NEW YORK;
`
`NEW YORK UNIVERSITY; GALDERMA :
`
`LABORATORIES, INC.;
`
`GALDERMA LABORATORIES, L.P.; and:
`
`SUPERNUS PHARMACEUTICALS
`
`
`Plaintiffs
`
`v.
`
`Civ. No. 09-184-LPS
`
`MYLAN PHARMACEUTICALS INC.,
`
`Defendants.
`
`MYLAN PHARMACEUTICALS INC.,
`
`Plaintiffs
`
`v.
`
`Civ. No. 1O-892-LPS
`
`THE RESEARCH FOUNDATION OF
`STATE UNIVERSITY OF NEW YORK;
`NEW YORK UNIVERSITY; GALDERMA :
`LABORATORIES, INC.;
`GALDERMA LABORATORIES, L.P.; and :
`SUPERNUS PHARMACEUTICALS
`
`Defendants.
`
`OPINION
`Jack B. Blumenfeld, Maryellen Noreika, MORRIS, NICHOLS, ARSHT & TUNNELL, LLP,
`Wilmington, DE; Gerald J. Flattmann, Jr., Christine Willgoos, Joseph O'Malley, Melanie Rupert,
`PAUL, HASTINGS, JANOFSKY & WALKER LLP, New York, NY, Attorneys for Plaintiffs.
`
`Richard L. Horwitz, David E. Moore, POTTER, ANDERSON & CORROON, LLP, Wilmington,
`DE; David S. Steur, Matthew R. Reed, Kirin K. Gill, Palo Alto, CA; Tung-On Kong, San
`Francisco, CA; Lori P. Westin, San Diego, CA, WILSON SONSINI GOODRICH & ROSATI,
`Attorneys for Defendant.
`
`August 26,2011
`Wilmington, DE
`
`
`
`IN THE UNITED STATES DISTRICT COURT
`
`FOR THE DISTRICT OF DELA WARE
`
`
`THE RESEARCH FOUNDATION OF
`
`STATE UNIVERSITY OF NEW YORK;
`
`NEW YORK UNIVERSITY; GALDERMA :
`
`LABORATORIES, INC.;
`
`GALDERMA LABORATORIES, L.P.; and:
`
`SUPERNUS PHARMACEUTICALS
`
`
`Plaintiffs
`
`v.
`
`Civ. No. 09-184-LPS
`
`MYLAN PHARMACEUTICALS INC.,
`
`Defendants.
`
`MYLAN PHARMACEUTICALS INC.,
`
`Plaintiffs
`
`v.
`
`Civ. No. 1O-892-LPS
`
`THE RESEARCH FOUNDATION OF
`STATE UNIVERSITY OF NEW YORK;
`NEW YORK UNIVERSITY; GALDERMA :
`LABORATORIES, INC.;
`GALDERMA LABORATORIES, L.P.; and :
`SUPERNUS PHARMACEUTICALS
`
`Defendants.
`
`OPINION
`Jack B. Blumenfeld, Maryellen Noreika, MORRIS, NICHOLS, ARSHT & TUNNELL, LLP,
`Wilmington, DE; Gerald J. Flattmann, Jr., Christine Willgoos, Joseph O'Malley, Melanie Rupert,
`PAUL, HASTINGS, JANOFSKY & WALKER LLP, New York, NY, Attorneys for Plaintiffs.
`
`Richard L. Horwitz, David E. Moore, POTTER, ANDERSON & CORROON, LLP, Wilmington,
`DE; David S. Steur, Matthew R. Reed, Kirin K. Gill, Palo Alto, CA; Tung-On Kong, San
`Francisco, CA; Lori P. Westin, San Diego, CA, WILSON SONSINI GOODRICH & ROSATI,
`Attorneys for Defendant.
`
`August 26,2011
`Wilmington, DE
`
`
`
`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 2 of 77 PageID #: 10733
`
`r ~ ~.,
`
`- j '
`
`~I-''')~
`Stark, U.S. District Judge:
`
`In July 2011, the Court held a four-day bench trial in this patent infringement action
`
`brought pursuant to the Hatch-Waxman Act. The case arises from Defendant's efforts to bring to
`
`market a generic version of Plaintiffs' Oracea® drug product, a once-daily 40 milligram (mg)
`
`administration of doxycycline indicated for the treatment of acne rosacea. Plaintiffs assert that
`
`claims of five separate patents are infringed. Defendants contend that all five patents are
`
`invalid. 1 As explained below, the Court concludes that the asserted claims of one patent-in-suit
`
`are infringed and valid. The preliminary injunction entered in July 2010 will remain in effect
`
`pending the Court's receipt and review of supplemental briefing as to an appropriate permanent
`
`remedy.2
`
`I.
`
`PARTIES
`
`FINDINGS OF FACT
`
`1.
`
`Plaintiff The Research Foundation of State University of New York ("RF
`
`SUNY") is a private, non-profit corporation organized and existing under the laws of the State of
`
`New York, having a principal place of business in Albany, New York. (Statement of
`
`
`
`Uncontested Facts (C.A. 09-184-LPS D.L 257-1 3) ("SUF")'; 1)
`
`IThere are five patents-in-suit. The "Ashley Patents" are U.S. Patent No. 7,211,267 ("the '267
`patent") (PTX 1) and U.S. Patent No. 7,232,572 ("the '572 patent") (PTX 2). The "Amin
`Patents" are U.S. Patent No. 5,789,395 ("the '395 patent") (PTX 3) and U.S. Patent No.
`5,919,775 ("the '775 patent") (PTX 4). Finally, the "Chang Patent" is U.S. Patent No. 7,749,532
`("the' 532 patent"). (PTX 5)
`
`2This opinion constitutes the Court's findings of fact and conclusions oflaw pursuant to Fed. R.
`Civ. Proc. 52(a).
`
`3All citations to Docket Index ("D.I.") entries are to C.A. 09-184-LPS, unless otherwise noted.
`
`
`
`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 3 of 77 PageID #: 10734
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`Plaintiff New York University ("NYU") is a private, non-profit corporation
`
`organized and existing under the laws of the State of New York, having a place of business in
`
`New York, New York. (SUF ~ 2)
`
`3.
`
`Plaintiff Galdenna Laboratories Inc. ("GU") is a corporation organized and
`
`existing under the laws of the State of Delaware, having a principal place of business in Fort
`
`Worth, Texas. (SUF ~ 3)
`
`4.
`
`Plaintiff Galdenna Laboratories, L.P. ("GLLP") is a privately held partnership
`
`registered in the State of Texas, having a principal place of business in Fort Worth, Texas. (SUF
`
`~ 4)
`
`5.
`
`Plaintiff Supemus Phannaceuticals, Inc. ("Supemus") is a corporation organized
`
`and existing under the laws of the State of Delaware, having a principal place ofbusiness in
`Rockville, Maryland. (SUF ~ 5t
`
`6.
`
`Defendant Mylan Phannaceuticals Inc. ("Mylan") is a corporation organized and
`
`existing under the laws of the State of West Virginia, having a principal place of business in
`
`Morgantown, West Virginia. (SUF ~ 6)
`
`II.
`
`DOXYCYCLINE
`
`7.
`
`The structural fonnula of doxycycline monohydrate is:
`
`4Plaintiffs RF, SUNY, NYU, GU, GLLP, and Supemus are referred to collectively throughout
`this Opinion as "Plaintiffs" or "Galdenna."
`
`2
`
`
`
`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 4 of 77 PageID #: 10735
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`•
`
`
`(SUF ~ 41)
`
`8.
`
`Doxycycline is a member of the tetracycline class of antibacterial drugs. (SUF ~
`
`42)
`
`9.
`
`Doxycycline is an antibiotic tetracycline compound. (SUF ~ 44)
`
`10.
`
`There are two general categories of antibiotics: bacteriostatic agents, which inhibit
`
`bacterial growth; and bactericidal agents, which kill bacteria. (SUF ~ 45)
`
`11.
`
`Generic doxycycline is commercially available in at least 50 mg, 75 mg, 100 mg,
`
`150 mg, and 200 mg dosage forms. (SUF ~ 46)
`
`12.
`
`Periostat® is a 20 mg dose of doxycycline administered twice-daily to a human
`
`and is indicated for treatment of periodontal disease. (SUF ~ 47)
`
`13.
`
`According to its approved label, Periostat® has a steady state Cmax of 0.790 J.lg/mL
`
`(SUF~ 48)
`
`3
`
`
`
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`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 5 of 77 PageID #: 10736
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`III. ROSACEA AND ITS TREATMENT
`
`14.
`
`Rosacea is a long-lasting, chronic inflammatory disorder. (Tr. 71)5
`
`15.
`
`Historically, rosacea has been treated by oral administration of antibiotics in
`
`antibiotic dosages and/or administration of topical gels and creams to treat the signs and
`
`symptoms of the disease. (PTX 209 at 1249; Tr. 75,534-36)
`
`16.
`
`The most common oral treatments for rosacea prior to the launch of Oracea®
`
`were antibiotic doses oftetracyclines. (PTX 209 at 1249; Tr. 534-36)
`
`IV. Oracea®
`
`17.
`
`Plaintiff GLLP currently holds New Drug Application ("NDA") 50-805 on
`
`Oracea® brand doxycycline capsules ("Oracea®"), which was approved by the U.S. Food and
`
`Drug Administration ("FDA") on May 26, 2006. (SUF,-r 49)
`
`18.
`
`GLLP is the exclusive distributor of Oracea® in the United States. (SUF,-r 50)
`
`19.
`
`The active ingredient in Oracea® is doxycycline monohydrate. (SUF ~ 51)
`
`20.
`
`Oracea® is a capsule dosage fonn for oral administration. (SUF,-r 52)
`
`21.
`
`The dosage strength of Oracea® is 40 mg. (SUF ~ 53)
`
`22.
`
`Oracea® is an oral phannaceutical composition of doxycycline to be administered
`
`once-daily. (SUF ~ 54)
`
`23.
`
`Oracea® is indicated for the treatment of only inflammatory lesions (papules and
`
`pustules) of rosacea in adult patients. (SUF,-r 56)
`
`24.
`
`Oracea® is a hard shell gelatin capsule filled with two types of doxycycline beads,
`
`5The trial transcript is docketed at D.L 270,271,272, and 273. All references to the trial
`transcript are in the fonnat "Tr." followed by the page number.
`
`4
`
`
`
`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 6 of 77 PageID #: 10737
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`30 mg immediate-release ("IR") beads and 1 0 mg delayed-release ("DR") beads (coated with an
`
`enteric polymer). (SUF ~~ 57-58)
`
`25.
`
`Oracea® does not contain a bisphosphonate compound. (SUF ~ 59)
`
`26.
`
`Oracea® contains one or more pharmaceutical excipients. (SUF ~ 60)
`
`27.
`
`Oracea® is the first and only orally administered, systemically delivered drug
`
`approved by the FDA for the treatment ofrosacea. (PTX 426 at GAL 0229992; Tr. 540)
`
`28.
`
`Oracea® treats rosacea in a human. (PTX 426 at GAL 0229992; PTX 381 at
`
`GAL 0240969-70; Tr. 73, 129-30)
`
`29.
`
`Oracea®, when administered once-daily, is administered in an amount that
`
`reduces lesion count and an amount that is effective to treat the papules and pustules of rosacea.
`
`(PTX 426 at GAL 0229996-97; PTX 381 at GAL 0240969-70; Tr. 73, 287-88, 727)
`
`30.
`
`Oracea® is administered long-term, i.e., over a period of time longer than eight to
`
`ten days. (PTX 426 at GAL 0229993, -96-97; SUF ~ 38)
`
`31.
`
`Oracea® is administered by "sustained release," i.e., a method of drug delivery to
`
`achieve a certain level of the drug over a particular period oftime. (PTX 426 at GAL 0229993,
`
`95, -96)
`
`32.
`
`Oracea®, when administered once daily, is administered in an amount that results
`
`in no reduction of skin microflora during a six-month treatment. (PTX 426 at GAL 0229996;
`
`PTX 394; 459, 612-15)
`
`33.
`
`In vivo microbiological studies utilizing a similar drug exposure to Oracea® for
`
`up to 18 months demonstrated no detectable long-term effects on bacterial flora of the oral
`
`cavity, skin, intestinal tract, and vagina. (PTX 426 at GAL 0229996; PTX 394; PTX 413; PTX
`
`5
`
`
`
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`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 7 of 77 PageID #: 10738
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`200; PTX 201)
`
`34.
`
`Oracea® should not be used for treating bacterial infections, providing
`
`antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms associated
`
`with any bacterial disease. (PTX 426 at GAL 0229996)
`
`35.
`
`Patients should not take Oracea® to treat infections caused by bacteria germs or
`
`viruses. (PTX 426 at GAL 0229998)
`
`V.
`
`MYLAN'S GENERIC PRODUCT
`
`36.
`
`Defendant Mylan submitted Abbreviated New Drug Application ("ANDA")
`
`90-855 to the FDA under § 505(1) of the Federal Food, Drug and Cosmetic Act ("FFDCA"),
`
`seeking FDA approval for the commercial manufacture, use, and sale of a generic version of
`
`Oracea® ("Mylan's Generic Product" or "Mylan's ANDA Product") before the expiration of the
`
`'267 patent, the '572 patent, the '395 patent, and the '775 patent. (SUF ~ 61)
`
`37.
`
`ANDA 90-855 identifies Mylan as the manufacturer of Mylan's Generic Product.
`
`(SUF~ 62)
`
`38.
`
`The FDA approved ANDA 90-855 on July 1,2010. (SUF ~ 63)
`
`39. Mylan's Generic Product will contain the package insert approved by the FDA for
`
`Mylan's Generic Product ("Mylan's Label," "Mylan Label," or "Label"). (SUF ~ 64)
`
`40.
`
`41.
`
`The active ingredient in Mylan's Generic Product is doxycycline. (SUF ~ 65)
`
`The dosage strength of Mylan's Generic Product is 40 mg. (SUF ~ 66)
`
`42. Mylan's Generic Product is a hard shell gelatin capsule filled with two types of
`
`doxycycline beads, 30 mg IR and 10 mg DR. (SUF ~ 67)
`
`43. Mylan's Generic Product does not contain a bisphosphonate compound. (SUF ~
`
`6
`
`
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`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 8 of 77 PageID #: 10739
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`68)
`
`
`69)
`
`44.
`
`FDA has found Mylan's Generic Product to be bioequivalent to Oracea®. (SUF ~
`
`45.
`
`The statements in the approved package insert for Mylan's Generic Product are
`
`true. (Memorandum Opinion granting Preliminary Injunction (D.l. 177) at 9; see also 18 U.S.c.
`
`§ 1001; 21 U.S.c. §§ 355b(a)(l), 355c(a); Tr. 323)
`
`46.
`
`The doxycycline in Mylan's Generic Product is doxycycline monohydrate. (DTX
`
`2091 at MYL-D118692-93; DTX 2267 at MYL-D000206; Tr. 98-99)
`
`47. Mylan's Label instructs doctors and patients that one doxycycline capsule (40 mg)
`
`of Mylan's Generic Product should be taken once-daily by oral administration. (DTX 2091 at
`
`MYL-DI18686-87; DTX 2267 at MYL-D000220; Tr. 83, 100-01)
`
`48. Mylan's Generic Product is indicated for the treatment of only inflammatory
`
`lesions (papules and pustules) of rosacea in adult patients. (DTX 2091 at MYL-D 118686-87; Tr.
`
`82)
`
`49. Mylan's Label instructs doctors and patients to use Mylan's Generic Product to
`
`treat rosacea in a human. (DTX 2091 at MYL-D118686-87, -97; Tr. 82)
`
`50. Mylan's Generic Product, when administered once-daily in accordance with
`
`Mylan's Label, is administered in an amount that reduces lesion count and that is effective to
`
`treat the papules and pustules of rosacea. (DTX 2091 at MYL-DI18695-96; Tr. 82-83)
`
`51. Mylan's Generic Product is administered long-term, i.e., over a period of time
`
`longer than eight to ten days. (DTX 2091 at MYL-D118687, -95-96; Tr. 84)
`
`7
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`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 9 of 77 PageID #: 10740
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`VI.
`
`PATENTS-IN-SUIT
`
`A.
`
`The Ashley Patents
`
`1.
`
`Ashley '267 Patent
`
`52.
`
`U.S. Application Number 10/117,709, from which the '267 patent issued, was
`
`filed on April 5, 2002. (SUF ~ 7)
`
`53.
`
`The '267 patent issued on May 1,2007, naming Robert A. Ashley as the sole
`
`inventor and listing CollaGenex Pharmaceuticals, Inc. as assignee. (SUF ~ 8) The '267 patent is
`
`entitled "Methods of Treating Acne." (PTX 1)
`
`54.
`
`GLI is the current assignee of the '267 patent. (SUF ~ 9)
`
`55.
`
`The '267 patent claims priority from provisional application no. 60/325,489, filed
`
`September 26,2001 and provisional application no. 60/281,916, filed April 5, 2001. (SUF ~ 10)
`
`56.
`
`The '267 patent is set to expire on April 5, 2022. (SUF ~ 11)
`
`2
`
`Ashley '572 Patent
`
`57.
`
`U.S. Application Number 111061,866, from which the '572 patent issued, was
`
`filed on February 18, 2005. (SUF ~ 12)
`
`58.
`
`The '572 patent issued on June 19,2007, naming Robert A. Ashley as the sole
`
`inventor and listing CollaGenex Pharmaceuticals, Inc. as assignee. (SUF ~ 13) The '572 patent
`
`is entitled, "Methods of Treating Rosacea." (PTX 2)
`
`59.
`
`GLI is the current assignee of the '572 patent. (SUF ~ 14)
`
`60.
`
`The '572 patent is a continuation of application no. 101272,499, filed on October
`
`15,2002, and issued as U.S. Patent No. 7,014,858, which is a continuation of application no.
`
`101117,709, which issued as the '267 patent. (SUF ~ 15)
`
`8
`
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`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 10 of 77 PageID #: 10741
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`61.
`
`The '572 patent claims priority from provisional application no. 60/281,916, filed
`
`April 5,2001 and provisional application no. 60/325,489, filed September 26,2001. (SUF ~ 16)
`
`62.
`
`The '572 patent is set to expire on April 5, 2022. (SUF ~ 17)
`
`3.
`
`Facts relating to infringement and validity of Ashley Patents
`
`63.
`
`Dr. Webster, who was called at trial by Galderma, is an expert in the field of
`
`clinical dermatology and microbiology. (Tr. 70; PTX 248)6
`
`64.
`
`Dr. Chambers, who was called at trial by Mylan, is an expert in the field of
`
`infectious diseases and antimicrobial agents, including antibiotic resistance and the
`
`pharmacokinetics and pharmacodynamics of antimicrobial agents. (Tr. 552; DTX 2102)
`
`65.
`
`Dr. Randall Stafford, who was called at trial by Mylan, is an expert in the field of
`
`clinical epidemiology, including the use prescription patterns generated by IMS Health. (Tr. 416;
`
`DTX 2208)
`
`66.
`
`Dr. Barbara Gilchrest, who was called at trial by Mylan, is an expert in the field of
`
`clinical dermatology with a specific focus in the treatment of acne and rosacea. (Tr. 449; DTX
`
`2135)
`
`67.
`
`A microorganism is a single cellular life form or sub-life form, including a
`
`bacterium, a virus, a yeast, or protozoan. (Tr. 557)
`
`68. Microorganisms live everywhere on and in our bodies. (Tr. 557)
`
`69.
`
`Approximately 100,000,000,000,000 bacterial cells inhabit the human body. (Tr.
`
`149-50, 557)
`
`6There is no dispute that each of the experts who testified at trial is a person having at least
`ordinary skill in the art with respect to the patents about which that expert testified.
`
`9
`
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`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 11 of 77 PageID #: 10742
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`70.
`
`In our bodies, the number of bacterial cells is greater than the number of human
`
`cells by a factor of 10. (Tr. 557)
`
`71.
`
`Doxycycline is among the most potent known antimicrobial agents. (Tr.558)
`
`72.
`
`Doxycycline is "broad spectrum," which means that it affects a large number of
`
`organisms. (Tr. 558)
`
`73.
`
`Doxycycline is a protein synthesis inhibitor that inhibits the growth of
`
`microorganisms by paralyzing their protein machinery. (Tr. 559)
`
`74. When administered orally, doxycycline is absorbed into the bloodstream and
`
`travels wherever blood goes in the body. (Tr. 558-59)
`
`75.
`
`The inhibitory effect caused by doxycycline can be measured in several ways,
`
`including reduction in count of an organism and the emergence of organisms resistant to
`
`doxycycline. (Tr. 559-60, 562-66)
`
`76.
`
`In vivo microbiological studies utilizing a similar drug exposure to Mylan's
`
`Generic Product for up to 18 months demonstrated no detectable long-term effects on bacterial
`
`flora ofthe oral cavity, skin, intestinal tract, and vagina. (DTX 2091 at MYL-DI18694; PTX
`
`394; PTX 413; PTX 200; PTX 201; Tr. 90-95, 325-26, 608-09, 612-14, 616-17, 620, 621-25)
`
`77. Mylan's Generic Product, when administered as 40 mg of doxycycline once a day,
`
`is administered in an amount that results in no reduction of skin microflora during a six-month
`
`treatment. (DTX 2091 at MYL-DI18694; PTX 394; Tr. 88-93,326,459,61 15)
`
`78.
`
`The assessment of whether an antibiotic substance has activity against
`
`microorganisms should not be limited to examining only certain types of categories of bacteria.
`
`(Tr. 151)
`
`10
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`
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`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 12 of 77 PageID #: 10743
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`79.
`
`The purpose of the Haffajee study was to examine subgingival microbiological
`
`changes in human subjects with periodontitis. (DTX 2097 at 148; Tr. 561)
`
`80.
`
`Patients in the Haffajee study received one of four treatments: 1) scaling and root
`
`planning ("SRP") alone; 2) SRP and doxycycline (20 mg twice-daily for 3 months); 3) SRP and
`
`metronidazole (150 mg thrice-daily for 14 days); and 4) SRP and azithromycin (500 mg once
`
`daily for 3 days). (DTX 2097 at 149; Tr. 561-62)
`
`81.
`
`Samples of subgingival plaque and saliva were taken at baseline, two weeks, three
`
`months, nine months and twelve months. (DTX 2097 at 150; Tr. 561)
`
`82.
`
`Each sample was measured for the percentage of total isolates that were resistant
`
`to 4 J.1g1ml of doxycycline at each time point. (DTX 2097 at 152 (Figure 3); Tr. 566-67)
`
`83.
`
`Figure 3 in the Haffajee study is a graphic representation of the percentage of total
`
`isolates resistant to 4 J.1g/ml of doxycycline at each time point in both the doxycycline group and
`
`placebo group. (DTX 2097 at 152 (Figure 3); Tr. 562-63,566-70)
`
`84.
`
`At time zero (i.e., prior to administration of drug), the percentage of total isolates
`
`resistant to 4 J.1g/ml of doxycycline are virtually identical in both the doxycycline and placebo
`
`groups approximately 10% of the isolates are resistant. (DTX 2097 at 152 (Figure 3); Tr. 567
`
`68)
`
`85.
`
`At the two week time point, the percentage of resistant isolates in the doxycycline
`
`group spiked from 10% to approximately 45%, whereas in the placebo group, the two week data
`
`indicated virtually no change in the percentage of isolates resistant to doxycycline. (DTX 2097 at
`
`152 (Figure 3); Tr. 568)
`
`86.
`
`The spike in percentage of resistant isolates in the doxycycline group at the two
`
`11
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`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 13 of 77 PageID #: 10744
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`week time period is due to significant inhibition of growth caused by exposure to doxycycline.
`
`(DTX 2097 at 152 (Figure 3); Tr. 562-66, 568)
`
`87.
`
`The significant inhibition of growth ofmicroorganisms susceptible to doxycycline
`
`allowed microorganisms resistant to doxycycline to increase in numbers. (DTX 2097 at 152
`
`(Figure 3); Tr. 562-66, 568)
`
`88.
`
`The statistical analysis included in the Haffajee study confirms that there is
`
`virtually no chance that the data in Figure 3 resulted from random occurrence. (DTX 2097 at 152
`
`(Figure 3); Tr. 568)
`
`89.
`
`The data in Figure 3 ofthe Haffajee study provides conclusive evidence that
`
`Mylan's Generic Product will significantly inhibit the growth of microorganisms in the oral
`
`cavity. (DTX 2097 at 152 (Figure 3); Tr. 568-70)
`
`90.
`
`The Haffajee study did not detect any long-term effect of 40 mg dose of
`
`doxycycline. (DTX 2097 at 152 (Figure 3); Tr. 568-69)
`
`91.
`
`The purpose of the Thomas study was to assess whether doxycycline changes
`
`antibiotic susceptibility of the oral microflora in adults with periodontitis. (DTX 2121 at 1472;
`
`Tr. 571-72)
`
`92.
`
`Patients in the Thomas study received one of the following treatments: 20 mg
`
`doxycycline twice daily, 20 mg doxycycline once daily, 10 mg of doxycycline once daily or
`
`placebo. (DTX 2121 at 1473 (Table 1); Tr. 571-72)
`
`93.
`
`Samples of subgingival plaque were taken at baseline, twelve months,
`
`fifteen-to-eighteen months, and twenty-one to twenty-four months. (DTX 2121 at 1473 (Table
`
`1); Tr. 571-72)
`
`12
`
`
`
`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 14 of 77 PageID #: 10745
`
`94.
`
`The Thomas study measured the doxycycline MIC50 values for Actinomyces
`
`species isolates at each sample period. (DTX 2121 at 1477 (Figure 2A); Tr. 572)
`
`95.
`
`An increase in MIC50 values in the presence of an antibiotic indicates emergence
`
`of drug resistant cells due to inhibition of susceptible cells. (DTX 2121 at 1477 (Figure 2A); Tr.
`
`572)
`
`96.
`
`Figure 2A in the Thomas study is a graphic representation of the MIC50 data for
`
`Actinomyces species isolates at each sample period. (DTX 2121 at 1477 (Figure 2A); Tr.
`
`572-73)
`
`97.
`
`At baseline, the MIC50 values of all four groups are at or near 1. (DTX 2121 at
`
`1477 (Figure 2A); Tr. 572-73)
`
`98.
`
`At twelve months, the MIC50 values in the 20 mg twice daily and 20 mg once
`
`daily groups jumped to 32, while the placebo group remained relatively constant. (DTX 2121 at
`
`1477 (Figure 2A); Tr. 572-73)
`
`99.
`
`The difference between the baseline and twelve month data is due to the
`
`significant inhibition of growth of microorganisms susceptible to doxycycline, which facilitates
`
`growth of microorganisms resistant to doxycycline. (DTX 2121 at 1477 (Figure 2A); Tr. 573)
`
`100. The Thomas study reflects the same results as the Haffajee study administration
`
`of a 40 mg daily dose of doxycycline caused an increase in the number ofmicroorganisms
`
`resistant to doxycycline. (DTX 2121 at 1477 (Figure 2A); Tr. 573-74)
`
`101. The Thomas study did not detect any long term effect of a 40 mg dose of
`
`doxycycline. (DTX 2121 at 1477 (Figure 2A); Tr. 574)
`
`102. The purpose of the Walker 2000 study was to determine whether treatment with a
`
`l3
`
`
`
`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 15 of 77 PageID #: 10746
`
`40 mg daily dose of doxycycline exerted an antimicrobial effect on the micro flora associated
`
`with adult periodontitis. (DTX 2120 at 1465; Tr. 575-76)
`
`103.
`
`Patients in the Walker 2000 study received one of the following treatments: 20 mg
`
`doxycycline twice-daily or placebo. (DTX 2120 at 1466; Tr. 575-76)
`
`104. Each patient also received scaling and root planning in half of their mouth; thus,
`
`there were effectively 4 treatment groups: SRP-placebo, SRP-doxycycline, placebo, and
`
`doxycycline. (DTX 2120 at 1466; Tr. 575-76)
`
`105.
`
`Samples of subgingival plaque were taken at baseline, three months, six months,
`
`nine months, and twelve months. (DTX 2120 at 1466; Tr. 575-76)
`
`106. The Walker 2000 study measured the mean percentage of spirochetes (a type of
`
`microorganism) relative to the total microscopic flora at each sampling period. (DTX 2120 at
`
`1467-68 (Tables 1,2 & 3); Tr. 576-77)
`
`107. The mean percentage of spirochetes data, which appears in Tables 1-3, shows that
`
`a 40 mg daily-dose of doxycycline significantly inhibited the growth of microorganisms. (DTX
`
`2120 at 1467-68 (Tables 1,2 & 3); Tr. 576-77, 579)
`
`108. Table 1 provides data regarding small spirochetes. (DTX 2120 at 1467 (Table 1);
`
`Tr. 577)
`
`109.
`
`In Table 1, at baseline, the mean percentage of small spirochetes in the
`
`SRP-doxycycline and SRP-placebo groups is nearly identical approximately 10.35%. (DTX
`
`2120 at 1467 (Table 1); Tr. 577-78)
`
`110. At three months, the number of small spirochetes was significantly reduced in the
`
`doxycycline group to 4.32%, whereas the percentage in the placebo group was relatively
`
`14
`
`
`
`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 16 of 77 PageID #: 10747
`
`unchanged at 9.59%. (DTX 2120 at 1467 (Table 1); Tr. 578)
`
`111. According to the statistical analysis in Walker 2000, that difference is statistically
`
`significant
`
`i.e., very unlikely to be the result of random chance. (DTX 2120 at 1467 (Table 1);
`
`Tr.578)
`
`112. The significant reduction in the mean percentage of small spirochetes was due to
`
`the exposure of doxycycline and resulting significant inhibition of growth. (DTX 2120 at 1467
`
`(Table 1); Tr. 578)
`
`113. Table 2 (data regarding reduction oflarge spirochetes) and Table 3 (data regarding
`
`reduction of intermediate spirochetes) also show significant inhibition of growth. (DTX 2120 at
`
`1467-68 (Tables 2 & 3); Tr. 579)
`
`114. The Walker 2000 study did not detect any long term effect of 40 mg dose of
`
`doxycycline. DTX 2120 at 1467 (Table 1); Tr. 578-79.
`
`115. The FDA reviewed the clinical microbiology studies described in PTX 394
`
`("Skidmore"), PTX 413 ("Walker 2005"), PTX 200 ("Walker 2000"), and PTX 201 ("Thomas")
`
`during the approval process for Oracea®, and Mylan's Label relies on these studies. (Tr. 90-95,
`
`612-13,615-16,622-23,626)
`
`116. Mylan is unaware of any in vivo microbiology studies of Mylan's Generic Product
`
`or a product with similar drug exposure that demonstrate a detectable long-term effect on
`
`bacterial flora ofthe oral cavity, skin, intestinal tract, or vagina. (Tr. 325-26)
`
`117. Mylan is unaware of any in vivo microbiology studies of Mylan' s Generic Product
`
`or a product with similar drug exposure that demonstrate a detectable long-term effect on the
`
`bacterial flora at any site in the human body other than the oral cavity, skin, intestinal tract, and
`
`15
`
`
`
`
`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 17 of 77 PageID #: 10748
`
`vagina. (Ir. 326)
`
`118. Neither Mylan nor any of its experts has tested Mylan's Generic Product,
`
`Oracea®, or a product with a similar drug exposure to determine whether it will significantly
`
`inhibit the growth of microorganisms, e.g., bacteria. (If. 328,659-60)
`
`119. Mylan's Generic Product should not be used for treating bacterial infections,
`
`providing antibacterial prophylaxis, or reducing the numbers or eliminating microorganisms
`
`associated with any bacterial disease. (DIX 2091 at MYL-DI18687, -94~ Tr. 89, 324-25,
`
`606-07, 608)
`
`120. When administered once daily in accordance with Mylan's Label, the plasma
`
`concentrations of doxycycline achieved with Mylan's Generic Product during administration are
`
`less than the concentration required to treat bacterial diseases. (DTX 2091 at MYL-D 118694;
`
`Ir. 89-90, 607)
`
`121. Mylan's Generic Product should not be used for the treatment of infections.
`
`(DTX 2091 at MYL-DI18682, -97, Ir. 606-07)
`
`122.
`
`Patients should not take Mylan's Generic Product to treat infections caused by
`
`bacterial germs or viruses. (DTX 2091 at MYL-DI18683, -99)
`
`123. Exceeding the recommended dosage for Mylan's Generic Product may result in an
`
`increased incidence of side effects including the development of resistant organisms. (DIX 2091
`
`at MYL-DI18687)
`
`124. Nothing in Mylan's Label instructs doctors or patients to administer Mylan's
`
`Generic Product with a bisphosphonate compound. (DTX 2091~ Tr. 84-85)
`
`125. The doxycycline in Mylan's Generic Product is administered by "sustained
`
`16
`
`
`
`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 18 of 77 PageID #: 10749
`
`release," i.e., a method of drug delivery to achieve a certain level of the drug over a particular
`
`period of time. (DTX 2091 at MYL-D118687, -93; Tr. 100)
`
`126. Both ofthe Ashley Patents identifY Periostat® as "an especially preferred
`
`embodiment" of the inventions. (SUF ~ 70; PTXl, 2; Tr. 457,460)
`
`127. Periostat® is an oral antibiotic tetracycline compound that provides a 40
`
`milligram daily dose of doxycycline (20 mg BID). (PTX 1 at col. 5 lines 63-67; Tr. 143)
`
`128. Dr. Lawrence Feldman is a physician who specializes in dermatology, including
`
`the treatment of patients with rosacea. (Tr. 333,335-37)
`
`129. Dr. Feldman is afflicted with rosacea, including the papules and pustules of
`
`rosacea. (Tr. 344, 408-09)
`
`130.
`
`In October 1998 or 1999, Dr. Feldman attended a dermatology meeting in Las
`
`Vegas, Nevada. (Tr.338-40)
`
`131. At the convention, Dr. Feldman learned "new[] ideas," including "Periostat as
`
`being a treatment for rosacea." (Tr. 341-42)
`
`132. Dr. Feldman learned that use ofPeriostat® to treat rosacea was a "new kind of
`
`idea in dermatology where an antibiotic could work as anti-inflammatory and not kill bacteria
`
`and it was just the dawn ofthat whole idea." (Tr.403)
`
`133. While taking Periostat® for his gingivitis, the Periostat® improved Dr. Feldman's
`
`rosacea. (Tr. 344-45, 408-09)
`
`134.
`
`In January 2000, Dr. Feldman contacted CollaGenex and requested "professional
`
`courtesy samples of Periostat" to continue his use. (Tr. 366-67)
`
`135. CollaGenex provided Dr. Feldman with 300-400 professional courtesy samples of
`
`17
`
`
`
`
`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 19 of 77 PageID #: 10750
`
`Periostat®. (Tr. 367)
`
`136.
`
`In late January or early February 2000, Dr. Feldman used the professional courtesy
`
`samples ofPeriostat® to treat his rosacea. (Tr. 409-10)
`
`137. Periostat® reduced Dr. Feldman's pustules. (Tr. 344-45, 409)
`
`138. On February 19, 2000, Dr. Feldman diagnosed a patient as suffering from rosacea,
`
`including rosacea pustules. (DTX 1559; Tr. 356)
`
`139. On February 19, 2000, Dr. Feldman gave his patient a three month prescription for
`
`Periostat®, and one three month refill. (DTX 1559; Tr. 359)
`
`140. Dr. Feldman prescribed "Periostat 20 BID [twice daily] due to its
`
`anti-inflammatory effect with decreased risk of side effects." (DTX 1559; Tr. 357)
`
`141. Dr. Feldman's personal use ofPeriostat® led him to anticipate that Periostat®
`
`would improve his patient's condition. (Tr. 345, 362-63; DTX 1559)
`
`142. Dr. Feldman did not prescribe a bisphosphonate compound to his patient. (Tr.
`
`408; DTX 1559)
`
`143.
`
`In 2004, Dr. Feldman saw his patient again, at which time he did not notice
`
`anything about her rosacea and the patient did not say anything about her rosacea. (Tr. 365-66)
`
`144. Dr. Feldman was free to discuss, publicly or privately, his own personal use of
`
`Periostat® to treat rosacea, including the specific dosage regimen he used. (Tr. 408)
`
`145. Dr. Feldman's patient was free to discuss, publicly or privately, her use of
`
`Periostat® to treat rosacea, including the specific dosage regimen she used. (Tr. 159,408)
`
`146. Apart from this litigation, Dr. Feldman has never disclosed the Feldman patient
`
`record to anyone else. (Tr. 348-49,405,504)
`
`18
`
`
`
`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 20 of 77 PageID #: 10751
`
`147. Dr. Feldman stored the original of the Feldman patient record in a secure, locked
`
`storage facility. (Tr. 348-49,405,504)
`
`148. Mylan has not identified Dr. Feldman's patient.
`
`149. Mylan has not produced any testimony from Dr. Feldman's patient.
`
`150. Mylan has not produced the prescription of Periostat® to Dr. Feldman's patient.
`
`151. Dr. Feldman never published, publicly presented, or in any other way made public
`
`his prescribing ofPeriostat® to his patient, or his own personal use ofPeriostat®. (Tr.399-400,
`
`410, 500-02, 505-06)
`
`152. Dr. Feldman never (1) attempted to sell the idea of using Periostat®to treat
`
`rosacea, (2) informed CollaGenex that Periostat® could be used to treat rosacea, or (3)
`
`considered submitting a patent application for the use ofPeriostat® to treat rosacea. (Tr. 400,
`
`506)
`
`153.
`
`Prior to February 19, 2000, Dr. Feldman was not personally aware of anyone who
`
`had prescribed Periostat® for the treatment of rosacea. (Tr. 403)
`
`154. Periostat® is FDA-approved for the treatment of periodontitis, and has off-label
`
`uses other than the treatment ofrosacea. (Tr. 418, 442)
`
`155. The IMS Health Periostat® data demonstrates that Dr. Feldman prescribed a
`
`patient Periostat®, a prescription which was actually dispensed at a pharmacy. (Tr. 432; DTX
`
`2211)
`
`156. The IMS Data does not provide any patient-identifYing information. (Tr.435,
`
`440-41)
`
`157. The IMS Data does not provide patient diagnosis information, and the word
`
`19
`
`
`
`Case 1:09-cv-00184-LPS Document 278 Filed 08/26/11 Page 21 of 77 PageID #: 10752
`
`"rosacea" does not appear anywhere in the IMS Data. (Tr. 435, 441-42)
`
`158. None ofDTX 1764 ("Murphy"); DTX 1484 ("Cotterill"); DTX 1901
`
`("Sneddon"); DTX 2067 ("Wereide"); DTX 1703 ("Marmion"); DTX 1418 ("Bartholomew")
`
`(collectively, "the six Gilchrest References") discloses the administration of any antibiotic
`
`tetracycline compound in a sub-antibacterial amount or an amo
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