Paper No. _______
`Filed: April 23, 2015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`COALITION FOR AFFORDABLE DRUGS VI LLC
`
`PETITIONER
`
`V.
`
`CELGENE
`
`PATENT OWNER
`
`___________________
`
`CASE NO.: UNASSIGNED
`PATENT NO. 6,315,720
`FILED: OCTOBER 23, 2000
`ISSUED: NOVEMBER 13, 2001
`INVENTORS: BRUCE A. WILLIAMS AND JOSEPH K. KAMINSKI
`
`TITLE: METHODS FOR DELIVERING A DRUG TO A PATIENT WHILE
`AVOIDING THE OCCURRENCE OF AN ADVERSE SIDE EFFECT KNOWN
`OR SUSPECTED OF BEING CAUSED BY THE DRUG
`___________________
`
`DECLARATION OF
`JEFFREY FUDIN, R.PH., PHARM.D., DAAPM, FCCP, FASHP
`
`CFAD VI 1027-0001
`
`
`Filed: April 23, 2015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`COALITION FOR AFFORDABLE DRUGS VI LLC
`
`PETITIONER
`
`V.
`
`CELGENE
`
`PATENT OWNER
`
`___________________
`
`CASE NO.: UNASSIGNED
`PATENT NO. 6,315,720
`FILED: OCTOBER 23, 2000
`ISSUED: NOVEMBER 13, 2001
`INVENTORS: BRUCE A. WILLIAMS AND JOSEPH K. KAMINSKI
`
`TITLE: METHODS FOR DELIVERING A DRUG TO A PATIENT WHILE
`AVOIDING THE OCCURRENCE OF AN ADVERSE SIDE EFFECT KNOWN
`OR SUSPECTED OF BEING CAUSED BY THE DRUG
`___________________
`
`DECLARATION OF
`JEFFREY FUDIN, R.PH., PHARM.D., DAAPM, FCCP, FASHP
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`CFAD VI 1027-0001
`
`
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`I, Jeffrey Fudin, R.Ph., Pharm.D., DAAPM, FCCP, FASHP, hereby declare as
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`follows:
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`I.
`
`Introduction
`I am over the age of eighteen and otherwise competent to make this
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`1.
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`declaration.
`
`2.
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`I have been retained as an expert witness on behalf of the COALITION
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`FOR AFFORDABLE DRUGS VI LLC for the above–captioned inter partes review
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`(IPR). I am being compensated for my time in connection with this IPR at my
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`standard legal consulting rate, which is $450 per hour. I understand that the petition
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`for inter partes review involves U.S. Patent No. 6,315,720 (“the ’720 Patent”), which
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`resulted from U.S. Application No. 09/694,217 (“the ’217 application”), which was
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`filed October 23, 2000, its earliest priority date. The ’720 Patent names Bruce A.
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`Williams and Joseph K. Kaminski as inventors and lists Celgene Corporation as the
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`original assignee. The ’720 Patent was issued on November 13, 2001.
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`3.
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`In preparing this declaration and formulating my opinions, I have
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`reviewed the ’720 Patent and considered each of the documents cited herein, in light
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`of the knowledge of person of ordinary skill in the art (“POSA”) (i.e., a person of
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`ordinary skill in the field of prescribing and dispensing pharmaceutical ingredients) as
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`of October 23, 2000.
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`
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`2
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`CFAD VI 1027-0002
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`
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`II.
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`My Background and Qualifications
`I am presently the Director of the PGY2 Pain and Palliative Care Pharmacy
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`4.
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`Residency at the Samuel Stratton Department of Veterans Affairs Medical Center
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`located at 113 Holland Avenue, Albany, New York (“Samuel Stratton”). I have held
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`this position since April of 2012. I am also currently the Clinical Pharmacy Specialist
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`at the Pain Management Department at Samuel Stratton and have held that position
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`since June of 1994. I worked as a Clinical Pharmacy Specialist in
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`Oncology/Hematology and as Staff Pharmacist at Samuel Stratton from July of 1982
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`until June 1994.
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`5.
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`As a Clinical Pharmacy Specialist, I work in close collaboration with
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`medical staff members in the management of various acute and chronic pain disease
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`states. I order and interpret clinical laboratory tests necessary to monitor and support
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`drug therapy based on consult requests made by physicians to (a) monitor disease
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`states, (b) assess medication regimens, and (c) adjust, initiate, or discontinue therapy
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`for individual patients.
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`6.
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`I received my B.S. in Pharmacy from Albany College of Pharmacy
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`(Union University) in May of 1981, received my Pharm.D. from the same school, but
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`name was changed to Albany College of Pharmacy and Health Sciences, in May of
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`1998, and completed an Oncology/Hematology Fellowship in October 1981 at the
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`Upstate Medical Center in Syracuse, New York.
`3
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`CFAD VI 1027-0003
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`
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`7.
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`Since October 1998, I have held the title Adjunct Associate Professor of
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`Pharmacy Practice at Albany College of Pharmacy & Health Sciences/Union
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`University in Albany, New York. I teach a course entitled “Pain Management
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`Pharmacotherapy,” PHM 551. I am also an Adjunct Assistant Professor of Pharmacy
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`Practice at University of Connecticut School of Pharmacy located in Storrs,
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`Connecticut, and Adjunct Associate Professor of Pharmacy at Western New England
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`University College of Pharmacy located in Springfield, Massachusetts.
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`8.
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`From February 1989 to October 1989, as the Director of Clinical
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`Pharmacy Affairs of O.P.T.I.O.N. (Outpatient Parenteral Therapy and
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`Intravenous Ongoing Nutrition) Care, I had direct experience planning, setting
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`up, and registering two pharmacies. One was located at 57 Phila Street, Saratoga,
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`New York, and the other, an O.P.T.I.O.N. Care facility, was located at 58 Hackett
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`Boulevard, Albany, New York. At this time, I had direct experience with the types
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`of computerized billing and patient record systems that were required for
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`pharmacies by Medicare, Medicaid, and various third party insurance payers.
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`9.
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`I am currently a registered pharmacist in New York and am assigned
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`the license number 34085. I am also board certified as a Diplomate to the
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`American Academy of Pain Management. I am a Fellow to the American College
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`of Clinical Pharmacy and a Fellow to the American Society of Heath-system
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`
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`4
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`CFAD VI 1027-0004
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`
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`Pharmacists. In addition, I am currently certified in American Heart Association
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`Basic Life Support for Healthcare Providers (CPR and AED) until September of
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`2015.
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`10.
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`I have co–authored at least 65 articles in peer-reviewed scientific and
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`medical journals. I am the author of seven chapters, including several chapters related
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`to pharmaceuticals, including opioids and analgesics. Much of my publications involve
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`research in the field of analgesic therapy and the effects of such therapies on patients
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`and the therapies’ legal distribution, including chain of custody from manufacturer
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`to wholesaler, to pharmacy, and eventually to the patients.
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`11.
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`In certain circumstances, drug ordering, distribution to pharmacies,
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`and dispensing to patients are overseen by the Federal Risk Evaluation Mitigation
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`Strategies (REMS) program which requires additional training and certification
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`because of certain dangers inherent to the drug.
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`12.
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`In some cases, certain pharmaceutical manufacturers have taken steps
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`to require such training even without FDA requirement.
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`13.
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`I am an expert in the field of prescribing pharmaceutical drugs, including
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`the use of computer systems for regulating access to prescription drugs and the
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`potential influence of these distribution systems on medication access to patients and
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`caregivers.
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`
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`5
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`CFAD VI 1027-0005
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`
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`14. My full professional background is detailed in my curriculum vitae,
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`which is included with this declaration as Ex. 1028.
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`III.
`
`List of Documents Considered in Formulating Opinion
`15.
`I have reviewed the ’720 Patent, its prosecution file history as well as
`
`the prior art relevant to the Petition. In particular, I have reviewed the following:
`
`(1) Powell et al. (Postgrad. Med. J. 70:901 (1994)) (“Powell”) (Ex. 1006); (2)
`
`Dishman et al. (Am. J. Hosp. Pharm. 51: 899 (1994)) (“Dishman”) (Ex. 1007); (3)
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`Cunningham, U.S. Pat. No. 5,832,449 (“Cunningham”) (Ex. 1008); (4) Gardner et al.
`
`(“Assessing the effectiveness of a computerized pharmacy system.” Decision
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`Support Systems in Critical Care. Springer New York, 1994 at 174–183)
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`(“Gardner”) (Ex. 1015); (5) Zeldis et al. (“S.T.E.P.S.: A Comprehensive Program
`
`for Controlling and Monitoring Access to Thalidomide.” Clinical Therapeutics,
`
`Vol. 21, No. 2 (1999)) (“Zeldis”) (Ex. 1011); (6) Burleson (“Review of Computer
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`Applications in Institutional Pharmacy 1975–1981.” Am. J. Hosp. Pharm., 39:53–
`
`70 (1982)) (“Burleson”) (Ex. 1016); (7) Mann et al. (“Passage of Chemicals into
`
`Human and Animal Semen: Mechanisms and Significance.” Critical Reviews in
`
`Toxicology, Vol. 11, 1:1–14 (1982)) (“Mann”) (Ex. 1018); (8) Vanchieri
`
`(“Preparing for Thalidomide’s Comeback.” Annals of Internal Medicine,” 127:10,
`
`951–54 (1997)) (“Vanchieri”) (Ex. 1019); (9) Shinn et al. (Drug Inform. J., Vol. 17,
`
`pp. 205–210 (1982)) (“Shinn”) (Ex. 1020); (10) Linnarsson (“Decision support for
`6
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`
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`CFAD VI 1027-0006
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`
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`drug prescription integrated with computer–based patient records in primary
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`care.” Med. Inform., 18:2, pp. 131–142 (1993)) (“Linnarsson”) (Ex. 1021); (11)
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`Grönroos (“A medication database – a tool for detecting drug interactions in
`
`hospital.” Eur. J. Clin. Pharmacol., 53:13–17 (1997)) (“Grönroos”) (Ex. 1022); (12)
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`Soyka (Eur. Arch. Psychiatry Clin. Neurosci., 242:362–372 (1993)) (“Soyka”) (Ex.
`
`1023); (13) Hamera (“Alcohol, Cannabis, Nicotine, and Caffeine Use and
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`Symptom Distress in Schizophrenia.” J. Nerv. Ment. Dis., 183:559–565 (1995))
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`(“Hamera”) (Ex. 1024); (14) Kosten (“Substance Abuse and Schizophrenia:
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`Editors’ Introduction.” Schizophrenia Bulletin, 23:2, 181–186 (1997)) (“Kosten”)
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`(Ex. 1025); (15) Menill (“Substance Abuse and Women on Welfare.” The National
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`Center on Addiction and Substance Abuse at Columbia Univ. (June 1994))
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`(“Menill”) (Ex. 1026); (16) Mitchell et al. (N. Engl. J. Med. 333:101–06 (1995))
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`(“Mitchell”) (Ex. 1010); and “Thalidomide Back—Under Strict Control,” JAMA:
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`Medical News and Perspectives, 278:14, 1135–37 (1997) (“JAMA”).
`
`IV.
`
`Person of Ordinary Skill in the Art
`16.
`I understand that a POSA is a hypothetical person presumed to be aware
`
`of all pertinent art, and is a person of ordinary creativity. A POSA in pharmaceutical
`
`prescriptions as of October 23, 2000 (the earliest possible priority date of the ’720
`
`Patent) would typically have either a Pharm. D. or a B.S. in pharmacy with
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`approximately 5–10 years of experience and a license to practice as a registered
`7
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`
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`CFAD VI 1027-0007
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`
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`pharmacist in any one or more of the United States.
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`17. A POSA may work as part of a multi–disciplinary team and draw upon
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`not only his or her own skills, but also work collaboratively with other team members
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`that have their own unique specialized skillset, training, and knowledge base, in order
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`to best solve a given problem and care for varying patient populations.
`
`V.
`
`The ’720 Patent Specification and Prosecution History
`18.
`I have considered the disclosure and file history of the ’720 from the
`
`perspective of a POSA as of the earliest priority date of the ’720 Patent–October 23,
`
`2000.
`
`19. The ’720 Patent describes “methods for the delivery of drugs known or
`
`suspected of causing an adverse side effect, especially teratogenic drugs, to patients.”
`
`(Ex. 1001 at 3:31–34.) The ’720 Patent generally describes methods for “the
`
`distribution to patients of drugs, particularly teratogenic drugs, in ways wherein
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`such distribution can be carefully monitored and controlled.” (Ex. 1001 at 1:13–16.)
`
`20. A teratogenic drug is an agent that, upon administration to the mother
`
`or father, may disturb the normal growth and development of an embryo or fetus.
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`21. The background section of the ’720 specification states that prior
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`“[m]ethods for monitoring and educating patients to whom a drug is distributed
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`have been developed in connection with” isotretinoin, including a “pregnancy
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`
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`8
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`CFAD VI 1027-0008
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`
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`prevention program.” (Ex. 1001 at 2:13–20.) Isotretinoin, marketed under the brand
`
`name Accutane®, is a known teratogenic drug.
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`22. The specification references a study done at the Slone Epidemiology
`
`Unit of Boston University that surveyed patients to assess the success of the
`
`isotretinoin program and found it to be effective. (Ex. 1001 at 2:18–23.)
`
`23. The invention of the ’720 Patent was purportedly conceived in the
`
`context of the introduction of an FDA–approved version of thalidomide, a known
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`teratogenic drug beneficial for treating a variety of diseases, including a form of
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`leprosy.
`
`24. The methods of the ’720 Patent can be summarized in four steps: (1)
`
`filling prescriptions for the drug only after consulting a “computer readable storage
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`medium” to confirm that the prescribers, pharmacies, and patients are registered in
`
`a computer database; (2) assigning patients to risk groups based on the degree of
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`risk that taking the drug will lead to a side effect, and entering the risk group
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`assignment in the “computer readable storage medium;” (3) determining whether
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`the adverse effect that is likely to occur is acceptable; and (4) generating a
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`“prescription approval code to said pharmacy before said prescription is filled.”
`
`(Ex. 1001 at 2:49–3:4, 18:16-42.)
`
`25. The ’720 Patent specification also teaches that “[t]he invention is not
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`
`
`9
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`CFAD VI 1027-0009
`
`
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`limited to distribution of teratogenic drugs; other potentially hazardous drugs may
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`also be distributed in accordance with embodiments of this invention … in such a
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`fashion that persons for whom such drugs are contraindicated will not receive
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`them.” (Ex. 1001 at 3:21–26.)
`
`26.
`
`In one embodiment, “[i]f the prescriber is not registered in the
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`computer readable storage medium, the prescriber will be ineligible to prescribe the
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`drug. Similarly, if the pharmacy is not registered … the pharmacy will be ineligible
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`to dispense the drug.” (Ex. 1001 at 8:33–38.) And, patients must also be registered
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`in the computer readable storage medium. (Id. at 5:61–63.)
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`27. Registration can be achieved by mail, facsimile or on–line transmission
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`and the prescriber may be asked to provide certain information as part of the
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`registration, including name, address, and health care institution affiliation. (Id. at
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`4:54–59, 5:1–5.) A pharmacy that can fill the prescription for the drug can also
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`become registered in a computer readable medium in a similar manner. (Id. at 5:17–
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`60.)
`
`28. Patients are also registered in the computer readable storage medium.
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`(Id. at 5:61–63.) Registration of the patient can take place at a registered pharmacy,
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`or can be carried out by the physician (Id. at 6:3–10.) Registration will involve filling
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`in a registration card of form and providing information such as name, gender,
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`10
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`CFAD VI 1027-0010
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`
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`mailing address, date of birth, and the like. (Id. at 6:11–14.) Information that is
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`probative of the risk of known side effects will also be collected from the patient.
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`(Id. at 6:30–33.) This information can then be compared with a predefined set of
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`risk parameters for the drug which allows for assignment of the patient to particular
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`risk group. (Id. at 6:33–36.)
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`29. For teratogenic drugs, “the prescriber preferably provides counsel on
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`the importance of using at least two forms of highly effective birth control
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`methods.…” (Id. 1001 at 9:26–31.)
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`30.
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`In another embodiment, the patient must sign an informed consent
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`form prior to receiving the drug. (Id. at 10:41–43.) After the counseling step, the
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`patient may receive limited amounts of the drug from a registered pharmacy, and
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`may not receive refills without a renewal prescription from the prescriber, subject
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`to conditions such as a negative pregnancy test. (Id. at 11:62–12:8.)
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`31. During the prosecution of the ’720 Patent, the examiner did not
`
`consider the prior art references cited in the petition.
`
`32.
`
` The examiner did consider, but did not cite, a divisional of the
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`Cunningham reference. (See id. at Cover; Ex. 1009 at Cover.)
`
`VI. The ’720 Patent Claims
` The Language of the Claims
`A.
`33. The ’720 Patent has two independent claims and 30 dependent claims.
`11
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`CFAD VI 1027-0011
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`
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`Claim 1 is representative, which is reproduced below:
`
`Claim 1. In a method for delivering a drug to a patient in need of the
`drug, while avoiding the occurrence of an adverse side effect known or
`suspected of being caused by said drug, wherein said method is of the
`type in which prescriptions for said drug are filled only after a computer
`readable storage medium has been consulted to assure that the prescriber
`is registered in said medium and qualified to prescribe said drug, that the
`pharmacy is registered in said medium and qualified to fill the
`prescription for said drug, and the patient is registered in said medium
`and approved to receive said drug, the improvement comprising:
`a. defining a plurality of patient risk groups based upon a predefined
`set of risk parameters for said drug;
`b. defining a set of information to be obtained from said patient,
`which information is probative of the risk that said adverse side effect
`is likely to occur if said drug is taken by said patient;
`c. in response to said information set, assigning said patient to at least
`one of said risk groups and entering said risk group assignment in said
`medium;
`d. based upon said information and said risk group assignment,
`determining whether the risk that said adverse side effect is likely to
`occur is acceptable; and
`e. upon a determination that said risk is acceptable, generating a
`prescription approval code to be retrieved by said pharmacy before
`said prescription is filled.
`
`(Ex. 1001 at 18:17–42.)
`
`
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`12
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`CFAD VI 1027-0012
`
`
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`34. The dependent claims, Claims 2–27, recite the following limitations:
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`• Claim 2: “in response to said risk group assignment, said patient is
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`counseled as to the risks of taking said drug and advised as to risk
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`avoidance measures” (Ex. 1001 at 18:43–45);
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`• Claim 3: “said counseling comprises full disclosure of said risks” (Ex.
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`1001 at 18:46–47);
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`• Claim 4: “said prescription is filled only following said full disclosure
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`and informed consent of said patient” (Ex. 1001 at 18:48–50);
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`• Claim 5: “said risk group assignment and said informed consent is
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`verified by said prescriber at the time that said patient is registered in
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`said computer readable storage medium” (Ex. 1001 at 18:51–54);
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`• Claim 6: “said risk group assignment and said informed consent is
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`transmitted to said computer readable storage medium by facsimile
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`and interpreted by optical character recognition software” (Ex. 1001
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`at 18:55–58);
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`• Claim 7: “said set of information includes the results of diagnostic
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`testing (Ex. 1001 at 18:58–60);
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`• Claim 8: “said diagnostic testing is probative of the onset of said
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`adverse side effect” (Ex. 1001 at 18:61–62);
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`13
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`CFAD VI 1027-0013
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`• Claim 9: “said diagnostic testing is probative of the concentration of
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`said drug in a tissue of said patient” (Ex. 1001 at 18:63–65);
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`• Claim 10: “said diagnostic testing comprises genetic testing” (Ex.
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`1001 at 18:66–67);
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`• Claim 11: “said side effect is likely to arise in said patient” (Ex. 1001
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`at 19:1–2);
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`• Claim 12: “said side effect is likely to arise in a foetus carried by said
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`patient” (Ex. 1001 at 19:3–4);
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`• Claim 13: “said side effect is likely to arise in a recipient or a foetus
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`carried by a recipient of the bodily fluid of said patient” (Ex. 1001 at
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`19:5–7);
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`• Claim 14: “said recipient is a sexual partner of said patient” (Ex. 1001
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`at 19:8–9);
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`• Claim 15: “[t]he method of claim 1 further comprising: f. defining for
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`each said risk group a second set of information to be collected from
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`said patient on a periodic basis; g. obtaining said second set of
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`information from said patient; and h. entering said second set of
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`information in said medium before said patient is approved to receive
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`said drug” (Ex. 1001 at 19:10–17);
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`14
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`CFAD VI 1027-0014
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`• Claim 16: “said second set of information comprises a survey
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`regarding said patient's behavior and compliance with said risk
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`avoidance measures” (Ex. 1001 at 19:18–20);
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`• Claim 17: “said survey is conducted telephonically using an integrated
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`voice response system” (Ex. 1001 at 19:21–23);
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`• Claim 18: “said patient is a female of childbearing potential and said
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`second set of information comprises the results of a pregnancy test”
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`(Ex. 1001 at 19:24–26);
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`• Claim 19: “said periodic interval comprises about 28 days” (Ex. 1001
`
`at 19:27–28);
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`• Claim 20: “further comprising providing said patient with a
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`contraceptive device or formulation” (Ex. 1001 at 19:29–30);
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`• Claim 21: “said adverse side effect comprises a teratogenic effect”
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`(Ex. 1001 at 19:31–32);
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`• Claim 22: “said drug is thalidomide” (Ex. 1001 at 19:33–34);
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`• Claim 23: “said teratogenic effect is likely to arise in a foetus carried
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`by said patient” (Ex. 1001 at 19:35–36);
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`
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`15
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`CFAD VI 1027-0015
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`
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`• Claim 24: “said teratogenic effect is likely to arise in a foetus carried
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`by a recipient of the bodily fluid of said patient” (Ex. 1001 at 19:37–
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`39);
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`• Claim 25: “said recipient of the bodily fluid of said patient is a sexual
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`partner of said patient” (Ex. 1001 at 19:40–41);
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`• Claim 26: “said set of information includes the results of a pregnancy
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`test” (Ex. 1001 at 19:42–43);
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`• Claim 27: “said prescription is filled for no more than about 28 days.”
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`(Ex. 1001 at 20:1–2.)
`
`35. The independent Claim 28 repeats the language of Claim 1 with the
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`following limitation: “wherein said adverse side effect is likely to arise in patients who
`
`take said drug in combination with at least one other drug.” (Ex. 1001 at 20:3–31.)
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`36. The dependent claims, Claims 29–32, recite the following limitations:
`
`• Claim 29: “said set of information is also probative of the likelihood
`
`that said patient may take said drug and said other drug in
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`combination” (Ex. 1001 at 20:3–31);
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`• Claim 30: “said set of information includes the results of diagnostic
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`testing” (Ex. 1001 at 20:35–36);
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`
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`16
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`CFAD VI 1027-0016
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`• Claim 31: “said diagnostic testing comprises testing for evidence of the
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`use of said other drug” (Ex. 1001 at 20:37–39.);
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`• Claim 32: “said diagnostic testing comprises testing for evidence
`
`which is indicative of the onset of said adverse side effect.” (Ex.
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`1001 at 20:40–43.)
`
` The Meaning of Selected Terms in the Claims of the ’720 Patent
`B.
`37.
`It is my understanding that the claim terms in a patent subject to IPR
`
`must be understood in their broadest reasonable interpretation in light of the
`
`specification of the patent.
`
`38. The terms in the claims of the ’720 Patent are used in accordance with
`
`their plain and ordinary meaning, as exemplified by the terms presented below.
`
`1. “Consulted”
`39. The term “consulted” means: “accessed and considered.” (Ex. 1030 at
`
`3.)
`
`2. “Teratogenic effect”
`40. The term “teratogenic effect” means: “any effect that disturbs the
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`normal growth and development of an embryo or fetus.” (Ex. 1030 at 3.)
`
`3. “Adverse side effect”
`41. The term “adverse side effect” means: “any unfavorable abnormality,
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`defect, mutation, lesion, degeneration or injury which may be caused by taking the
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`
`
`17
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`CFAD VI 1027-0017
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`drug.” (Ex. 1030 at 6.)
`
`42. A POSA would have understood that the remaining terms in Claims 1–
`
`32 are plain on their face. I have given the terms their plain and ordinary meaning
`
`under a broadest reasonable interpretation in light of the specification.
`
`VII. Overview of the State of the Art and Summary of Prior Art References
` State of the Relevant Art as of October 2000
`A.
`43. By October 23, 2000, persons of ordinary skill in the art understood that
`
`teratogenic drugs may cause birth defects, and were aware that such drugs either
`
`already used, or needed, restrictive safeguards before prescription.
`
`44. One notable example of a drug marketed using methods to prevent its
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`use in pregnant patients is isotretinoin, marketed under the trade name Accutane®.
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`This drug, suspected to be a potent teratogen based on animal testing, became part of
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`a manufacturer–sponsored Pregnancy Prevention Program (“PPP”). (Ex. 1010 at
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`101.)
`
`45. The PPP program, which had multiple components, included the
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`distribution to physicians of a kit that included informed consent documents and
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`information for patient counseling. In particular, patients were warned against the
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`teratogenic risk of Accutane® and the need to prevent pregnancy. Patients were also
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`advised as to the proper methods of birth control available. (Ex. 1010 at 103.)
`
`46.
`
`In addition to the Accutane® PPP, another well–known restricted drug
`
`
`
`18
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`CFAD VI 1027-0018
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`
`
`distribution program in existence prior to 2000 regulated clozapine (trade name
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`Clozaril®). (Ex. 1012 at 111–12.) The clozapine patients were also required to submit
`
`to weekly white blood cell (WBC) testing and could only have a prescription for
`
`clozapine filled if the test results fell within a pre–designated range. (Ex. 1007 at 899;
`
`see Ex. 1012 at 112; Ex. 1014 at 8.)
`
`47. Thalidomide is a drug that originated in Germany in 1957. Doctors
`
`initially prescribed the drug as a sedative, but quickly noticed its effectiveness in
`
`treating a form of leprosy, erythema nodosum leprosum. (Ex. 1001 at 1:40-50; Ex.
`
`1011 at 320–21.)
`
`48. However, shortly after thalidomide came on the market, doctors realized
`
`that the drug caused severe birth defects in infants whose mothers took the drug
`
`while pregnant. (Ex. 1011 at 320.) As a result, thalidomide was generally taken off of
`
`most markets by 1962. (Ex. 1001 at 1:44–45.)
`
`49. Due to thalidomide’s therapeutic effects, the drug was reintroduced in
`
`the United States in the 1990s. On July 16, 1998, the FDA approved the drug to treat
`
`a rare form of leprosy, erythema nodosum leprosum (ENL). (See Ex. 1006 at 901; Ex.
`
`1011 at 320.)
`
`50.
`
`In an effort to ensure the safety of thalidomide use, the FDA invoked
`
`the restricted distribution provisions under Subpart H of its regulations (21 C.F.R.
`
`
`
`19
`
`CFAD VI 1027-0019
`
`
`
`§ 314.520), which are directed to products with safety issues that cannot be addressed
`
`under ordinary approval conditions. (See Ex. 1031, April 21, FDA Approvable Letter
`
`(Sept. 19, 1997) at 1 and Approval Letter (July 16, 1998) at 1.)
`
`51.
`
`Prior to October 2000, the dramatic birth defects caused by thalidomide
`
`warranted a monitoring system that included controls directed at minimizing
`
`pregnancy. In pharmacy schools, the history of thalidomide is taught to support case
`
`studies that show what could happen without proper monitoring and evaluation of
`
`drug product properties by adequate and acceptable laboratory, animal, and human
`
`studies.
`
`52. As a result, doctors, pharmacists, and regulators interested in bringing
`
`thalidomide back to the market with restrictions to protect fetuses from its teratogenic
`
`effects were aware of both the Accutane® PPP as well as the clozapine restricted
`
`distribution program. (Ex. 1012 at 110–11; see Ex. 1014 at 1.)
`
`53. The computer registration of patients has been a common practice used
`
`by physicians and pharmacists to track their patients since at least 1975. (See, e.g.,
`
`Ex. 1016 at 53; Ex. 1015 at 174, 182.)
`
`54. The use of computers to prescribe drug distribution for hazardous drugs
`
`has been around since long before 1990, but at least by 1990, pharmacies were using
`
`computers to fill prescriptions. (See, e.g., Ex. 1015 at 174.)
`
`
`
`20
`
`CFAD VI 1027-0020
`
`
`
`55.
`
`It was well understood long before October 23, 2000 the advantages of
`
`using a computer to track patient information and use that date data in restricting
`
`prescriptions. Restrictions have historically been based on gender, weight, allergies,
`
`and other physical considerations, as well as mental considerations.
`
`56.
`
`It was well known in the art prior to 2000 to keep prescription records in
`
`a computerized system. (See, e.g., Ex. 1015 at 174; Ex. 1016 at 56, 60–63, 68.) Such
`
`records would include information such as the patient’s gender, allergies, height,
`
`weight, and other health–related measures. (See Ex. 1016 at 59.)
`
`57. Additionally, patients often were required to receive counseling on birth
`
`control and to fill–out informed consents for contraception, which were kept by
`
`pharmacies and doctors. The informed consents were part of the records on clients
`
`that were kept in the conventional practices by physicians and pharmacists.
`
`58.
`
`Physicians and pharmacists would use this data to determine (1) whether
`
`a patient should be prescribed and provided a certain drug given its profile, and (2)
`
`how long a patient should take the medication.
`
`59. Thus, in the case of thalidomide or any other teratogenic drug, a POSA
`
`would have been motivated to combine well–known prior art restricted drug
`
`distribution methods, including counseling–based avoidance of pregnancy, and a
`
`computerized tracking system that allows only registered access to prescriptions when
`
`
`
`21
`
`CFAD VI 1027-0021
`
`
`
`certain condition (e.g., non–pregnancy) are met.
`
`60.
`
`Indeed, those of ordinary skill in the art were motivated to combine the
`
`method for avoiding pregnancy with a computerized tracking system that only permits
`
`filling prescriptions for the drug when certain conditions (e.g., non-pregnancy) are met.
`
`(See Ex. 1033 at 1136 (“Celgene has drafted a plan that it hopes will prevent fetal
`
`exposure to the drug. … The plan is built on experience with restrictions on such
`
`other drugs with severe adverse effects as Accutane … , used to treat severe acne, and
`
`Clozaril … , used to treat schizophrenia … [and] a tracking system would be in place
`
`to ensure compliance.”); Ex.1012 at 111–12.)
`
` Review of the Relevant Prior Art
`B.
`1. Mitchell (Ex. 1010)
`61. Mitchell discloses a pregnancy prevention program implemented to
`
`minimize pregnancies among women treated with the known teratogenic drug
`
`isotretinoin. (See Ex. 1010 at 101–05.) The program sought “to keep the drug available
`
`while minimizing the teratogenic hazard.” (Id. at 105.) Additionally, the program—
`
`targeted at both prescribers and patients—instructed prescribers to “warn patients of
`
`risks, obtain negative pregnancy tests, and delay therapy until the second or third day
`
`of the next normal menstrual period.” (Id. at 101.) The program also provided
`
`materials to patients such as information brochures and contraceptive information.
`
`(Id. at 101.)
`
`
`
`22
`
`CFAD VI 1027-0022
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`
`
`62. Mitchell also describes counseling patients in relation to isotretinoin’s
`
`teratogenic effects. (Id. at 105.) I note that some implementations of the program
`
`included warnings about the “need to have a negative blood pregnancy test before
`
`starting therapy…and to use effective birth control one month before starting
`
`therapy, during therapy, and one month after completing it.” (Id. at 103.)
`
`2. Dishman (Ex. 1007)
`63. Dishman discloses a program for controlling the dispensing of clozapine,
`
`an antipsychotic drug, to veterans. (Ex. 1007 at 899.) Clozapine treatment is
`
`associated with a number potentially fatal serious side effects, such as “life–
`
`threatening side effect of agranulocytosis,” and it was well understood by persons of
`
`ordinary skill in the art long before October 23, 2000. (See, e.g., Ex. 1012 at 112.)
`
`64. Dishman describes a monitoring program instituted by the Department
`
`of Veterans Affairs (“VA”) in 1991 to prevent contraindicated individuals from
`
`receiving clozapine. (Ex. 1007 at 900.) Specifically, Dishman teaches that the VA’s
`
`program established a National Clozapine Coordinating Center (“NCCC”) to “review
`
`each clozapine candidate’s file before granting approval for use and weekly
`
`tracking.…” (Id. at 900.) Prior to this approval, each patient underwent extensive
`
`evaluation and documentation to identify contraindications, including pregnancy. (Id.
`
`at 900.)
`
`65. Additionally, for prescription or use of clozapine, prescribers and
`23
`
`
`
`CFAD VI 1027-0023
`
`
`
`patients had to register with the Clozaril National Registry, which requires weekly
`
`monitoring of a patient’s white blood cell counts and limits the quantity of medicine
`
`dispensed at one time. (Id. at 899.) This process “requires the cooperation and
`
`coordinated efforts of the patient, physician, laboratory, and pharmacy.” (Id. at 899.)
`
`66. The NCCC also mandated that each hospital have a computerized
`
`clozapine prescription lockout system, which ties the hospital’s laboratory database to
`
`the outpatient pharmacy dispensing software. (Id. at 900.)
`
`67. According to Dishman, the program only allowed clozapine prescriptions
`
`to be processed when the white blood cell counts were within defined limits, i.e., when
`
`certain pre–defined clinical criteria are met. (Id. at 900.) The NCCC guidelines require
`
`extensive patient evaluation and documentation by pharmacist and provider. In order
`
`to receive clozapine, patients had to undergo a complete physical examination,
`
`including laboratory tests. (Id. at 900.)
`
`68.
`
`It is further noted by Dishman that patients were screened by the
`
`pharmacist to determine eligibility for treatment with clozapine. (Id. at 900.)
`
`Therefore, a POSA, reading Dishman, would have understood that pharmacists sent
`
`information to the NCCC and after approval, the patient would be enrolled in the
`
`hospital’s clozapine track
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