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
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`
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`CFAD VI 1021-0001
`
`
`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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`
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`CFAD VI 1021-0001
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`
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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.
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`Introduction
`1.
`I am over the age of eighteen and otherwise competent to make this
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`declaration.
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`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 a 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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`CFAD VI 1021-0002
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`II. My Background and Qualifications
`4.
`I am presently the Director of the PGY2 Pain and Palliative Care Pharmacy
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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 1021-0003
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`7.
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`Since October 1998, I have held the title of Adjunct Associate Professor
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`of 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 Diplomat 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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`4
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`CFAD VI 1021-0004
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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,
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`including the use of computer systems for regulating access to prescription drugs and
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`the potential influence of these distribution systems on medication access to patients
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`and caregivers.
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`
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`5
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`CFAD VI 1021-0005
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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. 1022.
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`III. List of Documents Considered in Formulating Opinion
`15.
`I have reviewed the ’720 Patent, its prosecution file history, and the
`
`prior art relevant to the Petition. In particular, I have reviewed the following: (1)
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`THALOMID™ (thalidomide) Capsules Revised Package Insert (15 July 1998)
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`(“Thalomid PI”) (Ex. 1006); (2) Powell et al. (Postgrad. Med. J. 70:901 (1994))
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`(“Powell”) (Ex. 1007); (3) Dishman et al. (Am. J. Hosp. Pharm. 51: 899 (1994))
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`(“Dishman”) (Ex. 1008); (4) Cunningham, U.S. Pat. No. 5,832,449 (“Cunningham”)
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`(Ex. 1009); (5) Mitchell et al. (N. Engl. J. Med. 333:101–06 (1995)) (“Mitchell”)
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`(Ex. 1011); (6) Gardner et al. (“Assessing the effectiveness of a computerized
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`pharmacy system.” Decision Support Systems in Critical Care. Springer New
`
`York, 1994 at 174–183) (“Gardner”) (Ex. 1016); (7) Zeldis et al. (“S.T.E.P.S.: A
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`Comprehensive Program for Controlling and Monitoring Access to Thalidomide.”
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`Clinical Therapeutics, Vol. 21, No. 2 (1999)) (“Zeldis”) (Ex. 1012); (8) Burleson
`
`(“Review of Computer Applications in Institutional Pharmacy 1975–1981,” Am. J.
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`Hosp. Pharm., 39:53–70 (1982)) (“Burleson”) (Ex. 1017); (9) Keravich et al. (Am. J.
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`Health–Syt. Pharm., 56:1721–25 (1999)) (“Keravich”) (Ex. 1018); (10) Steiner et al.
`
`(“A General Method of Compliance Assessment Using Centralized Pharmacy
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`Records.” Medical Care, Vol. 26, No. 8, (August 1988)) (“Steiner”) (Ex. 1019); (11)
`6
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`CFAD VI 1021-0006
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`Pestotnik et al. (“Therapeutic Antibiotic Monitoring: Surveillance Using a
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`Computerized Expert System.” Am. J. Med., Vol. 88, page 43 (January 1990))
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`(“Pestotnik”) (Ex. 1020); and (12) CDC Meeting (Centers for Disease Control,
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`Preventing Birth Defects, March 26, 1997 (“CDC”) (Ex. 1015).
`
`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
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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 given problems and care for varying patient populations.
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`V. The ’720 Patent Specification and Prosecution History
`18.
`I have considered the disclosure and file history of the ’720 from the
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`perspective of a POSA as of the earliest priority date of the ’720 Patent–October 23,
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`2000.
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`19. The ’720 Patent describes “methods for the delivery of drugs known or
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`
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`7
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`CFAD VI 1021-0007
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`
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`suspected of causing an adverse side effect, especially teratogenic drugs, to patients.”
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`(Ex. 1001 at 3:31–34.) The ’720 Patent generally describes methods for “the
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`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.)
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`20. A teratogenic drug is an agent that, upon administration to the mother
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`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
`
`have been developed in connection with” isotretinoin, including a “pregnancy
`
`prevention program.” (Ex. 1001 at 2:13–20.) Isotretinoin, marketed under the brand
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`name Accutane®, is a known teratogenic drug.
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`22. The specification references a study done at the Slone Epidemiology
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`Unit of Boston University that surveyed patients to assess the success of the
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`isotretinoin program and found it to be effective. (Ex. 1001 at 2:18–23.)
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`23. The invention of the ’720 Patent was purportedly conceived in the
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`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.
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`24. The methods of the ’720 Patent can be summarized in four steps: (1)
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`
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`8
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`CFAD VI 1021-0008
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`
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`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
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`computer database; (2) assigning patients to risk groups based on the degree of risk
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`that taking the drug will lead to a side effect, and entering the risk group assignment
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`in the “computer readable storage medium;” (3) determining whether the adverse
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`effect that is likely to occur is acceptable; and (4) generating a “prescription
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`approval code to said pharmacy before said prescription is filled.” (Ex. 1001 at
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`2:49–3:4; 18:16-42.)
`
`25. The ’720 Patent specification also teaches that “[t]he invention is not
`
`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.)
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`26.
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`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 online transmission
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`9
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`CFAD VI 1021-0009
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`
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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.)
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`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
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`filling in a registration card or form and providing information such as name,
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`gender, mailing address, date of birth, and the like. (Id. at 6:11–14.) Information
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`that is probative of the risk of known side effects will also be collected from the
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`patient. (Id. at 6:30–33.) This information can then be compared with a predefined
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`set of risk parameters for the drug which allows for assignment of the patient to a
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`particular 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. 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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`10
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`CFAD VI 1021-0010
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`
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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
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`consider Thalomid PI, Keravich, or Cunningham references. (See Ex. 1001 at Cover.)
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`32. The examiner did consider, but did not cite, a divisional of the
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`Cunningham reference. (See id. at Cover; Ex. 1010 at Cover.)
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`VI. The ’720 Patent Claims
`A. The Language of the Claims
`33. The ’720 Patent has two independent claims and 30 dependent claims.
`
`Claim 1 is representative, which is reproduced below:
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`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;
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`
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`11
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`CFAD VI 1021-0011
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`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.)
`
`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
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`is counseled as to the risks of taking said drug and advised as to
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`risk avoidance measures” (Ex. 1001 at 18:43–45);
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`• Claim 3: “said counseling comprises full disclosure of said risks”
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`(Ex. 1001 at 18:46–47);
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`• Claim 4: “said prescription is filled only following said full
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`disclosure and informed consent of said patient” (Ex. 1001 at
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`18:48–50);
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`12
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`
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`CFAD VI 1021-0012
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`
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`• Claim 5: “said risk group assignment and said informed consent
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`is verified by said prescriber at the time that said patient is
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`registered in said computer readable storage medium” (Ex. 1001
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`at 18:51–54);
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`• Claim 6: “said risk group assignment and said informed consent
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`is transmitted to said computer readable storage medium by
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`facsimile and interpreted by optical character recognition
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`software” (Ex. 1001 at 18:55–58);
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`• Claim 7: “said set of information includes the results of
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`diagnostic 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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`• Claim 9: “said diagnostic testing is probative of the
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`concentration of said drug in a tissue of said patient” (Ex. 1001
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`at 18:63–65);
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`• Claim 10: “said diagnostic testing comprises genetic testing”
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`(Ex. 1001 at 18:66–67);
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`• Claim 11: “said side effect is likely to arise in said patient”
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`(Ex. 1001 at 19:1–2);
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`13
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`CFAD VI 1021-0013
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`• Claim 12: “said side effect is likely to arise in a foetus carried by
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`said patient” (Ex. 1001 at 19:34);
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`• Claim 13: “said side effect is likely to arise in a recipient or a
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`foetus carried by a recipient of the bodily fluid of said patient”
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`(Ex. 1001 at 19:5–7);
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`• Claim 14: “said recipient is a sexual partner of said patient”
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`(Ex. 1001 at 19:8–9);
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`• Claim 15: “[t]he method of claim 1 further comprising: f.
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`defining for each said risk group a second set of information to
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`be collected from said patient on a periodic basis; g. obtaining
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`said second set of information from said patient; and h. entering
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`said second set of information in said medium before said
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`patient is approved to receive said drug” (Ex. 1001 at 19:10–17);
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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
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`integrated voice response system” (Ex. 1001 at 19:21–23);
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`• Claim 18: “said patient is a female of childbearing potential and
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`14
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`CFAD VI 1021-0014
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`said second set of information comprises the results of a
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`pregnancy test” (Ex. 1001 at 19:24–26) ;
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`• Claim 19: “said periodic interval comprises about 28 days”
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`(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
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`effect” (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
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`carried by said patient” (Ex. 1001 at 19:35–36);
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`• Claim 24: “said teratogenic effect is likely to arise in a foetus
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`carried by a recipient of the bodily fluid of said patient”
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`(Ex. 1001 at 19:37–39);
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`• Claim 25: “said recipient of the bodily fluid of said patient is a
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`sexual 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
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`pregnancy test” (Ex. 1001 at 19:42–43);
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`• Claim 27: “said prescription is filled for no more than about 28
`15
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`CFAD VI 1021-0015
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`days.” (Ex. 1001 at 20:1–2.)
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`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:
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`• Claim 29: “said set of information is also probative of the
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`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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`• Claim 31: “said diagnostic testing comprises testing for evidence of
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`the use of said other drug”(Ex. 1001 at 20:37–39);
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`• Claim 32: “said diagnostic testing comprises testing for evidence
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`which is indicative of the onset of said adverse side effect.” (Ex. 1001
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`at 20:40–43.)
`
`B. The Meaning of Selected Terms in the Claims of the ’720
`Patent
`It is my understanding that the claim terms in a patent subject to IPR
`
`37.
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`must be understood in their broadest reasonable interpretation in light of the
`
`specification of the patent.
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`
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`16
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`CFAD VI 1021-0016
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`38. The terms in the claims of the ’720 Patent are used in accordance with
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`their plain and ordinary meaning, as exemplified by the terms presented below.
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`1. “Consulted”
`39. The term “consulted” means: “accessed and considered.” (Ex. 1023 at
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`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. 1023 at 3.)
`
`3. “Adverse side effect”
`41. The term “adverse side effect” means: “any unfavorable abnormality,
`
`defect, mutation, lesion, degeneration or injury which may be caused by taking the
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`drug.” (Ex. 1023 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
`A. State of the Relevant Art as of October 2000
`43. By October 23, 2000, persons of ordinary skill in the art understood that
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`teratogenic drugs may cause birth defects, and were aware that such drugs either
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`already used, or needed, restrictive safeguards before prescription.
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`
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`17
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`CFAD VI 1021-0017
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`44. One notable example of a drug marketed using methods to prevent its
`
`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. 1011 at 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. 1011 at 103.)
`
`46.
`
`In addition to the Accutane® PPP, another well-known restricted drug
`
`distribution program in existence prior to 2000 regulated clozapine (trade name
`
`Clozaril®). (Ex. 1013 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. 1008 at 899;
`
`see Ex. 1013 at 112; Ex. 1015 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.
`
`1012 at 320–21.)
`
`
`
`18
`
`CFAD VI 1021-0018
`
`
`
`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. 1012 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. (See Ex. 1007 at 901; Ex. 1012 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.
`
`§ 314.520), which are directed to products with safety issues that cannot be addressed
`
`under ordinary approval conditions. (See Ex. 1025, 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.
`
`
`
`19
`
`CFAD VI 1021-0019
`
`
`
`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. 1013 at 110–11; see Ex. 1015 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. 1017 at 53; Ex. 1016 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. 1016 at 174.)
`
`55.
`
`It was well understood long before October 23, 2000, the advantages of
`
`using a computer to track patient information and use that 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 also well known in the art prior to 2000 to keep prescription
`
`records in a computerized system. (See, e.g., Ex. 1016 at 174; Ex. 1017 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. 1017 at 59.)
`
`57. Additionally, patients often were required to receive counseling on birth
`
`
`
`20
`
`CFAD VI 1021-0020
`
`
`
`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
`
`certain condition (e.g., non-pregnancy) are met.
`
`B. Summary of the Petition’s Prior Art References
`1. Thalomid PI (Ex. 1006)
`60. Thalomid PI is a package insert that is included in the distribution of
`
`thalidomide. Thalomid PI is dated 15 July 1998. (Ex. 1006 at 1.) Thalomid PI contains
`
`the information regarding the “System for Thalidomide Education and Prescribing
`
`Safety” (“S.T.E.P.S.”). (Id.)
`
`61. Thalomid PI describes a method for delivering thalidomide to a patient in
`
`need of the drug, while avoiding the occurrence of severe, life-threatening birth
`
`defects. (Id.) Specifically, Thalomid PI recites:
`
`21
`
`
`
`CFAD VI 1021-0021
`
`
`
`BECAUSE OF THIS TOXICITY AND IN AN EFFORT TO MAKE
`THE CHANCE OF FETAL EXPOSURE TO THALOMID AS
`NEGLIGIBLE AS POSSIBLE, THALOMID IS APPROVED FOR
`MARKETING ONLY UNDER A SPECIAL RESTRICTED
`DISTRIBUTION PROGRAM APPROVED BY THE FOOD AND
`DRUG ADMINISTRATION. THIS PROGRAM IS CALLED THE
`“SYSTEM FOR THALIDOMIDE EDUCATION AND
`PRESCRIBING SAFETY (S.T.E.P.S.).”
`
`(Id.)
`
`62. Thalomid PI also discloses:
`
`UNDER THIS RESTRICTED DISTRIBUTION PROGRAM, ONLY
`PRESCRIBERS AND PHARMACISTS REGISTERED WITH THE
`PROGRAM ARE ALLOWED TO PRESCRIBE AND DISPENSE
`THE PRODUCT. IN ADDITION, PATIENTS MUST BE ADVISED
`OF, AGREE TO, AND COMPLY WITH THE REQUIREMENTS
`OF THE S.T.E.P.S. PROGRAM IN ORDER TO RECEIVE
`PRODUCT.
`(Ex. 1006 at 1.)
`
`63. Thalomid PI further teaches that “[a] prescription for thalidomide for a
`
`woman of childbearing potential must not be issued by the prescriber until a written
`
`report of a negative pregnancy test has been obtained by the prescriber.” (Id at 2.)
`
`64.
`
`Further, Thalomid PI discloses that, for these women to receive the drug,
`
`“[t]wo reliable forms of contraception must be used simultaneously. …Women of
`
`
`
`22
`
`CFAD VI 1021-0022
`
`
`
`childbearing potential should be referred to a qualified provider of contraceptive
`
`methods, if needed.” (Id.)
`
`65. Thalomid PI further discloses that “[t]halidomide is contraindicated in
`
`sexually mature MALES.…” (Id. at 4.)
`
`2. Keravich (Ex. 1018)
`66. Keravich discloses that “[t]he various physician, patient, and pharmacy
`
`requirements for participation in the System for Thalidomide Education and
`
`Prescribing Safety (S.T.E.P.S.) program and procedures that institutions may
`
`implement in order to comply with these requirements are described.” (Ex. 1018 at
`
`Abstract.)
`
`67. Keravich also discloses that the “goal of the S.T.E.P.S. program is to
`
`ensure that there is no fetal exposure to thalidomide.” (Id. at 1721.)
`
`68. Keravich further discloses the dispensing process for thalidomide. (Id. at
`
`1722–23.)
`
`3. Cunningham (Ex. 1009)
`69. Cunningham discloses a “new and improved method of dispensing,
`
`tracking and managing pharmaceutical product samples by communicatively linking
`
`prescribers and pharmacies to a central computing station.” (Ex. 1009 at Abstract.)
`
`Specifically, before filling any prescription for a pharmaceutical trial product, the
`
`pharmacy must upload defined information into the central computing station.
`
`
`
`23
`
`CFAD VI 1021-0023
`
`
`
`(Ex. 1009 at 11:6–13.) Only if the central computing station establishes that the
`
`uploaded information is valid, can the central computing station issue a pharmacy
`
`approval code, and the pharmacy can dispense the pharmaceutical product. (Ex. 1009
`
`at 11:13–23.)
`
`VIII. Legal Standards
`A. Anticipation
`I understand that an anticipation analysis involves comparing a claim to
`
`70.
`
`the prior art to determine whether a POSA would anticipate the claimed invention in
`
`view of the prior art, and in light of the general knowledge in the art. I also
`
`understand that to anticipate a claim, a prior art reference must disclose each and
`
`every claim limitation, either expressly or inherently. I also understand that to explain
`
`the meaning of a prior art reference, a POSA can refer to a secondary reference.
`
`B. Obviousness
`I understand that an obviousness analysis involves comparing a claim to
`
`71.
`
`the prior art to determine whether the claimed invention would have been obvious to
`
`a POSA in view of the prior art, and in light of the general knowledge in the art. I also
`
`understand that when a POSA would have reached the claimed invention through
`
`routine experimentation, the invention may be deemed obvious.
`
`72.
`
`I also understand that obviousness can be established by combining or
`
`modifying the teachings of the prior art to achieve the claimed invention. It is further
`
`
`
`24
`
`CFAD VI 1021-0024
`
`
`
`my understanding that where there is a reason to modify or combine the prior art to
`
`achieve the claimed invention, there must also be a reasonable expectation of success
`
`in so doing to render the claimed invention obvious. I understand that the reason to
`
`combine prior art references can come from a variety of sources, not just the prior art
`
`itself or the specific problem the patentee was trying to solve. I also understand that
`
`the references themselves need not provide a specific hint or suggestion of the
`
`alteration needed to arrive at the claimed invention; the analysis may include recourse
`
`to logic, judgment, and common sense available
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