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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`AMNEAL PHARMACUETICIALS
`Petitioner
`
`v.
`
`SUPERNUS PHARMACEUTICALS, INC.
`Patent Owner
`
`U.S. Patent No. 8,206,740
`_____________________
`
`Inter Partes Review Case No. Unassigned
`_____________________
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`Declaration of Glenn A. Van Buskirk, Ph.D.
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`TABLE OF CONTENTS
`
`
`Overview ......................................................................................................... 3
`I.
`II. My Background and Qualifications ................................................................ 7
`III. List of Documents I Considered in Formulating My Opinion ..................... 10
`IV. Person of Ordinary Skill in the Art ............................................................... 12
`V.
`The '740 Patent Specification ....................................................................... 13
`VI. The Claims of the '740 patent ....................................................................... 15
`VII. State of the Art as of April 7, 2003............................................................... 18
`VIII. Summary Chart of My Opinion in View of the Art ..................................... 30
`IX. Basis of My Opinion with Respect to Obviousness ..................................... 30
`X. Ground 1: the '932 publication (claims 1, 2, 5-15, and 19-22) .................... 32
`XI. Ground 2: the '932 publication and the '748 patent (claims 1, 2, 5-15, and 19-
`22) ................................................................................................................. 86
`XII. Ground 3: the '106 publication and the '748 patent (claims 1, 2, 5-15, and 22)
` .................................................................................................................... 181
`XIII. Ground 4: the '106 publication, the '748 patent, and Webster (claims 19-21)
` .................................................................................................................... 255
`XIV. Secondary Considerations of Nonobviousness .......................................... 278
`XV. Conclusion .................................................................................................. 286
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`I.
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`I, Glenn Van Buskirk, hereby declare as follows.
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`Overview
`I am over the age of eighteen (18) and otherwise competent to make
`1.
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`this declaration.
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`2.
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`I have been retained as an expert witness on behalf of AMNEAL
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`PHARMACEUTICALS, L.L.C and AMNEAL PHARMACEUTICALS COMPANY PVT. LTD.
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`(together "AMNEAL") for the above-captioned inter partes review (IPR). I am
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`being compensated for my time in connection with this IPR at my standard
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`consulting rate, which is $400 per hour. I understand that the petition for inter
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`partes review involves U.S. Patent No. 8,206,740 ("the '740 patent"), Exhibit
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`1001, which resulted from U.S. Application No. 12/155,676 ("the
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`'676
`
`application"), filed on June 6, 2008, naming Rong-Kun Chang, Arash Raoufinia,
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`and Niraj Shah as inventors. The '740 patent issued on June 26, 2012, from the
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`'676 application. I further understand that, according to the USPTO records, the
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`'740 patent is currently assigned to Supernus Pharmaceuticals, Inc. ("the
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`patentee").
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`3.
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`In preparing this Declaration, I have reviewed the '740 patent and
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`considered each of the documents cited herein, in light of general knowledge in the
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`art. In formulating my opinions, I have relied upon my experience in the relevant
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`art. In formulating my opinions, I have also considered the viewpoint of a person
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`of ordinary skill in the art (i.e., a person of ordinary skill in the field of drug
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`delivery and formulation, defined further below in Section IV) as of April 7, 2003.
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`4.
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`The independent claims (claims 1 and 19) of the '740 patent are
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`directed to a pharmaceutical composition of doxycycline that, when given at a
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`once-daily dosage, will give a steady-state blood level of doxycycline of a
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`minimum of 0.1 µg/ml and a maximum of 1.0 µg/ml. Claim 1 is directed to the
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`pharmaceutical composition itself; claim 19 is directed to a method of treating
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`rosacea with the pharmaceutical composition. The pharmaceutical composition
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`claimed in the '740 patent comprises an immediate release (IR) portion comprising
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`30 mg doxycycline and a delayed release (DR) portion comprising 10 mg
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`doxycycline. The pharmaceutical composition of the '740 patent also comprises
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`one or more pharmaceutically acceptable excipients. Additional dependent claims
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`recite various excipients and a process for preparing the pharmaceutical
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`composition.
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`5.
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`Prior art references disclose oral pharmaceutical compositions of
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`doxycycline with the same features as claimed in the '740 patent. For example, the
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`prior art reference “the '932 publication” (Exhibit 1002; Exhibit 1003) discloses
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`oral pharmaceutical compositions of doxycycline that, when given in a daily
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`dosage, give steady-state blood levels of a minimum of 0.1 µg/ml and a maximum
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`of 1.0 µg/ml. The '932 publication further discloses compositions of doxycycline
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`in a 40 mg dose that comprise IR and DR portions with a range of IR:DR ratios,
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`including 30 mg doxycycline in the IR portion and 10 mg doxycycline in the DR
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`portion (i.e., a 75:25 IR:DR ratio of doxycycline). The compositions of the '932
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`publication also include one or more pharmaceutically acceptable excipients. The
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`'932 publication discloses that the pharmaceutical compositions are useful for the
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`treatment of rosacea.
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`6.
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`Prior art reference "the '106 publication" (Exhibit 1004) discloses
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`controlled release formulations of doxycycline that, when given in a daily dosage,
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`give steady-state blood levels of a minimum of 0.1 µg/ml and a maximum of 1.0
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`µg/ml. The '106 publication further discloses compositions of doxycycline that
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`comprise IR and DR portions with a range of IR:DR ratios, including 75:25. The
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`compositions of the '106 publication also include one or more pharmaceutically
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`acceptable excipients.
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`7.
`
`Prior art reference "the '748 patent” (Exhibit 1005) discloses oral
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`pharmaceutical compositions of the tetracycline known as minocycline in a once-
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`daily formulation that contains IR and DR portions and has an improvedimproved
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`controlled release profile. The '748 patent discloses that the controlled release
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`formulation is improved by increasing the ratio of IR to DR portions in the
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`formulation, with a range of ratios that includes 75:25.
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`8.
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`Prior art reference "Webster" (Exhibit 1018) discloses the use of low
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`dose doxycycline (as low as 50 mg) for the treatment of rosacea. Webster
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`discloses that the efficacy of tetracyclines in rosacea treatment is likely due to the
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`anti-inflammatory properties of the drugs, rather than the antibacterial activity.
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`9.
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`The subject matter of multiple claims of the '740 patent is disclosed by
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`the '932 publication, the '106 publication, the '748 patent, and Webster, alone or in
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`various combinations.
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`10. Even if one were to find that no single cited reference discloses all of
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`the elements of a claim, a person of ordinary skill in the art would have had a
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`reason to arrive at the claimed invention with a reasonable expectation of success
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`in view of a combination of references.
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`a) A person of ordinary skill in the art would have had a reason to, and
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`would have had a reasonable expectation of success to, arrive at an
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`embodiment within the scope of claims 1, 2, 5-15, and 19-22 of the
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`'740 patent by reading the disclosure of the '932 publication.
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`b) A person of ordinary skill in the art would have had a reason to, and
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`would have had a reasonable expectation of success to, arrive at an
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`embodiment within the scope of claims 1, 2, 5-15, and 19-22 of the
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`'740 patent by combining the disclosure of the '932 publication with
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`the disclosure of the '748 patent.
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`c) A person of ordinary skill in the art would have had a reason to, and
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`would have had a reasonable expectation of success to, arrive at an
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`embodiment within the scope of claims 1, 2, 5-15, and 22 of the '740
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`patent by combining the disclosure of the '106 publication with the
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`disclosure of the '748 patent.
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`d) A person of ordinary skill in the art would have had a reason to, and
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`would have had a reasonable expectation of success to, arrive at an
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`embodiment within the scope of claims 19-21 of the '740 patent by
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`combining the disclosure of the '106 publication with the disclosures
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`of the '748 patent and Webster.
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`II. My Background and Qualifications
`I am an expert in the field of drug development and formulation, and I
`11.
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`have been an expert in this field since prior to 2003. I am presently the managing
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`member of Nonclinical Drug Development Consulting Services (NDDCS), LLC. I
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`obtained a Bachelor of Science degree in Pharmacy, a Master of Science degree in
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`Pharmaceutical Science, and a Ph.D. in Pharmaceutical Science from Rutgers
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`University in 1969, 1973, and 1979, respectively.
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`12.
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`I held the position of Scientist in the Dosage Form Design Group of
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`Ciba-Geigy Corporation from 1970-1976. I subsequently held the positions of
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`Scientist, Senior Scientist, and Group Leader in the Process Development Group at
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`the R.W. Johnson Pharmaceutical Research Institute (RWJPRI), a division of
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`Ortho-McNeil Pharmaceutical Corporation (1976-1980). I later served as Group
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`Leader, Section Head, Assistant Director, and Director of the Formulations Group
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`at RWJPRI (1980-1986). I also served as Director of Technical Development at
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`RWJPRI (1986-1989) and as Senior Director of Pharmaceutical Development –
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`Worldwide (1989-1995).
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`13.
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`I held the position of Vice President of Pharmaceuticals and
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`Analytical Development at Novartis Pharmaceuticals Corporation (1995-1997). I
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`subsequently served as Vice President of External Technology Development and
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`Liaisons at Novartis Pharmaceuticals (1997-1998).
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`14. After my time at Novartis, I held the position of Vice President of
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`Nonclinical Drug Development at Purdue Pharma LP (1998-2004). This role later
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`expanded to Vice President of Nonclinical Drug Development and Technology at
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`Purdue Pharma (2004-2005).
`
`15.
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`In 2005,
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`I established
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`the
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`independent consulting company
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`Nonclinical Drug Development Consulting Services, LLC. I currently serve as
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`Managing Member to provide expertise in product development, scale-up and
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`launch, and Scale-up and Post-Approval Changes (SUPAC) guidance to the
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`pharmaceutical industry.
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`16. My curriculum vitae is provided as Exhibit 1021.
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`17.
`
`I have contributed to over 30 New Product Registrations in the
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`capacity of project leader (one who oversees a drug development team) or
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`development team member (direct, hands-on contributions to drug development).
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`These products include capsules, tablets, suspensions, transdermal systems, topical
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`solutions, nasal sprays, suppositories, and creams. I was significantly responsible
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`as a team member in the New Product Registrations of: TEGRETOL® Chewable
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`(anti-seizure medication); IMODIUM® Capsules (anti-diarrhea medication);
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`SUPROFEN® Capsules
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`(non-steroidal
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`anti-inflammatory medication);
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`Thymopentin Injection (immune stimulant); ORTHO NOVUM 1/35® (oral
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`contraceptive); TERAZOL® Vaginal Cream
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`(antifungal medication);
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`LUTREPULSE® Injection (ovulation stimulant); EPREX®/PROCRIT® Injection
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`(anemia medication); LEUSTATIN® Injection (anti-cancer medication); and
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`PalladoneTM Capsules (analgesic).
`
`18.
`
`I have received several honors in my career, including four Johnson &
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`Johnson achievement awards in recognition of extraordinary accomplishments in
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`(i) design of the Ortho Pharmaceutical Pilot Plant to improve personnel safety
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`(e.g., building design, air filtration, safety showers for decontamination); (ii)
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`leadership of the LUTREPULSE® Project Team; (iii) leadership of the EPREX®
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`C,M&C Team; and (iv) developed an improved formulation of an oral
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`contraceptive product line that no longer required hazardous materials for
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`production (this improvement increased personnel safety). In 2005, I was elected
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`as an American Association of Pharmaceutical Scientists (AAPS) Fellow. I was
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`also elected as an American Association of Indian Pharmaceutical Scientists
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`(AAiPS) Fellow in 2005. In 1998, I was awarded the Special Presidential Citation
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`by AAPS for my work on development of the Scale-up and Post-Approval
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`Changes (SUPAC) Guidance Documents.
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`19. During my nearly 35 years of experience in international product
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`development and management, I have authored or co-authored many scientific
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`articles or published abstracts and given numerous technical presentations in the
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`areas of drug formulation, manufacturing and scale up, FDA approval, SUPAC
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`principles and guidance, and pharmaceutical consulting. I am also an inventor on
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`U.S. Patent No. 4,299,501, U.S. Patent Application No. 10/057,301 (US
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`2003/0152637 A1) and two EP patent applications. Each publication and
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`presentation is listed in my curriculum vitae, Exhibit 1021.
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`20.
`
`In view of my experiences and expertise outlined above, I am an
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`expert in the field of drug development and formulation.
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`III. List of Documents I Considered in Formulating My Opinion
`In formulating my opinion, I considered the following documents:
`21.
`
`Amneal
`Exhibit No.
`("AMN")
`1001
`
`Document
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`Chang et al., U.S. Patent No. 8,206,740, “Once daily
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`1002
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`1003
`
`1004
`
`1005
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`1006
`1007
`
`1008
`1009
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`1010
`1011
`
`1012
`
`1013
`
`1014
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`1015
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`formulations of tetracyclines” (filed June 6, 2008;
`issued June 26, 2012) ("the '740 patent")
`Ashley, WO 2002/080932, “Method of treating acne”
`(filed April 5, 2002; issued October 17, 2002) ("the '932
`publication")
`Ashley, U.S. Prov. Appl. No. 60/281,854 (filed April 5,
`2001) ("the '854 application")
`Ashley, WO 2002/083106, “Controlled delivery of
`tetracycline compounds and tetracycline derivatives”
`(filed April 5, 2002; issued October 24, 2002) ("the
`'106 publication")
`Sheth et al., U.S. Patent No. 5,348,748, “Pulsatile once-
`a-day delivery system for minocycline” (filed June
`23,1993; issued September 20, 1994) ("the '748 patent")
`File history of the '740 patent
`Chang et al., U.S. Patent No. 8,394,405, “Once daily
`formulations of tetracyclines” (filed December 17,
`2010; issued March 12, 2013) ("the '405 patent")
`File history of the '405 patent
`Chang et al., U.S. Patent No. 8,394,406, “Once daily
`formulations of tetracyclines” (filed December 17,
`2010; issued March 12, 2013) ("the '406 patent")
`File history of the '406 patent
`Physician’s Desk Reference pp. 1208-1210, 2442-2444,
`2735-2736 and 3357-3358, 56th ed. (2002)
`Skidmore et al., "Effects of Subantimicrobial-Dose
`Doxycycline in the Treatment of Moderate Acne," Arch.
`Dermatol. 139:439-464 (2003)
`Opinion, August 26, 2011, Mylan Pharm., Inc. v.
`Galderma Labs., Inc., No. 10-892-LPS (D. Del. 2011)
`Transcript of Bench Trial, July 5, 2011, Mylan Pharm.,
`Inc. v. Galderma Labs., Inc., No. 10-892-LPS (D. Del.
`2011, Vol. A, pp. 66-259 )
`Cole et al., "Enteric coated HPMC capsules designed to
`achieve intestinal targeting," Int. J. Pharmaceutics
`231:83–95 (2002)
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`1016
`
`1017
`
`1018
`
`1019
`
`1020
`
`Chang et al., US Patent No. 7,749,532, “Once daily
`formulations of tetracycline” (filed April 7, 2004; issued
`July 6, 2010) ("the '532 patent")
`Chambers, "Antimicrobial Agents: Protein Synthesis
`Inhibitors and Miscellaneous Antibacterial Agents," in
`Goodman & Gilman's The Pharmacological Basis of
`Therapeutics, Chapter 47, pp. 1239-1271 (2001)
`Webster, "Treatment of Rosacea," Seminars in
`Cutaneous Medicine & Surgery 20(3): 207-208 (2001)
`Joshi et al., US Patent No. 5,030,447, "Pharmaceutical
`compositions having good stability" (filed March 31,
`1988; issued July 9, 1991)
`Amendment in Response to September 9, 2010 Final
`Office Action and Substance of Interview in U.S. Appl.
`No. 10/474,240 (filed October 3, 2003)
`
`
`IV. Person of Ordinary Skill in the Art
`I understand that a person of ordinary skill in the art is one who is
`22.
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`presumed to be aware of all pertinent art, thinks along conventional wisdom in the
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`art, and is a person of ordinary creativity. A person of ordinary skill in the art
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`("POSA") would have had education and experience in drug delivery and
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`formulation as of 2003. The education and experience levels may vary between
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`persons of ordinary skill, with some persons holding a Bachelor's degree with
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`many years of experience and others holding higher degrees but having less work
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`experience. A POSA would have knowledge and skill relating to the use, function,
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`and formulation of pharmaceutical excipients; knowledge and training regarding
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`the equipment, processes and techniques used to analyze and test formulation
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`materials; and an understanding of pharmacokinetic principles and how they relate
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`to drug development. Such a person would have specific experience with modified
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`release drug systems.
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`23. A person of ordinary skill typically would work as part of a multi-
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`disciplinary team and draw upon not only his or her own skills, but also take
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`advantage of certain specialized skills of others in the team, to solve a given
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`problem. For example, a clinician may be part of the team.
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`V.
`
`The '740 Patent Specification
`I understand that this declaration is being submitted together with a
`24.
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`petition for inter partes review of claims 1, 2, 5-15, and 19-22 of the '740 patent.
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`25.
`
`I have considered the disclosure of the '740 patent in light of general
`
`knowledge in the art as of the earliest possible priority date of the '740 patent,
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`which I understand to be April 7, 2003.
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`26. The '740 patent specification is directed to oral pharmaceutical
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`compositions containing tetracyclines such as doxycycline for the treatment of
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`collagenase destructive enzyme-dependent diseases, such as periodontal disease
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`and acne, and acute and chronic inflammatory disease states, such as rosacea and
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`arthritis. [Exhibit 1001, col. 1, ll. 1-53.] The '740 patent specification is further
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`directed to a method of treating rosacea with oral pharmaceutical compositions
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`containing doxycycline and a process for preparing
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`the pharmaceutical
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`compositions. [Exhibit 1001, col. 2, ll. 64-67; col. 3, ll. 1-3.]
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`27. The doxycycline formulations disclosed in the '740 patent purportedly
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`solve certain problems associated with doxycycline administration, such as patient
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`compliance and unwanted side-effects of long-term administration. The '740
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`patent describes doxycycline formulations intended as once-daily doses, rather
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`than two or more doses per day. [Exhibit 1001, col. 3, ll. 49-51.] And, the '740
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`patent recites that the doxycycline formulations and dosages are able to retain the
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`beneficial effects of the drug (e.g., inhibitory activity against collagen destructive
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`enzymes) while avoiding unwanted antimicrobial drug activity that harms normal
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`microbial flora. [Exhibit 1001, col. 5, ll. 36-40.]
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`28. The '740 patent recites that when administered once-daily, the claimed
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`oral pharmaceutical compositions of doxycycline achieve steady-state blood levels
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`of doxycycline of a minimum of 0.1 µg/ml and a maximum of 1.0 µg/ml, more
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`preferably between about 0.3 and about 0.8 µg/ml. [Exhibit 1001, col. 3, ll. 52-
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`58.] The '740 patent recites that these steady-state blood levels of doxycycline are
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`desirable because
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`they allow for
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`the desired anti-collagenase and anti-
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`inflammatory activity of doxycycline, without being accompanied by undesirable
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`antibiotic activity. [Exhibit 1001, col. 3, ll. 59-61.]
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`29. The '740 patent recites that mixing immediate-release (IR) and
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`delayed-release (DR) doxycycline formulations in a single unit dosage provides the
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`desired steady-state blood levels of the drug when given at once-daily dosage, and
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`that the preferred ratio of IR to DR is 75:25. [Exhibit 1001, col. 8, ll. 9-14.] The
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`'740 patent also recites that one aspect of the drug formulation is an immediate
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`release formulation containing less than 50 mg but more than 25, preferably about
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`40 mg, doxycycline base. [Exhibit 1001, col. 2, ll. 43-45.]
`
`VI. The Claims of the '740 patent
`Independent claims 1 and 19 of the '740 patent are directed to:
`30.
`
`1. An oral pharmaceutical composition of
`doxycycline, which at a once-daily dosage will
`give steady state blood levels of doxycycline of
`a minimum of 0.1 µg/ml and a maximum of 1.0
`µg/ml, the composition consisting of (i) an
`immediate release (IR) portion comprising 30
`mg doxycycline; (ii) a delayed release (DR)
`portion comprising 10 mg doxycycline; and
`optionally, (iii) one or more pharmaceutically
`acceptable excipients.
`
`19. A method for treating rosacea in a mammal
`in need thereof, comprising administering an
`oral pharmaceutical composition of doxycycline
`comprising, which at a once-daily dosage will
`give steady state blood levels of doxycycline of
`a minimum of 0.1 µg/ml and a maximum of 1.0
`µg/ml, the composition consisting of (i) an
`immediate release (IR) portion comprising 30
`mg doxycycline; (ii) a delayed release (DR)
`portion comprising 10 mg doxycycline; and
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`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
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`optionally, (iii) one or more pharmaceutically
`acceptable excipients.
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`31. The claims recited above contain the following common elements:
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`• steady-state blood levels of doxycycline of a minimum of 0.1
`
`μg/ml and a maximum of 1.0 μg/ml;
`
`• an IR portion comprising 30 mg doxycycline;
`
`• a DR portion comprising 10 mg doxycycline, and
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`• one or more pharmaceutically acceptable excipients.
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`32. Doxycycline belongs to the tetracycline family of broad-spectrum
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`antibiotics. [Exhibit 1017, p. 1240.] Tetracycline family members have similar
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`structure, function, and utility [Exhibit 1017, pp. 1240-1243.] Tetracycline family
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`members are so closely related in terms of structure, function, and utility that they
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`are generally referred to as "tetracyclines." [Exhibit 1017, pp. 1240-1243.]
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`However, the tetracycline family members are not necessarily identical in
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`pharmacokinetic profiles. For example, the absorption efficiency of tetracycline
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`family members ranges from as low as 30% for chlortetracycline to 95% for
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`doxycycline or 100% for minocycline. [Exhibit 1017, p. 1242.]
`
`33. Doxycycline is a well-known active pharmaceutical ingredient that
`
`has been commercially available for decades. Doxycycline was first approved as
`
`an antibiotic by the FDA in 1967 and marketed by Pfizer Inc. under the brand
`
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`- 16 -
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`
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`name Vibramycin®. Vibramycin® was an immediate release (IR) capsule
`
`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
`
`formulation comprising doxycycline hyclate1 (equivalent to 50 mg doxycycline).
`
`Other dosage forms of doxycycline that were commercially available prior to April
`
`7, 2003, include Monodox® (IR capsule formulation of doxycycline monohydrate
`
`in amounts equivalent to 100 and 50 mg doxycycline), Periostat®2 (IR tablet
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`formulation of doxycycline hyclate
`
`in an amount equivalent to 20 mg
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`doxycycline), Vibra-Tabs® (IR tablet formulation of doxycycline hydrochloride
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`hemi-ethanolate hemihydrate equivalent to 100 mg doxycycline), and Doryx® (DR
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`pellet formulation of doxycycline hyclate equivalent to 100 mg of DR coated
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`pellets in capsules). [Exhibit 1011, pp. 1208-1210, 1208-1210, 2442-2444, 2735-
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`2746, 3357-3358.]
`
`34. As of April 7, 2003, a person of ordinary skill in the art reading the
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`publicly accessible references of the time would have recognized that a once-daily
`
`40 mg dose of doxycycline comprising an IR portion with 30 mg doxycycline and
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`a DR portion with 10 mg doxycycline provides steady-state blood levels of
`
`
`1 Doxycycline is clinically available in the form of several different salts, such as
`doxycycline hydrochloride (hyclate), doxycycline monohydrate, and doxycycline calcium.
`[Exhibit 1011, pp. 1208-1210, 1208-1210, 2442-2444, 2735-2746, 3357-3358.]
`2 I understand that Periostat® was approved by the FDA in 1998. I also understand that
`when administered orally as a twice–daily dosage (two 20 mg doses, 40 mg total doxycycline),
`Periostat® consistently achieved steady-state blood levels of doxycycline below those required
`for an antimicrobial effect. Specifically, the data in Exhibit 1012 indicate that Periostat®
`achieves an average steady-state blood level of 0.48 µg/ml. [Exhibit 1012, p. 460, column 1 and
`Figure 1.]
`
`
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`- 17 -
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`
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`
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`doxycycline of a minimum of 0.1 µg/ml and a maximum of 1.0 µg/ml because the
`
`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
`
`references, alone or in various combinations, disclose such compositions of
`
`doxycycline with these characteristics. A person of ordinary skill in the art reading
`
`the publicly accessible references of the time would have also recognized that the
`
`ratio of doxycycline in the IR and DR portions is not critical for achieving steady-
`
`state blood levels of doxycycline of a minimum of 0.1 µg/ml and a maximum of
`
`1.0 µg/ml, as long as the total amount of doxycycline in the dose was below the
`
`threshold required for antimicrobial activity.
`
`VII. State of the Art as of April 7, 2003
`35. As of April 7, 2003, oral pharmaceutical compositions of doxycycline
`
`that achieve steady-state blood levels between 0.1 µg/ml and 1.0 µg/ml were
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`known in the art. The medical benefits of achieving these steady-state blood levels
`
`of doxycycline, such as anti-inflammatory or anti-collagenase activities, were also
`
`known in the art. Furthermore, formulating pharmaceutical compositions of
`
`doxycycline to include IR and DR portions with 30 mg and 10 mg doxycycline
`
`(respectively) was known in the art.
`
`36. The '932 publication (Exhibit 1002). PCT Patent Application No.
`
`PCT/US02/10747, "Methods of Treating Acne," was published as WO
`
`2002/080932 ("the '932 publication) on October 17, 2002. Thus, the '932
`
`publication was published and publicly accessible prior to April 7, 2003. The '932
`
`
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`- 18 -
`
`
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`
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`publication was filed by CollaGenex Pharmaceuticals, Inc. and names Robert A.
`
`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
`
`Ashley as the sole inventor.
`
`37. The '932 publication is directed to methods of treating acne using oral
`
`pharmaceutical compositions of doxycycline. The '932 publication discloses that
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`"acne," for the purposes of the specification, includes acne rosacea. [Exhibit 1002,
`
`p. 6, l. 34 – p. 7, l. 4.]
`
`38. The doxycycline formulations disclosed in the '932 publication
`
`include once-daily formulations that can achieve serum concentrations of
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`doxycycline between about 0.1 and 0.8 µg/ml. [Exhibit 1002, p. 9, ll. 17-18; p.
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`10, ll. 25-29. The '932 publication also discloses a 40 mg dose of doxycycline and
`
`formulations that can include one or more pharmaceutically acceptable excipients
`
`[Exhibit 1002, p. 16, ll. 1-2; p. 14, ll. 25-29.]
`
`39. The '932 publication disclosed suspensions, tablets, pills, capsules,
`
`and other embodiments for the compositions of doxycycline. [Exhibit 1002, p. 14,
`
`ll. 14-14.] The '932 publication also discloses doxycycline formulations in
`
`immediate release or sustained release formulations. [Exhibit 1002, p. 15, ll. 19-
`
`30.]
`
`40.
`
`It is my understanding that the '854 application is incorporated in
`
`the '932 publication by reference in its entirety. U.S. Provisional Patent
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`Application No. 60/281,854, "Controlled Delivery of Tetracycline and Tetracycline
`
`
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`- 19 -
`
`
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`
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`Derivatives," (the '854 application; Exhibit 1003) was filed on April 5, 2001. The
`
`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
`
`'854 application lists Robert A. Ashley as the sole inventor. There are two
`
`subsequent patent applications that claim priority to the '854 application's filing
`
`date of April 5, 2001: PCT Patent Application No. PCT/US02/10748 (described in
`
`more detail below) and U.S. Patent Application No. 10/474,240 ("the '240
`
`application").
`
`41.
`
`It is my understanding that the '932 publication incorporates the '854
`
`application by reference in its entirety, which I understand to mean that the '932
`
`publication is generally treated as though the full text of the ‘854 application were
`
`included within the '932 publication. [Exhibit 1002, p. 15, ll. 23-30.]3
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`42. Disclosures in the '932 publication via the '854 application. The
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`'932 publication is directed to tetracycline formulations. The '932 publication
`
`discloses that doxycycline is a preferred tetracycline. [Exhibit 1003, p. 5, line 21.]
`
`The '932 publication discloses that doxycycline formulations may be useful for
`
`treating skin diseases or inflammatory disorders. [Exhibit 1003, p. 4., ll. 10-17.]
`
`43. The pharmaceutical compositions of doxycycline
`
`in
`
`the
`
`'932
`
`publication include at least one controlled-release agent. The '932 publication
`
`
`3 "Further description of methods of delivering tetracycline compounds by sustained
`release can be found in the patent application, "Controlled Delivery of Tetracycline and
`Tetracycline Derivatives," filed on April 5, 2001 and assigned to CollaGenex Pharmaceuticals,
`Inc. of Newtown, Pennsylvania. The aforementioned application is incorporated herein by
`reference in its entirety." [Exhibit 1002, p. 15, ll. 26-30.]
`
`
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`- 20 -
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`
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`discloses that the purpose of these controlled release formulations is to deliver a
`
`Inter Partes Review of USPN 8,206,740
`Declaration of Glenn A. Van Buskirk, Ph.D. (Exhibit 1022)
`
`dose of doxycycline below the level required for antimicrobial activity, such that
`
`the host is treated with the drug substantially without any antimicrobial activity.
`
`[Exhibit 1003, p.5, ll. 8-13.] The controlled-release agents disclosed in the '932
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`publication can include an instantaneous release agent, a sustained-release agent, a
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`delayed-release agent, and combinations thereof. [Exhibit 1003, p. 5, ll. 24-26.]
`
`The '932 publication further discloses that the preferred formulation has properties
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`resulting in at least 50%, more preferably greater than 80% of the tetracycline in
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`the composition being released in the upper GI tract. [Exhibit 1003, p. 16, ll. 12-
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`14.] In other words, the proporti
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