Patent No. 8,603,506
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`DR. REDDY'S LABORATORIES, LTD. and
`DR. REDDY'S LABORATORIES, INC.
`Requestors
`
`v.
`
`GALDERMA LABORATORIES, INC.
`Patent Owner
`
`Patent No. 8,603,506
`Issue Date: December 10,2013
`Title: METHOD OF TREATING ACNE
`
`Inter Partes Review No. Unassigned
`
`(Exhibit 1 004)
`DECLARATION OF MICHAEL PAYETTE, M.D., M.B.A.
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1004
`
`Exh. 1004
`
`
`Petition for Inter Partes Review
`Attorney Docket No. REDDY 7.1R-015
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`DR. REDDY'S LABORATORIES, LTD. and
`DR. REDDY'S LABORATORIES, INC.
`Requestors
`
`v.
`
`GALDERMA LABORATORIES, INC.
`Patent Owner
`
`Patent No. 8,603,506
`Issue Date: December 10,2013
`Title: METHOD OF TREATING ACNE
`
`Inter Partes Review No. Unassigned
`
`(Exhibit 1 004)
`DECLARATION OF MICHAEL PAYETTE, M.D., M.B.A.
`
`Dr. Reddy's Laboratories, Ltd., et al.
`v.
`Galderma Laboratories, Inc.
`IPR2015-__
`Exhibit 1004
`
`Exh. 1004
`
`
`
`
`
`I, MICHAEL PAYETTE, hereby declare as follows:
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`1.
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`2.
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`I am a U.S. citizen and a resident of the state of Connecticut.
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`I am a board-certified dermatologist and an assistant professor for the
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`Department of Dermatology at the University of Connecticut School of Medicine. I
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`hold a B.A. from Dartmouth College in Biochemistry in 2002, an MBA from the
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`University of Connecticut focusing on healthcare management in 2008, and my
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`medical degree is also from the University of Connecticut in 2008. My current
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`curriculum vitae is provided. (Exh. 1005.)
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`3.
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`I am primarily a clinical dermatologist and 70% of my time is
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`dedicated to direct patient care in an academic university setting. My clinical areas
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`of interest are complex medical dermatology and skin cancer, but I treat the entire
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`spectrum of dermatologic diseases and all age groups, from newborns to
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`geriatricians. I almost always have dermatology residents, residents in primary care
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`specialties, and/or medical students working with me in clinic. The nonclinical
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`30% of my time is dedicated to resident and medical student education as well as
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`to administrative duties inherent in running an ACGME (Accreditation Council for
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`Graduate Medical Education)-certified dermatology residency program.
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`4.
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`Outside of my clinical and administrative roles, I am an active
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`publisher in the field of dermatology. I have an interest in cost efficacy and
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`medical ethics. I serve as a peer-reviewer for submitted manuscripts for leading
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`
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`Exh. 1004
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`dermatology journals. I am a consultant to several pharmaceutical companies as
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`well (Amgen, Lilly, and Abbvie). Finally, I am a very active educator. I lecture to
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`medical students, medicine residents, dermatology residents, and other physicians
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`on all topics in dermatology, including the topics of acne and rosacea. I am
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`constantly educating medical students, medicine residents, and most importantly
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`dermatology
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`residents
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`in
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`the clinical setting, with emphasis on
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`the
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`pathophysiology, diagnosis, and medical management of dermatologic conditions.
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`5.
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`I have been retained by Lerner, David, Littenberg, Krumholz &
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`Mentlik, LLP (“counsel”) to provide my opinions in the field of dermatology, the
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`treatment of acne and rosacea as well as the treatment of certain symptoms
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`common to acne and rosacea. I have read and understood U.S. Patent
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`No. 8,603,506 (“the ‘506 Patent”) (Exh. 1001), its predecessors (Exhs. 1016, 1020,
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`1026, 1036), and all other references discussed in this declaration. I am being
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`compensated for my time in an amount consistent with my customary consulting
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`fee and my compensation is not contingent on my opinion or the outcome of this
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`proceeding.
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`A Person of Ordinary Skill In The Art
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`6.
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`I understand from counsel that patents such as the ‘506 Patent are
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`neither addressed to experts nor to laymen; rather they are addressed to persons of
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`ordinary skill in the relevant art at the time that the invention was made, which I
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`
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`2
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`Exh. 1004
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`
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`have been told by counsel to assume is April 5, 2001. I also understand from
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`counsel that factors relevant to the level of skill in the art include, without
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`limitation: the educational level of the inventor, the types of problems encountered
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`in the relevant area, prior art solutions to those problems, the rapidity with which
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`innovations are made, the sophistication of the technology, and the educational
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`level of active workers in the field. In my opinion, considering these factors, a
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`person of ordinary skill in the art would be a licensed, board-certified, and
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`practicing dermatologist. And when I give my opinions herein, unless stated
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`otherwise, it is my opinion of what such a person of ordinary skill in the art would
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`know or do at the time.
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`7.
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`I note first that the claims in question, which I understand to be
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`claims 1, 7, 8, 14, 15, and 20 of the ‘506 Patent (Exh. 1001 col.31 l.60 to col.32
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`l.65) are directed to methods of treating an extremely common symptom of
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`rosacea, a condition treated virtually every day by practicing dermatologists at
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`even the most entry level. Treating skin conditions is the province of medical
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`doctors in the U.S. As such, I would not consider those without formal medical
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`training to be persons of ordinary skill. That said, as discussed below, treatment
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`here involves administering a well-known active agent (doxycycline), in a
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`well-established way (orally), for treating conditions and symptoms that were
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`well-known by April 5, 2001 to be treated in that fashion (papules and pustules of
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`
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`3
`
`Exh. 1004
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`
`
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`rosacea). Furthermore, the relevant doses of the active agent were all already FDA
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`approved and commercially available. Accordingly, while the claims in question
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`are clearly directed to dermatologists, I would not consider this technology to be
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`sophisticated, particularly relative to other forms of dermatological medical
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`treatments or research.
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`8.
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`In reaching my conclusion, I have also considered the type of
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`problems addressed by the ‘506 Patent, and prior art solutions to these types of
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`problems. In my opinion they all involve balancing the need for treatment with a
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`pharmaceutically active agent and the need to avoid exposing the patient to
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`possible side effects and/or unintended consequences from the proposed treatment.
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`This is a problem that is faced by every treating physician, every time they
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`prescribe any medication, or decide not to do so. And the solutions, that of
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`deciding to prescribe anything, deciding what to prescribe, how much to prescribe,
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`and for how long, are well established and within the sound discretion of treating
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`dermatologists.
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`9. While some general practitioners (such as pediatricians, internal
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`medicine physicians, and family medicine physicians) do treat acne and rosacea,
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`they typically do so in a limited fashion, using select common therapies (often
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`advertised ones), and with adherence to the standard of care. They generally do not
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`have expertise in the pathophysiology of acne or rosacea, the variety of clinical
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`4
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`Exh. 1004
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`
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`presentations, or the array of treatment options. They are not likely to use off-label
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`therapies or manage challenging or refractory cases. Patients who fail first-line and
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`perhaps second-line therapies are referred to dermatologists for management.
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`Accordingly, while I believe a person of ordinary skill in the art must at least be a
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`medical doctor, I also believe that the ‘506 Patent is directed more specifically to
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`medical doctors formally trained in dermatology and board-certified in this
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`specialty.
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`10. Finally, I have been told by counsel that Robert A. Ashley, who is
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`listed as the inventor of the ‘506 Patent, has a master’s degree from Oxford in
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`biochemistry and no specific degrees in medicine. (Exh. 1052.) This is a lower
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`level of formal education than I would have expected in the field of treating acne
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`and rosacea and/or their specific symptoms, which is certainly a medical condition
`
`requiring a medical education.
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`11. Considering all of this, I think that a person of ordinary skill in the art
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`in April of 2001 would be a licensed, board-certified, and practicing dermatologist,
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`likely with as little as one year of experience in treating patients in a hospital,
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`clinical, and/or private setting. Such a dermatologist would, by virtue of their
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`relatively recent graduation from medical school and residency, likely be better
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`educated in current research and trends at the time and less dominated by
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`observations and practices learned by practicing physicians with more prolonged
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`
`
`5
`
`Exh. 1004
`
`
`
`
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`personal experience. But I would still expect more experienced dermatologists to
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`understand the current research and trends. I consider myself to be a person of at
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`least ordinary skill in this art. Moreover, because of my work experience and my
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`supervision of residents and medical students, and my review of the relevant
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`literature from the relevant time period (prior to April 5, 2001), I believe that I am
`
`well situated to understand what a person of ordinary skill in the art would have
`
`known and understood at the relevant time.
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`Definitions
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`12. The ‘506 Patent defines “rosacea” as merely a form of acne.
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`(Exh. 1001 col.4 ll.31-41 (“[f]or the purpose of this specification, acne includes all
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`known types of acne. Some types of acne include, for example, acne
`
`vulgaris . . . and acne rosacea.”).) Moreover, while the claims use the word
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`“rosacea,” the specification uses the term “acne rosacea,” a term that is generally
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`no longer used in dermatology. (Id. col.4 l.41; Exh. 1034, at 144 (“The disease
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`[rosacea] was originally called acne rosacea, a misleading term that unfortunately
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`persists.”).) Acne, and therefore the individual conditions subsumed by that term,
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`in turn, is defined as “a disorder of the skin characterized by papules, pustules,
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`cysts, nodules, comedones, and other blemishes or skin lesions.” (Exh. 1001 col.4
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`ll.24-26.)
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`
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`6
`
`Exh. 1004
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`
`
`
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`13. While this is clearly what the ‘506 Patent says, I find this to be an
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`inaccurate characterization and I believe a dermatologist of ordinary skill in the art
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`would as well. In my opinion, a dermatologist of ordinary skill in the art would not
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`lump things like acne vulgaris and rosacea together. They are similar in that they
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`are both skin conditions and both include inflammatory papules and pustules, but
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`species like acne vulgaris (common acne) and rosacea have totally different
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`pathophysiologies as well as different clinical presentations, including but not
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`limited to: body sites affected (acne vulgaris generally involves the face, chest,
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`shoulders, and back; rosacea is generally mid-facial), disease incidence (acne
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`vulgaris generally starts in adolescence; rosacea generally starts in adults),
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`associated symptoms (acne vulgaris can be associated with bone and joint
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`inflammation; rosacea is often associated with ocular inflammation), etc. The
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`‘506 Patent does correctly note that rosacea can be characterized by the
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`“permanent dilation of blood vessels (telangiectasias) [sic].” (Id. col.4 ll.41-43.)
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`This is not something that characterizes common acne at all. In contrast, while the
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`‘506 Patent suggests that all of the conditions it lumps together under the acne
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`umbrella are characterized by comedones, a dermatologist of ordinary skill in the
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`art knows that comedones are not a symptom of rosacea. And this is the only
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`symptom for which treatment is actually discussed. In truth, the two conditions are
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`far more different than they are similar.
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`7
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`Exh. 1004
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`14. As an aside, I am aware that another patent to the same inventor with
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`a similar specification actually claims treating telangiectasias of various origins,
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`including rosacea. (Exh. 1026, U.S. Patent No. 7,014,858.) However, I am not
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`aware of any evidence that antibiotics, at any dose level, are actually useful to this
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`end; the patent offers none. And now, 15 years or so after the first application
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`leading to the ‘506 Patent was filed, I know of no work that confirms that this
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`treatment is effective. The current standard of care for treating telangiectasias is
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`surgical ablation, typically via specific lasers (Exh. 1044, at 280). While Exh. 1044
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`is not prior art, it was published before the issuance of the ‘858 patent on
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`March 31, 2006. There is no drug treatment of any kind that I know of that treats
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`telangiectasias. I believe that a dermatologist of ordinary skill in the art would find
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`the suggestion that low dose antibiotics could treat telangiectasias to be non-
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`credible. Furthermore, it demonstrates a lack of understanding of rosacea.
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`15.
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`In fact, the ‘506 Patent barely mentions rosacea, doing so only twice:
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`once when identifying it, along with 29 other conditions, as species of “acne” and
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`once when explaining
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`that rosacea was characterized by erythema and
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`telangiectasia. (Exh. 1001 col.4 ll.41-43.) The ‘506 Patent never expressly
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`explained that treating even these two symptoms of rosacea was its goal, let alone
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`treating the other symptoms allegedly common to all of the various forms of acne
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`described. Indeed, there is almost as little discussion of papules and pustules as
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`
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`8
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`Exh. 1004
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`
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`
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`there is of rosacea. Papules and pustules are merely described as one of several
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`things that allegedly characterize acne in general (id. col.4 l.26) and as one of the
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`inflammatory lesions allegedly treated in treating acne vulgaris (id. col.19 ll.55-56,
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`col.20 l.17, col.20 ll.25-32). Nothing describes treating papules and pustules
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`generally, or treating papules and pustules of rosacea. In fact, the only symptom
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`specifically addressed is comedones (id. col.3 l.57, col.4 ll.44-47, col.7 ll.1-16),
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`which, as noted previously, is not a symptom of rosacea at all. And it provided no
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`data showing that it is possible to treat rosacea or any of its symptoms.
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`16. Nothing in the disclosure of the ‘506 Patent would have told a
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`dermatologist of ordinary skill in the art to use a specific dose of a specific
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`antibiotic for treating rosacea or its papules and pustules. Many different antibiotic
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`and indeed nonantibiotic compounds are described in the ‘506 Patent (id. col.4 l.58
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`to col.5 l.28, col.7 l.37 to col.8 l.25, Exs.1-36, col.20 l.45 to col.31 l.58) and many
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`different, and as discussed below, often contradictory, doses are described in the
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`’506 (see id. col.5 l.35 to col.6 l.43). Never is a dose of any particular drug
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`described as being useful for treating rosacea, let alone its papules and pustules.
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`17. Without the benefit of the claims, there is next to nothing in the
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`specification to suggest that a goal of the inventor was the treatment of papules and
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`pustules of rosacea or how, specifically, that was to be accomplished. Given that
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`rosacea was a clear afterthought, named in an outdated manner, identified virtually
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`
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`9
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`Exh. 1004
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`
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`not at all, not described or exemplified in connection with any specific treatment or
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`symptom, and discussed by symptoms that either do not exist (comedones), or
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`actually cannot be treated by antibiotics (telangiectasias), I believe that the
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`‘506 Patent did not have a clear disclosure capable of teaching a dermatologist of
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`ordinary skill in the art how to treat the papules and pustules of rosacea, much less
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`by the use of low dose doxycycline as claimed.
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`18. Note that in contrast to the ‘506 Patent, when I speak of acne and
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`when the papers generally cited herein discuss acne, I mean, and I understand the
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`authors of these papers to mean, the treatment of common acne or “acne vulgaris.”
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`This will be the case unless I, or the authors, specifically state otherwise or the
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`context makes it clear that the term is not being used generically.
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`19. Neither the term “papule” nor the term “pustule” appears to be
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`specifically defined in the ‘506 Patent. However, the patent does seem to
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`acknowledge that pustules are implicated in the “more inflammatory types of
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`acne.” (Id. col.1 ll.37-41.) “A papule is a small, solid, elevated lesion . . . smaller
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`than 1 cm in diameter, and the major portion of a papule projects above the plane
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`of the surrounding skin. . . . The elevation can be the result of metabolic deposits,
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`localized hyperplasia of cellular components of the epidermis or dermis, or
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`localized cellular infiltrates in the dermis.” (Exh. 1056, at 27.) “A pustule is a
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`circumscribed, raised lesion that contains a purulent exudate. . . . Pus, composed of
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`
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`10
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`Exh. 1004
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`
`
`
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`leukocytes, with or without cellular debris, may contain bacteria or may be
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`sterile . . . .” (Id. at 31.) “The inflammatory lesions [of acne] vary from small
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`papules with an inflammatory areola to pustules to large tender fluctuant nodules
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`and cysts . . . . All these lesions show an inflammatory infiltrate in the
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`dermis, . . . .” (Id. at 669.) “The predominant lesions [in rosacea] are papules and
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`pustules.” (Id. at 680; see also Exh. 1046, at 852, 958; Exh. 1047, at 1023, 1175.)
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`Papules and pustules are extremely common to both acne and rosacea (as well as
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`other skin disorders) and although the two diseases are distinct with distinct
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`underlying pathophysiologies, the resulting papules and pustules in both diseases
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`share common underlying properties in that they are inflammatory in nature.
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`20. Their term “antibiotic” and the phrase “having substantially no
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`antibiotic activity,” like the term “acne,” are not found in the claims. Nonetheless
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`the concept they embody is reflected in the doses recited in the claims and are, in
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`my opinion, in need of discussion and clarification. The ‘506 Patent teaches the
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`administration of an antibiotic drug ____ a drug known to have the potential to kill
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`microbes, but in an amount which is allegedly ineffective for that purpose.
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`Specifically, the methods “comprises administering systemically to the human a
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`tetracycline compound in an amount that is effective to treat acne but has
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`substantially no antibiotic activity
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`(i.e.
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`substantially no antimicrobial
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`activity) . . . .” (Exh. 1001 col.3 ll.46-50.) The ‘506 Patent further explains that the
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`
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`11
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`Exh. 1004
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`
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`amount of the antibiotic is the minimum amount necessary to treat acne, but is
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`“such that it does not significantly prevent the growth of microbes, e.g. bacteria.”
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`(Id. col.5 ll.33-35.)
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`21. Of course whether any particular amount of any particular antibiotic
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`drug provides substantially no antimicrobial activity will vary significantly, at a
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`minimum, with the drug, the microbe, and the patient. In my opinion, systemically
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`administering orally a 40mg dose, indeed even a 20mg dose, of doxycycline, will
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`have antibiotic activity. It surely will alter the flora of the digestive tract by killing
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`bacteria, if even temporarily. And the prolonged administration of such doses, even
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`if sub-therapeutic for its intended purpose, will necessarily retard bacterial growth
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`at least in the digestive tract.
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`22. Even the labels for PERIOSTAT and ORACEA, both 40mg doses of
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`doxycycline administered orally, acknowledge potential side effects linked directly
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`to the destruction of bacteria. ORACEA for example identifies the possibility of
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`Clostridium difficile-associated diarrhea, the overgrowth of non-susceptible
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`microorganisms, and the possibility of bacterial resistance developing. (Exh. 1043,
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`at 1000 Warnings/Precautions.) PERIOSTAT’s label states that therapy may result
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`in overgrowth of non-susceptible microorganism and increased incidence of
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`vaginal Candidiasis. (Exh. 1042, at 945 Precautions.) All of these conditions result
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`from the destruction of native microbes allowing the uncontrolled growth of
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`12
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`Exh. 1004
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`
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`others. Thus 40 mg doses of doxycycline are admittedly sufficient to “significantly
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`prevent the growth of microbes, e.g. bacteria.” (Exh.1001 col.5 ll.33-35.)
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`23.
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`It is difficult enough to reconcile the concepts of antibiotic and
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`allegedly “subantibiotic” amounts of drugs otherwise known to be antibiotics as
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`advocated in the ‘506 Patent. That difficulty is amplified, however, by the
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`‘506 Patent’s internally contradictory description of antibiotic and nonantibiotic
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`dose. In the context of doxycycline, for example, the ‘506 Patent states that
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`“antibiotic doses” include 50, 75, and 100mg/day. (Id. col.5 ll.43-44.) The
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`‘506 Patent also teaches that tetracycline compounds may be administered in a
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`dose which is 10-80% of the antibiotic dose. (See id. col.5 ll.38-40.) But 80% of a
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`100mg/day dose is 80mg. Is this an antibiotic or a subantibiotic dose? To confuse
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`matters further, the specification states that a daily amount of doxycycline from 30
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`to 60mg maintains human plasma concentrations below the threshold for a
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`significant antibiotic effect. (See id. col.5 ll.54-58.) But just two paragraphs earlier,
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`the same specification states that 50mg, which falls in this 30 to 60mg range, is an
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`antibiotic dose. So, according to the ‘506 Patent, is 50mg an antibiotic dose or a
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`dose too low for significant antibiotic effect?
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`24. Consequently, in discussing various aspects of the ‘506 Patent, I
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`intentionally use the term “allegedly subantimicrobial.” This is not a term of the
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`claims, but it is reflected in the doses recited as the rationale for administering a
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`13
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`Exh. 1004
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`dose that is below 50mg of doxycycline. I use this term here in view of the
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`difficulty in understanding the concept of an antimicrobial or nonantimicrobial
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`dose created by the ‘506 Patent.
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`Off-Label Use
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`25. A doctor may prescribe an FDA-approved medication for any use,
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`including so-called “off-label uses.” These are uses other than those found in the
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`FDA-approved prescribing information. Gabapentin, for example, is FDA
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`approved for the treatment of epilepsy and shingles. However, it has several
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`off-label uses for pain and other conditions. (Exh. 1055, at 559.) Aspirin is another
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`well-known example. Aspirin has long been known for the treatment of headaches,
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`inflammation, and fever. However, aspirin products are now often used once a day
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`as antiplatelet aggregation drugs in cardiac patients. Moreover, while aspirin is
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`often given at 500mg or more up to six times a day for fever, for example, it is
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`generally prescribed at a much lower level of 81mg once per day for antiplatelet
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`aggregation.
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`26. Similarly, the tetracycline medications are themselves an example of
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`off-label use. The tetracyclines in general, and doxycycline specifically, are well
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`known by dermatologists to have a plethora of off-label uses, including but not
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`limited to the following conditions: pyoderma gangrenosum (Exh. 1057, at 23-24),
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`Sweet’s syndrome (Exh. 1058, at 584-85), sarcoidosis, foreign body granulomas
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`
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`14
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`Exh. 1004
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`
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`(Exh. 1059, at 985), and numerous autoimmune bullous disorders, such as bullous
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`pemphigoid (Exh. 1060, at 670-72; Exh. 1061, at 305-06; Exh. 1062, at 74-76;
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`Exh. 1063, at 753-56, pemphigus vulgaris (Exh. 1065, at 998-99), cicatricial
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`pemphigoid (Exh. 1066, at 254-55), and linear IgA bullous disorders (Exh. 1065,
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`at 998-99).
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`27.
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`In fact, even PERIOSTAT can have off-label use, as was
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`acknowledged by the authors of a study looking into using PERIOSTAT
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`(apparently named “Dermostat” in the study) to treat inflammatory conditions:
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`“[p]eriostat was approved by the FDA in 1998, and it could currently be used for
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`its anti-inflammatory benefits with excellent results.” (Exh. 1015, at 2.) I see this
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`as mere confirmation that PERIOSTAT was available for off-label use and that
`
`doctors were free to use it, and indeed it appears they were doing so.
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`The Known Use Of Tetracyclines To Treat Papules And Pustules Of Rosacea
`
`28. The systemic use of the tetracycline family of medications in the
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`treatment of inflammatory acne and rosacea goes back at least about 50 years.
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`Indeed, to my knowledge, the earliest documentation of the use of tetracyclines to
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`treat rosacea dates back to 1966, when Sneddon IB noted in the British Journal of
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`Dermatology that, “There is no doubt that tetracycline controls not only
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`pustulation, which one could accept might be of bacterial origin, but the liability to
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`flushing and the permanent dilatation of the capillaries also clear in favourable
`
`
`
`15
`
`Exh. 1004
`
`
`
`
`
`cases.” (Exh. 1006, at 651.) “The mechanism of its beneficial action [tetracycline]
`
`is as yet unknown, but the observation that it controls not only pustulation but
`
`erythema suggests that it is not entirely an antibacterial or antidemodectic effect.”
`
`(Id. at 652.) Furthermore, Sneddon notes, “[m]any of the spate of dermatological
`
`textbooks published in the last two years mention tetracycline as a significant agent
`
`in treatment [of rosacea], and this must reflect the attitude of dermatologists as a
`
`whole, but there has been no statistical support for this opinion. Perhaps statistics
`
`are unnecessary when the treatment is so good that it obviously works.” (Id.
`
`at 649.) This would suggest to one of ordinary skill in the art that tetracyclines
`
`were already in wide use for treating rosacea as far back as the 1960s. In
`
`Sneddon’s study, tetracycline administration was successful in controlling rosacea
`
`in 87% of patients studied. (Id. at 651-52.) Sneddon did not expressly disclose oral
`
`antibiotics. However, he disclosed that patients were given a month’s supply of
`
`tetracycline or an indistinguishable placebo. Coupled with the prevalence of oral
`
`dosing, I believe a dermatologist of ordinary skill in the art would read Sneddon as
`
`disclosing administering oral antibiotics.
`
`29. Later studies corroborated Sneddon’s findings. A randomized
`
`double-blind controlled trial in 1971 demonstrated a benefit of tetracyclines in the
`
`treatment of papules and pustules of rosacea. (Exh. 1007, at 1050-51.) Controlled
`
`trials in 1980 (Exh. 1008, at 444) and 1983 (Exh. 1009, at 64) similarly showed
`
`
`
`16
`
`Exh. 1004
`
`
`
`
`
`improvement of inflammatory rosacea with administration of oxytetracycline,
`
`another early member of the tetracycline family (Exh. 1054, at 21). While the term
`
`“acne rosacea” is not used specifically in Sneddon’s study nor the related studies
`
`listed above, the fact that these studies are investigating “papules and pustules of
`
`rosacea” implies to me that a dermatologist of ordinary skill in the art would
`
`interpret
`
`these studies as investigating
`
`inflammatory rosacea, which was
`
`historically termed “acne rosacea”.
`
`30. The disclosure of the ‘506 Patent clearly contemplates the use of
`
`tetracyclines, but the claims of the ‘506 Patent are specific to doxycycline. But,
`
`well before the filing of the ‘506 Patent, dermatologists would have tended to favor
`
`doxycycline over other earlier used members of the tetracycline family. “Although
`
`first-generation tetracycline remains useful, the second-generation tetracyclines in
`
`the form of minocycline and doxycycline hyclate, and, most recently, doxycycline
`
`monohydrate, offer a number of advantages over tetracycline.” (Exh. 1067, at 415.)
`
`“The newer tetracyclines have markedly
`
`increased bioavailability, greatly
`
`improved absorption in the presence of foods, and a broader range of antibacterial
`
`activity. The increased bioavailability allows for once-daily administration in the
`
`treatment of acne and a twice-daily regimen for soft tissue infections and
`
`chlamydia.” (Id.) Fasting is not required when taking doxycycline. However,
`
`tetracycline absorption is significantly influenced by food and dairy products. (See
`
`
`
`17
`
`Exh. 1004
`
`
`
`
`
`id. at 412.) The relative side effect profile, the ability to dose less drug and less
`
`frequently, and the greater flexibility of dosing in terms of administering with or
`
`without food leading to better compliance (See id. at 414), as well as the
`
`recognition amongst dermatologists of the efficacy of doxycycline in acne, would
`
`have made doxycycline preferable to tetracycline in the mind of treating
`
`dermatologists well before the ‘506 Patent was filed.
`
`31. An early report of doxycycline in the treatment of cutaneous rosacea
`
`(earlier reports exist for ocular rosacea) was the 1997 study by Torresani that
`
`showed that doxycycline doses ranging from 100-200mg/day improved the
`
`erythema, telangiectasia, papules and pustules of rosacea in 17 patients.
`
`(Exh. 1010, at 942-45.) In particular, the number of papules and pustules decreased
`
`from 20-30 lesions to <5 on average. (Id. Figs.3, 4.) Interestingly, while finding
`
`doxycycline to be effective, Torresani found a second agent, clarithromycin, to be
`
`even more potentially attractive. (Id. at 945.) Torresani does not expressly disclose
`
`oral antibiotics but the length of the study, frequency of dosing, and the prevalence
`
`of oral dosing, I believe a dermatologist of ordinary skill in the art would read
`
`Torresani as disclosing administering oral antibiotics.
`
`32.
`
`In August 2000, JB Bikowski published a case report documenting
`
`successful treatment of two patients with inflammatory rosacea with monotherapy
`
`of doxycycline monohydrate. (Exh. 1011.) Note, in particular, the “nodules”
`
`
`
`18
`
`Exh. 1004
`
`
`
`
`
`mentioned and shown in Figure 3. (See id. at 150.) This is a typical illustration of a
`
`deep inflammatory papule/pustule. While the paper is not totally clear on this
`
`point, the reference to “systemic antibiotic therapy” would be understood by a
`
`dermatologist of ordinary skill in the art as a reference to oral administration. Oral
`
`antibiotics are expressly mentioned on page 149, and the patients were dosed at
`
`home with follow-ups in the office. One patient was initially treated with
`
`100mg/day to obtain clearance, then maintained on the same dose. The second
`
`patient was initially treated with 50mg/day to obtain clearance, then maintained on
`
`50mg every other day. (Id.) Both patients remained clear in long-term follow-up.
`
`Taking into account that the half-life of the doxycycline is 18 hours, then the
`
`expected dose at the end of one day would be less than half of the initial dose
`
`given. (See Exh. 1042, at 954 (“Doxycycline is eliminated with a half-life of
`
`approximately 18 hours by renal and fecal excretion of unchanged drug.”).) Thus,
`
`by April 5, 2001 it was known that even in relatively low doses, doxycycline could
`
`be used to successfully treat the papules and pustules of rosacea.
`
`The Role Of Inflammation In Papules And Pustules
`And the Role of Tetracyclines as Anti-inflammatory Agents
`
`33.
`
` It is well documented that the pathogenesis of papules and pustules of
`
`rosacea is intimately tied to the immune system and that inflammation is an
`
`essential component and the final common denominator of papule and pustule
`
`formation. In rosacea, there “is erythema and telangiectasia making up the vascular
`
`
`
`19
`
`Exh. 1004
`
`
`
`
`
`component, and on the other papules and pustules which constitute the
`
`inflammatory
`
`aspect.”
`
`(Exh. 1035,
`
`at 36). Additionally,
`
`in
`
`rosacea,
`
`“[b]acteriological studies of these pustules [of inflammatory rosacea] reveal
`
`nothing of interest.” (Exh. 1034, at 145.)
`
`34.
`
`Importantly, the tetracycline family of medications was known to
`
`have numerous effects on inflammatory conditions and pathways Exh. 1017,
`
`at 111-14; Exh. 1018, at 533; Exh. 1019, at 52-53; Exh. 1021, at 520-21;
`
`Exh. 1022, at 1311-13; Exh. 1023, at 1166-67; Exh. 1024, at 14015-019;
`
`Exh. 1025, at 260-62; Exh. 1027, at 15; Exh. 1028, at 690-91; 1029, at 668-69;
`
`Exh. 1030, at 444-45; Exh. 1031, at 311-12; Exh. 1032, at 178-79.) Some of these
`
`mechanisms were also explicitly demonstrated to be addressed by doxycycline.
`
`(Exh. 1023,
`
`at 1166-67; Exh. 1024,
`
`at 14015-019; Exh. 1025,
`
`at 260-62;
`
`Exh. 1030, at 444-45; Exh. 1031, at 311-12; Exh. 1032, at 178-79.)
`
`35. Of particular relevance to the issue of treating papules and pustules is
`
`the fact that the tetracycline family has been shown to directly impact overall white
`
`blood cell chemotaxis, and in particular the chemotaxis of polymorphonuclear
`
`(PMN) white blood cells (also known as neutrophils). (Exh. 1019, at 52-54.) White
`
`blood cells, and
`
`in particular neutrophils, predominantly comprise
`
`the
`
`inflammatory infiltrate of the papules and pustules of rosacea. (Exh. 1034, at 147.)
`
`Therefore, impeding the white blood cells’ ability to track to these sites would
`
`
`
`20
`
`Exh. 1004
`
`
`
`
`
`decrease the quantity of the white blood cells in papules and pustules and thus
`
`result in direct improvement of the papules and pustules of rosacea.
`
`36. The tetracycline family has also been shown to accelerate neutrophil
`
`apoptosis, which limits the ability of white blood cells to damage su
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