`
`
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`AMNEAL PHARMACEUTICIALS, LLC
`Petitioner
`
`v.
`
`SUPERNUS PHARMACEUTICALS, INC.
`Patent Owner
`
`U.S. Patent No. 8,394,405
`_____________________
`
`Case IPR2013-00371
`_____________________
`
`Declaration of Dr. Elaine S. Gilmore, M.D., Ph.D.
`
`

`

`
`
`
`Case IPR2013-00371
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`TABLE OF CONTENTS
`
`Overview ......................................................................................................... 1 
`I. 
`Summary of opinions ...................................................................................... 2 
`II. 
`III.  My background and qualifications ................................................................. 3 
`IV.  List of documents I considered in formulating my opinions .......................... 6 
`V. 
`Basis of my analysis with respect to long-felt need and commercial success 9 
`VI.  Rosacea background ..................................................................................... 10 
`VII.  The claimed inventions of the '405 patent do not satisfy a long-felt unmet
`need for the treatment of rosacea .................................................................. 12 
`A.  Dr. Webster does not show a long-felt need recognized in
`the art ................................................................................................... 13 
`B.  Any need for a once-daily, sub-antimicrobial dose of
`doxycycline for the treatment of rosacea was already
`satisfied by the prior art ....................................................................... 17 
`VIII.  Dr. Webster overstates the impact on patient compliance when comparing
`twice-daily dosing of Periostat® to once-daily dosing of Oracea® for the
`treatment of rosacea. ..................................................................................... 20 
`A.  Dr. Webster provides no actual evidence of poor patient
`compliance for twice-daily Periostat® ................................................ 21 
`Published literature shows comparable patient compliance
`rates between
`twice-daily Periostat® and once-daily
`Oracea® ............................................................................................... 22 
`IX.  The sales of Oracea® are not due to the claimed inventions of the '405
`patent ............................................................................................................. 25 
`A.  Dr. Webster provides no evidence that the sales of Oracea®
`are a direct result of the claimed invention ......................................... 25 
`B.  Dr. Webster does not consider other factors that attribute to
`commercial success ............................................................................. 26 
`Conclusion .................................................................................................... 29 
`
`X. 
`
`B. 
`
`
`
`
`- i -
`
`

`

`
`
`
`I.
`
`Case IPR2013-00371
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`I, Elaine S. Gilmore, hereby declare as follows.
`
`Overview
`1.
`
`I am over the age of eighteen (18) and otherwise competent to make
`
`this declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of AMNEAL
`
`PHARMACEUTICALS, L.L.C and AMNEAL PHARMACEUTICALS COMPANY PVT. LTD.
`
`(together "AMNEAL") for the above-captioned inter partes review (IPR). I am being
`
`compensated for my time in connection with this IPR at my standard consulting
`
`rate, which is $375 per hour. I understand that the petition for inter partes review
`
`involves U.S. Patent No. 8,394,405 ("the '405 patent"), Exhibit 1007, which
`
`resulted from U.S. Application No. 12/926,932 ("the '932 application"), filed on
`
`December 17, 2010, naming Rong-Kun Chang, Arash Raoufinia, and Niraj Shah as
`
`inventors. The '405 patent issued on March 12, 2013, from the '932 application. I
`
`further understand that, according to the USPTO records, the '405 patent is
`
`currently assigned to Supernus Pharmaceuticals, Inc. ("the patentee"). I understand
`
`that the earliest possible priority date for the '405 patent is April 7, 2003.
`
`3.
`
`I understand that certain claims of the '405 patent are directed to a
`
`pharmaceutical composition of doxycycline comprising an instantaneous release
`
`(IR) and delayed release (DR) formulation that, when given at a once-daily dosage,
`
`will give a steady-state blood level of doxycycline of a minimum of 0.1 μg/ml and
`
`
`
`- 1 -
`
`

`

`Case IPR2013-00371
`
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`
`a maximum of 1.0 μg/ml. I understand that certain claims of the '405 patent are
`
`directed to a method of treating rosacea using the pharmaceutical composition.
`
`4.
`
`I understand that certain documents associated with this inter partes
`
`review proceeding are considered confidential. I reviewed the Proposed Protective
`
`Order (Exhibit 2171) and signed the corresponding acknowledgement form.
`
`
`
`II.
`
`Summary of opinions
`5.
`
`I have been asked by Counsel for Amneal to consider and respond to
`
`the testimony of Supernus's declarant, Dr. Guy Webster, concerning secondary
`
`considerations of nonobviousness. Dr. Webster states in his declaration that
`
`Oracea® purportedly fulfilled a long-felt, unmet need for the treatment of rosacea.
`
`[Ex2018, ¶¶ 31-37.] I disagree that there was a long-felt, unmet need for a once-
`
`daily sub-antimicrobial doxycycline dosage formulation – e.g., for the treatment of
`
`rosacea – because (i) doxycycline formulations available in the prior art (e.g.,
`
`Periostat® and once-daily generic doxycycline) were routinely prescribed for
`
`rosacea and achieved the same clinical benefits as Oracea®; and (ii) Dr. Webster
`
`overstates the impact on patient compliance when comparing twice-daily dosing of
`
`Periostat® to once-daily dosing of Oracea® for the treatment of rosacea.
`
`6.
`
`Even if there were a "need" for a once-daily sub-antimicrobial
`
`doxycycline dosage formulation, I disagree with Dr. Webster's opinion that the
`
`
`
`
`- 2 -
`
`

`

`Case IPR2013-00371
`
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`
`need was not satisfied until Oracea® launched in 2006. [Ex2018, ¶33.] Any such
`
`need would have been satisfied by the disclosures in the prior art.
`
`7.
`
`Dr. Webster also states in his declaration that the purported
`
`commercial success of Oracea® is directly attributed to the claimed inventions of
`
`the '405 patent. [Ex2018, ¶¶ 39-40.] I disagree with Dr. Webster that the
`
`commercial sales of Oracea® are attributable to the claimed invention of the '405
`
`patent. Dr. Webster provides no evidence that the sales of Oracea® are a direct
`
`result of the claimed invention. Dr. Webster also fails to consider other factors that
`
`contribute to sales, such as being the only FDA-approved oral therapy for rosacea,
`
`Galderma’s specialty in the dermatology field, marketing tactics, and Galderma's
`
`practice of distributing free samples, as I discuss below.
`
`
`
`III. My background and qualifications
`8.
`I am an expert in the field of dermatology and in the treatment of
`
`patients suffering from dermatological disorders.
`
`9.
`
`I am presently Assistant Professor of Dermatology, Medical Director
`
`of University Dermatology Associates (Henrietta, NY), and Director of the
`
`Medical Student Dermatology Course and Clerkship at the University of Rochester
`
`School of Medicine and Dentistry, Department of Dermatology. I am Board
`
`Certified in Dermatology by the American Board of Dermatology. I have worked
`
`
`
`
`- 3 -
`
`

`

`Case IPR2013-00371
`
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`
`and taught extensively in the fields of cell and molecular physiology and
`
`dermatology. I also have an academic-based clinical practice in a tertiary referral
`
`hospital
`
`treating patients with general dermatological disorders,
`
`including
`
`numerous patients suffering from acne and rosacea. My curriculum vitae is
`
`provided as Exhibit 1057.
`
`10.
`
`I earned a Bachelor of Science degree in Biology and a Bachelor of
`
`Arts degree in Chemistry from Providence College, summa cum laude, in 1996. I
`
`earned an M.D. and Ph.D. from the University of North Carolina at Chapel Hill in
`
`2003 and 2001, respectively. My doctoral research focused on cell and molecular
`
`physiology, specifically on ion channel regulation in the lungs and kidneys. I
`
`completed a residency in dermatology at Yale-New Haven Hospital in 2006 and a
`
`research fellowship in dermatology at Yale in 2008.
`
`11.
`
`I have received several honors in my career, including the Brian P.
`
`Flanagan Faculty Teaching Award at the University of Rochester (2013); Wilmot
`
`Cancer Research Fellowship Grant (2011); Wilmot Cancer Center Lymphoma
`
`SPORE Career Development Award (2011); Dermatology Foundation Fellowship
`
`Grant (2007); Medical Scientist Training Program (MSTP) Scholarship (1996-
`
`2003); University of North Carolina Travel Grant (2000); Renaissance Physiology
`
`Department Travel Award (2000); John B Graham Research Society Travel Grant
`
`(1999); John B. Graham Research Society (Inducted) (1999); Howard Holderness
`
`
`
`
`- 4 -
`
`

`

`Case IPR2013-00371
`
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`
`Fellowship (1997-98); NIH Summer Research Training Grant (1997) and the
`
`Roddy Foundation Scholarship (1992-1996).
`
`12.
`
`In addition to my clinical practice and my duties as a professor of
`
`medicine, I am also actively involved in scientific research programs. For example,
`
`I am presently investigating the pathogenesis of itch in patients with lymphoma. I
`
`have presented my work at national and international dermatology meetings. I have
`
`served as a co-clinical investigator on several clinical trials in cutaneous
`
`lymphoma, epidermolysis bullosa and cutaneous lupus.
`
`13.
`
`I am the author or co-author of many medical publications involving
`
`dermatology and related science. A complete list of my publications is found in my
`
`curriculum vitae (Exhibit 1057). I have served as a peer reviewer for basic science
`
`articles in the British Journal of Dermatology.
`
`14.
`
`I am a member of or affiliated with a number of organizations
`
`dedicated to dermatology, including the American Academy of Dermatology,
`
`American Contact Dermatitis Society, International Forum for the Study of Itch,
`
`International Society of Cutaneous Lymphoma, Society for Investigative
`
`Dermatology, and the American Academy of Dermatology Diversity Mentorship
`
`Program.
`
`15.
`
`In view of my education, experience, and expertise described above, I
`
`am an expert in the field of dermatology and in the treatment of patients suffering
`
`
`
`
`- 5 -
`
`

`

`Case IPR2013-00371
`
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`
`from dermatological disorders. Accordingly, I am an expert in the field of the
`
`invention.
`
`
`
`IV. List of documents I considered in formulating my opinions
`16.
`In formulating my opinions, I considered the following documents:
`
`Exhibit or
`Paper No.
`Paper 2
`
`Paper 1
`
`Paper 2
`
`Paper 8
`
`Paper 11
`
`Paper 8
`
`Paper 39
`
`Paper 40
`
`Paper 38
`1001
`
`1002
`
`1003
`
`1007
`
`Description
`Amneal's petition for inter partes review of US Patent No.
`8,206,740
`Amneal's petition for inter partes review of US Patent No.
`8,394,405
`Amneal's petition for inter partes review of US Patent No.
`8,394,406
`Patent Trial & Appeal Board, Decision to Institute, Case
`IPR2013-00368;
`Patent Trial & Appeal Board, Decision to Institute, Case
`IPR2013-00371;
`Patent Trial & Appeal Board, Decision to Institute, Case
`IPR2013-00372;
`Supernus' Patent Owner Response, Case IPR2013-00368;
`
`Supernus' Patent Owner Response, Case IPR2013-00371;
`
`Supernus' Patent Owner Response, Case IPR2013-00372;
`Chang et al., U.S. Patent No. 8,206,740, “Once daily
`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; published October 17, 2002) ("the '932
`publication")
`Ashley, U.S. Prov. Appl. No. 60/281,854 (filed April 5,
`2001) ("the '854 application")
`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")
`
`
`
`
`- 6 -
`
`

`

`1009
`
`1012
`
`1022
`1035
`1036
`
`1038
`
`1039
`
`1041
`
`1043
`
`1044
`
`1059
`
`1054
`
`1060
`
`1061
`
`1062
`
`Case IPR2013-00371
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`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")
`Skidmore et al., "Effects of Sub-antimicrobial-Dose
`Doxycycline in the Treatment of Moderate Acne" Arch.
`Dermatol. 139:439-464 (2003)
`Declaration of Glenn A. Van Buskirk, Ph.D.,
`Oracea® package insert
`Haffajee et al., "Microbiological changes associated with
`four different periodontal therapies for the treatment of
`chronic periodontitis," Oral Micro. Immuno. 23:148–157
`(2008)
`Preshaw et al., "Sub-antimicrobial Dose Doxycycline
`Enhances the Efficacy of Scaling and Root Planing in
`Chronic Periodontitis: A Multicenter Trial" J.
`Periodontol 75:1068-76 (2004)
`Preshaw et al., "Modified-Release Sub-antimicrobial Dose
`Doxycycline Enhances Scaling and Root Planing in Subjects
`With Periodontal Disease" J. Periodontol. 79:440-452 (2008)
`G.F. Webster, “Acne Vulgaris and Rosacea: Evaluation and
`Management,” clin. CORNERSTONE – Office Dermatol.
`4(1):15-22 (2001)
`G.F. Webster, “Acne vulgaris,” British Med. J. 325:475-479
`(2002)
`P.V. Harrison, "A comparison of doxycycline and
`minocycline in the treatment of acne vulgaris," Clin. Exp.
`Dermatol. 13:242-244 (1998)
`Pelle et al., Rosacea: II. Therapy. J. Am. Acad. Dermatol.,
`Vol. 51, No. 4 (Oct. 2004)
`Transcript of deposition of Guy Webster, M.D., Ph.D., Case
`IPR2013-00368; IPR2013-00371; and IPR2013-00372, May
`9, 2014
`Bikowski J.B., “Subantibacterial dose of doxycycline for
`acne and rosacea” SKINmed 2003; 2:234-245 (2003)
`Hurley et al., "Characterizing the Relationship Between Free
`Drug Samples and Prescription Patterns for Acne Vulgaris
`and Rosacea" JAMA Dermatol. 150(5):487-93 (2014),
`published online April 16, 2014
`Del Rosso et al., Two Randomized Phase III Clinical
`
`- 7 -
`
`
`
`
`
`
`
`

`

`Case IPR2013-00371
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`Trials Evaluating Anti-Inflammatory Dose Doxycycline (40
`mg doxycycline, USP capsules) Administered Once-Daily for
`Treatment of Rosacea" J. Am. Acad. Dermatol 56:791-802
`(2007)
`Sanchez et al., "A randomized, double-blind, placebo-
`controlled trial of the combined effect of doxycycline hyclate
`20-mg tablets and metronidazole 0.75% topical lotion in the
`treatment of rosacea," J. Am. Acad. Dermatol 53:791-97
`(2005)
`Thomas, J., et al., "Long-Term Use of Subantimicrobial Dose
`Doxycycline Does Not Lead to Changes in Antimicrobial
`Susceptibility" J. Periodontol. 71(9):1472-1483 (2000)
`Walker, C., et al., "Long-Term Treatment with Sub-
`antimicrobial Dose Doxycycline Exerts No Antibacterial
`Effect on the Subgingival Microflora Associated with Adult
`Periodontitis" J. Periodontol. 71(9):1465-1471 (2000)
`Web page print out of "Oracea® Care Card" application
`page, http://www.oracea.com/oracea-coupon
`Transcript of Deposition of Glenn A. Van Buskirk, Ph.D.,
`Case IPR2013-00368; IPR2013-00371; and IPR2013-00372,
`February 12, 2014
`Declaration of Edward M. Rudnic, Ph.D.
`Declaration of Henry G. Grabowski, Ph.D.
`Declaration of Guy F. Webster, M.D., Ph.D.
`Saini, S.D. et al., Effect of Medication Dosing Frequency on
`Adherence in Chronic Disease, The Am. J. Managed Care
`15:22 (2009)
`National Rosacea Society, Rosacea Review, "Rosacea Now
`Estimated to Affect at Least 16 Million Americans" (Winter
`2010)
`Package Insert for Finacea®
`MetroGel Prescribing Information
`Berman, B et al., Update on Rosacea and antiinflammatory-
`dose doxycycline, Drugs of Today 43(1):27-34 (2007)
`Bikowski, J.B. & Goldman, M., Rosacea: Where Are we
`Now? J. Drugs Dermatol. 3:251-261 (2004)
`Del Rosso et al., Comparison of Anti-Inflammatory Dose
`Doxycycline Versus Doxycycline 100 MG in the treatment of
`Rosacea, J. Drugs Derm 7(6):573-576 (2008)
`
`- 8 -
`
`1063
`
`1064
`
`1065
`
`1095
`
`2015
`
`2016
`2017
`2018
`2083
`
`2085
`
`2095
`2096
`2109
`
`2110
`
`2111
`
`
`
`
`
`
`
`

`

`
`
`
`V.
`
`Case IPR2013-00371
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`
`
`
`Basis of my analysis with respect to long-felt need and commercial success
`17.
`
`I understand that, in considering the obviousness of an invention, one
`
`must also consider whether there are any secondary considerations that support the
`
`non-obviousness of the invention. I understand that two such secondary
`
`considerations of non-obviousness include long-felt, but unmet, need and
`
`commercial success.
`
`18.
`
`I understand that a long-felt but unmet need may be evidence of non-
`
`obviousness when objective evidence shows (i) the need was a persistent need in
`
`the prior art that was recognized by those of ordinary skill in the art; (ii) the need
`
`was not satisfied by another product, technology, or disclosure in the art before the
`
`invention claimed in the patent; and (iii) the invention claimed in the patent
`
`satisfies the long-felt need. I also understand that actual evidence of a long-felt
`
`need (e.g., evidence of the need recognized in the prior art) must be provided to
`
`prove the existence of the need, as opposed to mere argument.
`
`19.
`
`I understand that "commercial success" (e.g., substantial market share)
`
`can be evidence of non-obviousness if there is proof that the commercial sales
`
`were a direct result of the patented technology. I understand that if a product is
`
`shown to be a commercial success, factors other than the patented technology must
`
`be considered as possible causes for the commercial success, such as being the first
`
`
`
`
`- 9 -
`
`

`

`Case IPR2013-00371
`
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`
`to enter the market, strong marketing/advertising efforts, discount programs, or
`
`free samples.
`
`
`
`VI. Rosacea background
`20.
`I agree with Dr. Webster that rosacea is a chronic inflammatory
`
`disorder of the skin. [Ex2018, ¶19.] I also agree with Dr. Webster that rosacea can
`
`manifest with a range of symptoms, including (1) flushing and redness, known as
`
`“erythema,” (2) bumps and pimple-like blemishes, known as “papules and
`
`pustules,” and (3) visible blood vessels, known as “telangiectasias.” [Ex2018, ¶
`
`20.]
`
`21. Pelle et al. (J. Am. Acad. Dermatol., 51(4):499-512 (2004) [Ex1059])
`
`describe a variety of treatments that have historically been used for rosacea, such
`
`as sunscreen, cosmetics, sulfa-based products, azelaic acid, tretinoin, and
`
`antibiotics. [Ex1059, 499-504; see also, Ex2018. ¶21.] Antibiotic drugs for the
`
`treatment of rosacea are usually available as either topical or oral formulations.
`
`[Ex1059, 502-503.] Commonly used topical formulations for rosacea treatment
`
`include creams and gels having metronidazole as the active ingredient, such as
`
`Metrogel® 0.75% or 1%. [Ex1059, 500-501.] Commonly used oral antibiotics for
`
`rosacea treatment include the tetracycline family of antibiotics, such as the
`
`
`
`
`- 10 -
`
`

`

`
`
`"second-generation
`
`Case IPR2013-00371
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`tetracyclines" minocycline and doxycycline.
`[Ex1059,
`
`503:2:21.]
`
`22. Pelle et al. state that higher doses of tetracyclines (i.e., doses of drug
`
`high enough to provide antimicrobial activity) have been used to successfully treat
`
`patients with rosacea for more than 40 years. [Ex1059, 503:1:3.] Published
`
`literature shows that the medical community also understood the potential benefits
`
`of using low-dose doxycycline, such as reduced antibiotic resistance with long
`
`term therapy. [Ex1059, 503:2:2; Ex1064; Ex1065.] Accordingly, published
`
`medical literature shows that clinicians were using low doses of doxycycline to
`
`treat rosacea by the late 1990s. [Ex1059, 503:2:2; Ex2110, 253; Ex1060, 241-243.]
`
`23. For example, clinicians were treating rosacea patients with Periostat®,
`
`a drug that was initially approved for the treatment of periodontitis, which
`
`delivered a total of 40 mg of doxycycline per day in two equally divided doses of
`
`20 mg. [Ex1059, 503:2:2.] Dr. Webster acknowledges the use of Periostat® for the
`
`treatment of rosacea in his declaration. [Ex2018, ¶26.] Dr. Webster's own
`
`publication shows that clinicians were also treating rosacea patients with generic
`
`doxycycline in 50 mg or 100 mg dosage forms administered once or twice-daily.
`
`[Ex1018, 208, Table 2; Ex1054, 77:16-17.] Periostat® (as well as its inexpensive
`
`1 Where applicable, I cite to exhibits using the following format
`
`page:column:paragraph.
`
`
`
`
`- 11 -
`
`

`

`Case IPR2013-00371
`
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`
`generic) and generic doxycycline both continue to enjoy popularity and widespread
`
`acceptance among dermatologists for the treatment of rosacea. I frequently
`
`prescribe my rosacea patients generic Periostat® or generic doxycycline in 50 mg
`
`or 100 mg dosage forms. I note that Dr. Webster also prescribes 50 mg generic
`
`doxycycline to his rosacea patients. [Ex1054, 77:12-17.]
`
`
`
`VII. The claimed inventions of the '405 patent do not satisfy a long-felt unmet
`need for the treatment of rosacea
`24.
`
`In his declaration, Dr. Webster states that there was a long-felt, unmet
`
`need for a “new, convenient rosacea
`
`therapy
`
`that permitted once-daily
`
`administration to increase patient compliance with that treatment, while still
`
`avoiding high blood levels linked to antibacterial "side effects." [Exhibit 2018,
`
`¶32.] Dr. Webster states that Oracea® fulfilled this purported long-felt need when
`
`the product launched in 2006. [Exhibit 2018, ¶33]
`
`25.
`
`I disagree with Dr. Webster that there was a long-felt, unmet need for
`
`a once-daily oral rosacea therapy that avoided antibacterial blood levels of the drug
`
`linked to antibiotic side effects. First, Dr. Webster does not identify a long-felt
`
`need for a once-daily, sub-antimicrobial dose of doxycycline – e.g., for the
`
`treatment of rosacea – that was recognized or articulated in the prior art (i.e., he
`
`provides no actual evidence of a long-felt need). And second, even if there were
`
`
`
`
`- 12 -
`
`

`

`Case IPR2013-00371
`
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`
`such a need, it was satisfied by the disclosures in the prior art. These points are
`
`discussed below.
`
`A. Dr. Webster does not show a long-felt need recognized in the art
`26. As stated above in ¶18, I understand that one of the requirements for a
`
`long-felt but unmet need is for the need to be a persistent need that was recognized
`
`in the prior art by those of ordinary skill in the art. I also understand that specific
`
`evidence of a long-felt need is required.
`
`27.
`
`In his declaration (Ex2018), Dr. Webster does not provide any
`
`supporting evidence of a long-felt need for a once-daily, sub-antimicrobial dose of
`
`doxycycline for the treatment of rosacea. Dr. Webster describes potential side
`
`effects associated with topical rosacea treatments (Ex2018, ¶22); commonly used
`
`antibiotic doses of doxycycline (Ex2018, ¶23); potential side effects associated
`
`with long-term therapy of antibacterial doses of doxycycline (Ex2018, ¶24); and
`
`the possibility of developing antibiotic resistance when using long-term therapy of
`
`antibacterial doses of doxycycline (Ex2018, ¶25). But Dr. Webster does not
`
`provide any actual evidence of a long-felt need for a once-daily sub-antimicrobial
`
`dose of doxycycline that was recognized in the prior art by those in the art. Nor
`
`does Dr. Webster provide any actual evidence that Oracea® has lower side effects
`
`than other available doxycycline treatments (e.g., once-daily 50 mg generic
`
`doxycycline).
`
`
`
`
`- 13 -
`
`

`

`
`
`
`Case IPR2013-00371
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`28. Furthermore, Dr. Webster provides no actual evidence of the alleged
`
`benefits of Oracea® listed in his declaration. For example, Dr. Webster states,
`
`“[u]nlike higher doses of doxycycline, however, the 30 mg IR, 10 mg DR
`
`doxycycline formulation of Oracea® achieves efficacy at blood levels below those
`
`linked to antibacterial side effects and therefore has essentially no side effects as
`
`seen in everyday practice.” [Ex2018, ¶28.] Dr. Webster cites Del Rosso et al.
`
`(2008) (Ex2111) to support his statement. After reviewing the Del Rosso 2008
`
`article, I found no evidence that Oracea® "has essentially no side effects as seen in
`
`every day practice." In fact, Ex2111 shows that some of the Oracea® patients in
`
`the study reported gastrointestinal adverse events. [Ex2111, Figure 5.] This is
`
`contrary to Dr. Webster's opinion that Oreacea® has "essentially no side effects."
`
`At best, the Del Rosso study shows that the number of gastrointestinal adverse
`
`events associated with generic doxycycline was not statistically significant
`
`compared to the number of gastrointestinal adverse events associated with
`
`Oracea®. [Ex2111, Table 5.] Dr. Webster confirmed at deposition that the
`
`difference in the number of gastrointestinal adverse events for Oracea® and 100
`
`mg doxycycline was not statistically significant in the Del Rosso study. [Ex1054,
`
`156:10-16; 157:7-15.] Finally, I note that the Del Rosso study compared the safety
`
`and efficacy of Oracea® to that of once-daily 100 mg doxycycline. [Ex2111.]
`
`
`
`
`- 14 -
`
`

`

`Case IPR2013-00371
`
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`
`According to Ex2111, the authors did not evaluate a comparison of Oracea® to
`
`once-daily 50 mg doxycycline.
`
`29.
`
`I am not aware of any study that directly compares the side effects of
`
`Oracea® to those of once-daily 50 mg doxycycline. Dr. Webster also stated that he
`
`is not aware of any study that directly compares the side effect profile of 50 mg
`
`generic doxycycline to Oracea®:
`
`Q. Doctor, are you aware of any head to head
`studies showing the side effect profile of 50 mg.
`of doxycycline to Oracea?
`
`A. I am not aware of any such study.
`
`[Ex1054, 35:6-10; see also, Ex1054, 77:7-11.]
`
`30. Therefore, Dr. Webster's statements that Oracea® has lower side
`
`effects compared to other doxycycline therapies (e.g., once-daily 50 mg
`
`doxycycline) are unsupported. Similarly, Dr. Webster’s statements that Oracea®
`
`has no antimicrobial effects are unsupported. [Ex2018, ¶ 28.] Again, Dr. Webster
`
`provides no actual evidence that long-term administration of Oracea® does not
`
`lead to development of antibiotic resistant strains of bacteria. Publications such as
`
`the 2008 study of Haffajee et al.,"Microbiological changes associated with four
`
`different periodontal therapies for the treatment of chronic periodontitis," Oral
`
`Micro. Immuno. 23:148–157 (2008) (Ex1036) suggest that even a "low dose" 40
`
`
`
`
`- 15 -
`
`

`

`Case IPR2013-00371
`
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`
`mg doxycycline treatment may have an effect on antibiotic resistance. Haffajee et
`
`al. compared
`
`the subgingival microbiological changes
`
`in patients after
`
`administering sub-antibacterial dose doxycycline ("SDD,"
`
`i.e., Periostat®),
`
`azithromycin, and metronidazole on the microbial gingival flora. The authors noted
`
`a high level of antibiotic resistant strains in patients who were administered sub-
`
`antibacterial dose doxycycline:
`
`Not surprisingly, the percentage of resistant isolates
`increased
`in subjects
`receiving adjunctive agents
`immediately after taking these agents, primarily because
`of a decrease in susceptible species. Levels had returned
`to baseline or close to baseline values at 12 months, with
`the exception of the high levels of species resistant to
`doxycycline observed in the saliva samples of subjects
`in the SDD group.
`
`[Ex1036, 155:1:2 (emphasis added).]
`
`31. The potential antimicrobial effects of Oracea® are further evidenced
`
`by the Oracea® package insert, which lists pseudomembranous colitis as a
`
`potential gastrointestinal side effect when taking Oracea®. [Ex1035, 1:2.]
`
`Specifically, the package insert states, "[p]seudomembranous colitis has been
`
`reported with nearly all antibacterial agents and may range from mild to life-
`
`threatening. Therefore, it is important to consider this diagnosis in patients who
`
`present with diarrhea subsequent to the administration of antibacterial agents. [Id.]
`
`
`
`
`- 16 -
`
`

`

`
`
`
`Case IPR2013-00371
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`32. Finally, even if Oracea® does have lower side effects compared to
`
`other doxycycline treatments, I disagree that the side effects associated with
`
`doxycycline are as great a concern as Dr. Webster indicates. For example, Dr.
`
`Webster himself published that the gastrointestinal side effects associated with
`
`doxycycline are easily mitigated by taking the medication with food. [Ex1043,
`
`476:2:4; see also, Ex1054, 34:11-22.] Thus, I disagree with Dr. Webster that there
`
`was a long-felt need for an oral, once-daily rosacea therapy with lower side effects
`
`than the existing therapies prior to 2003.
`
`
`
`B.
`
`Any need for a once-daily, sub-antimicrobial dose of doxycycline for
`the treatment of rosacea was already satisfied by the prior art
`
`33.
`
`I understand that a long-felt need does not need to be met by a
`
`commercial product per se, and can be met by disclosures in the prior art. Dr.
`
`Webster states that a "long-felt need existed for a new, convenient rosacea therapy
`
`that permitted once-daily administration to increase patient compliance with that
`
`treatment, while still avoiding high blood levels linked to antimicrobial effects."
`
`[Ex2018, ¶32.] According to Dr. Webster, "it was not until July 2006, when
`
`Oracea® launched, that those long-felt and unmet needs were fulfilled." [Ex2018,
`
`¶33.]
`
`34. Again, I disagree with Dr. Webster that there was a long-felt, unmet
`
`need for a once-daily sub-antimicrobial dosage formulation of doxycycline for the
`
`
`
`
`- 17 -
`
`

`

`Case IPR2013-00371
`
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`
`treatment of rosacea. Nonetheless, even if there were a long-felt need, I disagree
`
`with Dr. Webster's opinion that the need was not met until Oracea®'s launch in
`
`2006.
`
`35. Dr. Webster concedes that twice-daily Periostat® was effective for
`
`treating rosacea and maintained blood levels below those linked to the side effects
`
`of traditional antibiotic doxycycline dosages. [Ex2018, ¶¶26, 32.] Thus, according
`
`to Dr. Webster’s testimony, the only purported "unmet need" was for a once-daily
`
`formulation. But Dr. Webster overlooks the disclosures in the prior art, which
`
`would have met any purported long-felt need for a once-daily sub-antimicrobial
`
`doxycycline dose for the treatment of rosacea.
`
`36. For example, WO 2002/080932, ("the ‘932 publication") recites a 40
`
`mg dosage amount (two doses of 20 mg each) of doxycycline in the form of
`
`Periostat® as an especially preferred embodiment:
`
`embodiment,
`especially preferred
`an
`In
`doxycycline hyclate is administered at a 20
`milligram dose twice daily. Such a formulation
`is sold for the treatment of periodontal disease
`by CollaGenex Pharmaceuticals,
`Inc. of
`Newtown, Pennsylvania under the trademark
`Periostat ®.
`
`[Ex1002, 9:21-25 (emphasis added).]
`
`
`
`
`- 18 -
`
`

`

`
`
`
`Case IPR2013-00371
`Declaration of Elaine S. Gilmore, M.D., Ph.D. (Exhibit 1056)
`37. The '932 publication also describes once-daily and twice-daily dosing
`
`for increasing patient compliance:
`
`Second, the controlled release composition of
`the invention increases patient compliance.
`Instead of administering a
`low dose of
`tetracycline many times during the day, the
`composition of the invention allows the patient
`to administer the tetracycline one or two
`times a day. The controlled release of the
`tetracycline creates the desired dose profile
`below that which is necessary for an anti-
`microbial response in the host.
`
`[Exhibit 10032, 6:26-31 (emphasis added).]
`38. Therefore, the disclosures of the '932 publication satisfy any purported
`
`long-felt need for a once-daily, sub-antimicrobial dose of doxycycline.
`
`39. Dr. Webster's argument that Oracea® fills a need for a rosacea
`
`treatme