`
`
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`AMNEAL PHARMACEUTICALS, LLC
`Petitioner
`v.
`SUPERNUS PHARMACEUTICALS, INC.
`Patent Owner
`
`U.S. Patent No. 8,206,740 to Chang et al.
`Issue Date: June 26, 2012
`Title: Once Daily Formulations of Tetracyclines
`
`
`_____________________
`
`Inter Partes Review No. Unassigned
`_____________________
`
`
`
`Petition for Inter Partes Review of U.S. Patent No. 8,206,740 Under 35 U.S.C.
`§§ 311-319 and 37 C.F.R. §§ 42.1-.80, 42.100-.123
`
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`

`

`B. 
`
`TABLE OF CONTENTS
`I. 
`INTRODUCTION .......................................................................................... 1 
`OVERVIEW ................................................................................................... 1 
`II. 
`III.  GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL
`STATEMENTS .............................................................................................. 3 
`IV.  MANDATORY NOTICES (37 C.F.R. § 42.8(a)(1)) ..................................... 3 
`V. 
`STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(a)) ........................................... 4 
`VI.  CLAIM CONSTRUCTION ........................................................................... 5 
`VII.  PERSON OF SKILL IN THE ART & STATE OF THE ART ...................... 5 
`VIII.  IDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b)) .................. 7 
`A.  Ground 1: Independent Claims 1 and 19 Would Have Been
`Obvious in View of the '932 publication, which incorporates
`the '854 Application by reference ......................................................... 8 
`Ground 2: Independent Claims 1 and 19 Would Have Been
`Obvious Over the '932 publication in View of the '748
`Patent ................................................................................................... 19 
`Ground 3: Independent Claim 1 Would Have Been Obvious
`Over the '106 publication in View of the '748 Patent ......................... 30 
`D.  Ground 4: Independent Claim 19 Would Have Been
`Obvious Over the '106 publication in View of the '748
`patent, and Webster ............................................................................. 39 
`Obviousness of Dependent Claims 2, 5-15, and 20-22 Under
`Grounds 1-4 ......................................................................................... 41 
`Despite any Allegations of Objective Indicia, the Challenged
`Patent Claims Would Have Been Obvious ......................................... 47 
`1. 
`No Unexpected Results Over the Closest Prior Art ................. 48 
`2. 
`No Long Felt Unmet Need and/or Failure of Others ............... 50 
`3. 
`No Copying .............................................................................. 52 
`4. 
`No Commercial Success .......................................................... 53 
`IX.  CONCLUSION ............................................................................................. 55 
`
`
`C. 
`
`E. 
`
`F. 
`
`

`

`
`
`I.
`
`0BINTRODUCTION
`
`
`
`IPR of USPN 8,206,740
`
`AMNEAL PHARMACEUTICALS, LLC and AMNEAL PHARMACEUTICALS CO. (I)
`
`PVT. LTD. petition for Inter Partes Review, seeking cancellation of claims 1, 2, 5-
`
`15 and 19-22 of U.S. Patent No. 8,206,740 to Chang et al. ("the '740 patent")
`
`(AMN 1001), which is owned by Supernus Pharmaceuticals, Inc.
`
`II.
`
`1BOVERVIEW
`
`The challenged claims of the '740 patent never should have been issued
`
`because they are unpatentable over the art cited herein. Because Petitioner is — at
`
`a minimum — reasonably likely to prevail in showing unpatentability, the Petition
`
`should be granted and trial instituted on all of the challenged claims as set forth
`
`below.
`
`The '740 patent issued on June 26, 2012, and its earliest possible priority
`
`date ("EPD") is April 7, 2003. The '740 patent claims recite an oral composition
`
`of doxycycline (a well-known tetracycline) as well as a previously disclosed
`
`process for preparing the composition, and a well-known method for treating
`
`rosacea using the claimed composition.
`
`The composition claims recite that, at a once-daily dosage, the steady state
`
`blood levels of doxycycline are from 0.1 µg/ml to 1.0 µg/ml, and that the
`
`composition consists of (i) an immediate release (IR) portion comprising 30 mg
`
`doxycycline, and (ii) a delayed release (DR) portion comprising 10 mg
`
`
`
`1
`
`
`
`

`

`
`
`
`
`IPR of USPN 8,206,740
`
`doxycycline, and optionally one or more pharmaceutically acceptable excipients.
`
`The recited compositions were well known as of the EPD of the '740 patent.
`
`Oral pharmaceutical compositions comprising a total of 40 mg doxycycline
`
`distributed between an immediate release portion and a delayed release portion
`
`were well known. And the claimed ratio of the amount of doxycycline in the IR
`
`portion and in the DR portion would have immediately been envisaged by a skilled
`
`artisan given the teachings in the prior art. Even if a skilled artisan would not have
`
`immediately envisaged the 40 mg dose should be present in the claimed ratio, a
`
`skilled artisan would have arrived at the claimed composition through routine
`
`experimentation given the range of ratios in the prior art. When the general
`
`conditions, e.g., amounts of the components of a composition, are disclosed in the
`
`prior art, it is not inventive to discover the optimum or workable ranges by routine
`
`experimentation, absent a showing of the criticality of those amounts. No such
`
`evidence of criticality exists; and, in fact, Supernus admits that there is nothing
`
`critical regarding the claimed ratio of immediate release to delayed release
`
`doxycycline.
`
`The prior art also discloses that the oral compositions having the claimed
`
`amounts of doxycycline in the IR portion and DR portion were known to provide
`
`steady state blood levels within the claimed range. The compositions claimed in
`
`the '740 patent having the recited features were thus well known.
`
`
`
`2
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`

`

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`
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`IPR of USPN 8,206,740
`
`The '740 patent also claims a known process for preparing its claimed
`
`composition by combining the immediate release portion with the delayed release
`
`portion. The claimed method of treating rosacea with the claimed composition was
`
`similarly well-known as of the EPD.
`
`The prior art does not teach away from the claims and, even in view of any
`
`available evidence of secondary considerations, the claims would have been
`
`obvious. Claims 1, 2, 5-15 and 19-22 would therefore have been obvious as of the
`
`EPD of the '740 patent.
`
`III.
`
`2BGROUNDS FOR STANDING (37 C.F.R. § 42.104(a)); PROCEDURAL
`STATEMENTS
`
`Petitioner certifies that (1) the '740 patent is available for inter partes review;
`
`and (2) Petitioner is not barred or estopped from requesting inter partes review of
`
`any claim of the '740 patent on the grounds identified in this Petition. This Petition
`
`is filed in accordance with 37 CFR § 42.106(a). Concurrently filed herewith is a
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`Power of Attorney and an Exhibit List per § 42.10(b) and § 42.63(e), respectively.
`
`The required fee is paid via online credit card payment. The Office is authorized to
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`charge fee deficiencies and credit overpayments to Deposit Acct. No. 19-0036
`
`(Customer ID No. 45324).
`
`IV.
`
`3BMANDATORY NOTICES (37 C.F.R. § 42.8(a)(1))
`Each Real Party-In-Interest (37 C.F.R. § 42.8(b)(1)) is: Amneal
`
`Pharmaceuticals, LLC and Amneal Pharmaceuticals Co. (I) Pvt. Ltd.
`
`
`
`3
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`

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`
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`IPR of USPN 8,206,740
`
`Petitioner Provides Notice of Related Matters (37 C.F.R. § 42.8(b)(2)):
`
`Supernus Laboratories Inc.; Supernus Laboratories, L.P.; and Supernus
`
`Pharmaceuticals,
`
`Inc. v. Amneal Pharmaceuticals, LLC and Amneal
`
`Pharmaceuticals Co. (I) PVT, LTD, C.A. No. 11-1106-LPS (D. Del.) ("the '740
`
`patent litigation.")
`
`Designation of Lead and Back-Up Counsel (37 C.F.R. § 42.8(b)(3)):
`
`Lead Counsel
`Eldora L. Ellison (Reg. No. 39,967)
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`1100 New York Avenue, NW
`Washington, DC 20005
`202.772.8508 (telephone)
`202.371.2540 (facsimile)
`eellison-PTAB@skgf.com
`
`
`Back-Up Counsel
`Jonathan Tuminaro (Reg. No. 61,327)
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`1100 New York Avenue, NW
`Washington, DC 20005
`202.772.8967 (telephone)
`202.371.2540 (facsimile)
`jtumarino@skgf.com
`
`Notice of Service Information (37 C.F.R. § 42.8(b)(4)): Please direct all
`
`correspondence regarding this Petition to lead counsel at the above address.
`
`Petitioner consents to service by email at: eellison-PTAB@skgf.com and
`
`jtumarino@skgf.com.
`
`V.
`
`4BSTATEMENT OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFOR (37 C.F.R. § 42.22(a))
`
`Petitioner requests IPR and cancellation of claims 1, 2, 5-15 and 19-22.
`
`Petitioner's full statement of the reasons for the relief requested is set forth in detail
`
`in § VIII below.
`
`
`
`4
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`

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`IPR of USPN 8,206,740
`
`VI.
`
`5BCLAIM CONSTRUCTION
`
`In accordance with 37 C.F.R. § 42.100(b), the challenged claims must be
`
`given their broadest reasonable interpretations ("BRI") in light of the specification
`
`of the '740 patent.
`
`The '740 patent explicitly defines the terms "about" and "immediate release."
`
`(AMN 1001, 3:66 to 4:11.) The BRI of these terms therefore encompasses at least
`
`the definitions in the '740 patent.
`
`Amneal and Supernus have submitted a Joint Claim Construction Chart in
`
`the '740 patent litigation, construing "steady state blood level(s) of doxycycline" to
`
`mean "steady state plasma concentration(s) of doxycycline." (AMN 1023, p. 2)
`
`This is the BRI of this term.
`
`The BRI of the term "pellet" in claim 6 of the '740 patent is "bead or beadlet,
`
`but excluding a granule, tablet, powder, sachet, capsule, gel, dispersion or
`
`suspension." The term "pellets" in claims 7 and 10 of the '740 patent is construed
`
`to mean a plurality of such beads or beadlets. All other terms of all challenged
`
`claims are presumed to take on their ordinary and customary meanings.
`
`VII. 6BPERSON OF SKILL IN THE ART & STATE OF THE ART
`A person of ordinary skill in the art is presumed to be aware of all pertinent
`
`art, thinks along conventional wisdom in the art, and is a person of ordinary
`
`creativity. With respect to the '740 patent, a person of ordinary skill in the art
`
`
`
`5
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`

`

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`
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`IPR of USPN 8,206,740
`
`would have education and experience in drug delivery and formulation. The
`
`education and experience levels may vary between persons of ordinary skill, with
`
`some persons holding a Bachelor's degree with many years of experience and
`
`others holding higher degrees but having less work experience. A person of
`
`ordinary skill in the art would have knowledge and skill relating to the use,
`
`function, and formulation of pharmaceutical excipients; knowledge and training
`
`regarding the equipment, processes and techniques used to analyze and test
`
`formulation materials; and an understanding of pharmacokinetic principles and
`
`how they relate to drug development. Such a person would have specific
`
`experience with modified release drug systems.
`
`A person of ordinary skill typically would work as part of a multi-
`
`disciplinary team and draw upon not only his or her own skills, but also take
`
`advantage of certain specialized skills of others in the team, to solve a given
`
`problem. For example, a clinician may be part of the team.
`
`As of the EPD, compositions with an IR portion and a DR portion having
`
`doxycycline at the claimed amounts, and achieving the claimed steady state blood
`
`levels, were well known. (AMN 1002; AMN 1004.) Doxycycline was also known
`
`to be long-lasting (AMN 1017), obviating the need for a sustained release
`
`component in a controlled release formulation. It was also well known that such
`
`compositions were useful in treating rosacea. (AMN 1002 and AMN 1018.)
`
`
`
`6
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`

`

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`
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`IPR of USPN 8,206,740
`
`Further, an embodiment of AMN 1002, Periostat®, a 20 mg IR formulation given
`
`twice daily, was used to treat rosacea before the EPD. (AMN 1012). The prior art
`
`also disclosed once-daily formulations of minocycline, and it disclosed using that
`
`tetracycline in a narrow range of IR:DR ratios that subsumes the recited IR:DR
`
`ratio. (AMN 1005.) It was also well known that minocycline is a tetracycline
`
`having comparable structure, function and utility to doxycycline. (AMN 1017.)
`
`As evidenced by the references described herein, at least as of April 7, 2003,
`
`the EPD of the '740 patent, the subject matter claimed in claims 1, 2, 5-15 and 19-
`
`22 was well known to a POSA.
`
`VIII. 7BIDENTIFICATION OF CHALLENGE (37 C.F.R. § 42.104(b))
`IPR of the challenged claims of the '740 patent is requested on the grounds
`
`for unpatentability listed in the index below. Per 37 C.F.R. § 42.6(d), copies of the
`
`references are filed herewith. In support of
`
`the proposed grounds for
`
`unpatentability, this Petition is accompanied by a declaration of technical expert
`
`Dr. Glenn A. Van Buskirk (AMN 1022), which explains what the prior art would
`
`have conveyed to a POSA.
`
`Ground 35 U.S.C. (pre-
`March 16, 2013)
`§103
`§103
`
`1
`2
`
`3
`
`§103
`
`Index of Reference(s)
`
`'932 appl.
`'932 appl. in view of '748
`patent
`'106 appl. in view of '748
`patent
`
`'740 Patent
`Claims
`1, 2, 5-15, 19-22
`1, 2, 5-15, 19-22
`
`1, 2, 5-15, 22
`
`
`
`7
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`
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`

`

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`IPR of USPN 8,206,740
`
`4
`
`§103
`
`'106 appl. in view of '748
`patent and Webster
`
`19-21
`
`Claims 1 and 19 are the two independent claims of the '740 patent addressed
`
`in this Petition. The grounds for unpatentability of each independent claim will be
`
`addressed in turn before addressing the unpatentability of the dependent claims or
`
`any possible objective indicia of nonobviousness.
`
`Claim 1 is directed to a well-known and unpatentable oral pharmaceutical
`
`composition of doxycycline. The limitations of claim 1's dependent claims do not
`
`confer patentability on those compositions. Claim 19 is directed to a well-known
`
`and unpatentable method of treating rosacea using the composition of claim 1.
`
`Likewise, the additional limitations of the claims that depend from claim 19 also
`
`do not confer patentability on those methods.
`
`A.
`
`9BGround 1: Independent Claims 1 and 19 Would Have Been
`Obvious in View of the '932 publication, which incorporates the
`'854 Application by reference
`
`International Application Number PCT/US02/10747 to Robert A. Ashley,
`
`titled "Methods of Treating Acne" published on October 17, 2002, and was
`
`assigned International Publication Number WO 02/080932 ("the '932 publication")
`
`(AMN 1002). The '932 publication qualifies as prior art to the '740 patent under 35
`
`U.S.C. § 102(a) because it published before April 7, 2003, the EPD of the '740
`
`patent. This reference also qualifies as prior art under 35 U.S.C § 102(e)(1)
`
`because it is an English language publication of an international application
`
`
`
`8
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`

`

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`
`
`IPR of USPN 8,206,740
`
`(PCT/US02/10747) by another designating the United States, filed on April 5,
`
`2002, before the EPD of the '740 patent. The '932 publication claims priority to US
`
`Appl. No. 60/281,916, which also qualifies as prior art under 35 U.S.C. § 102(e).
`
`The '932 incorporates by reference, in its entirety, U.S. Appl. No.
`
`60/281,854, filed April 5, 2001, titled "Controlled Delivery of Tetracycline and
`
`Tetracycline Derivatives" ("the '854 application") (AMN 1003). (AMN 1002,
`
`15:23-30 and AMN 1022, ¶10-41) See, e.g., Hollmer v. Harari, 681 F.3d 1351,
`
`1353 (Fed. Cir. 2010) ("It is not inappropriate for an application to identify for the
`
`purposes of incorporation by reference a co-pending application by title, inventors,
`
`and a context-specific filing date, where such information is sufficient to identify
`
`the application at the time the information is presented. 37 C.F.R. § 1.57(g)(2).").
`
`As shown by the following claim chart and discussion herein, a POSA
`
`reading the
`
`'932 publication would have immediately envisaged the oral
`
`pharmaceutical formulation of claim 1. AMN 1022, ¶67-74. And even if a POSA
`
`would not have immediately envisaged the claimed subject matter, given the
`
`teachings of the '932 publication, a POSA would have arrived at the composition
`
`of claim 1 using only routine experimentation. In re Aller, 220 F.2d 454, 456,
`
`(CCPA 1955) "[W]here the general conditions of a claim are disclosed in the prior
`
`art, it is not inventive to discover the optimum or workable ranges by routine
`
`experimentation."; see In re Peterson, 315 F.3d 1325, 1330 (Fed. Cir. 2003) ("The
`
`
`
`9
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`

`

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`
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`IPR of USPN 8,206,740
`
`normal desire of scientists or artisans to improve upon what is already generally
`
`known provides the motivation to determine where in a disclosed set of percentage
`
`ranges is the optimum combination of percentages.").
`
`'740 patent claim 1
`
`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,
`
`Disclosure in '932 publication (AMN 1002), which
`incorporates the '854 application (AMN 1003)
`"For example, the tetracyclines [sic] compounds can be
`administered orally by any method known in the art"
`(AMN 1002, 14:14-15.)
`1
`
`0F
`
`"The method comprises the administration of a
`tetracycline compound to a human…." (AMN 1002,
`7:15-16. Some examples of antibiotic … tetracycline
`compounds include doxycycline…." (AMN 1002, 7:24-
`25. )
`
`"In a preferred embodiment, the tetracycline is
`doxycycline." (AMN 1003, 5:21.)
`"Some examples of the plasma antibiotic threshold levels
`of tetracyclines based on steady-state
`pharmacokinetics are as follows: 1.0 g/ml for
`doxycycline; 0.8 g/ml for minocycline; and 0.5 g/ml
`for tetracycline." (AMN 1002, 11:1-3.)
`
`"For example, doxycycline is administered in an amount
`which results in a serum concentration between about
`0.1 and 0.8 g/ml, more preferably between 0.4 and 0.7
`g/ml." (AMN 1002, 10:25-29.)
`
`"wherein said doxycycline is administered in an amount
`which provides a serum concentration in the range of
`about 0.1 to about 0.8 g/ml." (AMN 1002:55, claim
`19. )
`
`
`
`1 As used herein, boldface type in claim charts is added emphases.
`
`
`
`10
`
`
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`

`

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`IPR of USPN 8,206,740
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`"In general, the blood serum level [of tetracycline] will
`be between about 0.1 and 1.0 µg/ml …" (AMN 1003,
`5:17-20.)
`
`"The preferred blood serum level of doxycycline is 0.4-
`0.8 µg/ml[] over a period of 12-24 hours." (AMN 1003,
`5:21-22.)
`
`"In a preferred embodiment, to reduce the number of
`comedones, doxycycline is administered in a daily
`amount…" (AMN 1002, 9:17-18.)
`
`"In general, the blood serum level will be between
`about 0.1 and 1.0 µg/ml..." (AMN 1003, 5:17.)
`"For example, 40 milligrams of doxycycline may be
`administered by sustained release over a 24 hour period."
`(AMN 1002, 16:1-2.)
`
`"The composition also can include a controlled-release
`agent selected from the group consisting of an
`instantaneous-release agent, a sustained-release agent,
`a delayed-release agent, and combinations thereof."
`(AMN 1003, 5:24-28.)
`
`"It is preferred that at least 50%, more preferably
`greater than 80% of the tetracycline in the
`composition be released in the upper GI tract."
`(AMN 1003, 16:12-14.)
`"For the pharmaceutical purposes described above, the
`tetracycline compounds of the invention can be
`formulated per se in pharmaceutical preparations
`optionally with a suitable pharmaceutical carrier
`(vehicle) or excipient as understood by practitioners in
`the art. " (AMN 1002, 14:25-29.)
`
`"The composition of the invention can also include a
`combination of the tetracycline compound in a
`suitable pharmaceutical carrier (vehicle) or excipient
`as understood by practitioners in the art." (AMN 1003,
`9:24-26.)
`
`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.
`
`
`
`11
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`

`

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`
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`IPR of USPN 8,206,740
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`Claim 1: The '932 publication discloses orally administering tetracycline
`
`compounds, an example of which is doxycycline. (AMN 1002, 14:14-15 and
`
`AMN 1022, ¶67-68.) The '932 publication further discloses that when the
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`compositions are administered once a day, the controlled release composition
`
`provides a blood level of between about 0.1 and 1.0 µg/ml. (AMN 1003, 5:17-20
`
`and AMN 1022, ¶68.) The '932 also discloses a steady state plasma threshold level
`
`of between 0.1 µg/ml and 1.0, and specifically 1.0 µg/ml for doxycycline. (AMN
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`1002, 11:1-3) and AMN 1022, ¶69.)
`
`The
`
`'932 publication discloses
`
`the once-daily administration of 40
`
`milligrams of doxycycline over time. (AMN 1002, 16:1-2 and AMN 1022, ¶68.)
`
`The '932 publication discloses various compositions of various formulations,
`
`including compositions that include an instantaneous-release agent (i.e., an
`
`immediate release (IR) agent), a sustained-release agent, a delayed-release (DR)
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`agent, and combinations thereof. (AMN 1003, 5:24-28 and AMN 1022, ¶70.)
`
`Given this teaching and knowledge of those of skill in the art, a POSA would have
`
`formulated a controlled release composition of doxycycline with only IR and DR
`
`components (no sustained release component) because of (i) the general
`
`understanding in the art that doxycycline is a long-lasting drug (i.e., it has no need
`
`for a sustained release component) (AMN 1017, p. 1242, col. 1.); (ii) the '932
`
`publication's disclosure that sub-antimicrobial effects can be achieved with two
`
`
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`12
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`IPR of USPN 8,206,740
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`low doses (20 mg) of doxycycline (AMN 1002, 9: 12-15); and (iii) the disclosure
`
`of a preference for a greater amount of doxycycline in the IR component in the
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`'932 publication. (AMN 1003, 16:12-14.) The '932 publication therefore discloses
`
`a composition having 40 milligrams of doxycycline that has an IR portion and a
`
`DR portion. (AMN 1022, ¶68).
`
`The '932 publication also discloses that, preferably, at least half of the
`
`tetracycline should be released in the upper GI tract, i.e., be released immediately.
`
`(AMN 1003, 16:12-14 and AMN 1022, ¶74.) In a composition containing both an
`
`IR and DR component, this means that the ratio of IR:DR is at least 50:50. (AMN
`
`1022, ¶74).
`
`As confirmed by Dr. Van Buskirk, an expert in drug delivery and
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`formulation, the '932 publication therefore specifically directs one of skill in the art
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`to a preferred set of ratios, which includes the ratio recited in claim 1 of the '740
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`patent. (AMN 1022, ¶74.) Given the '932 publication's disclosure of an IR:DR
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`ratio of at least 50:50, a person of skill in the art would have immediately
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`envisaged each of the following IR:DR ratios: 50:50, 55:45, 60:40, 65:35, 70:30,
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`75:25, 80:20, 85:5, 90:10, and 95:5, because 5 and 10 percent increments are
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`common increments of ratios for drug formulation. (AMN 1022, ¶74.) Therefore, a
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`POSA would have immediately envisaged the claimed ratio upon reading the '932
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`publication. (Id.)
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`IPR of USPN 8,206,740
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`Considering the 40 mg dose of doxycycline and the desirable IR to DR ratios
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`(such as 50:50) disclosed in the '932 publication, POSA would have understood
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`that the IR component may comprise 20 mg to 40 mg doxycycline and the DR
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`component may comprise 0 mg to 20 mg doxycycline. (AMN 1022, ¶75) For
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`example, in a 40 mg dose of doxycycline, an IR:DR ratio of 50:50 would consist of
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`20 mg doxycycline in the IR portion and 20 mg doxycycline in the DR portion.
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`(Id.) Likewise, an IR:DR ratio of 80:20 would consist of 32 mg doxycycline in the
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`IR portion and 8 mg doxycycline in the DR portion; and an IR:DR ratio of 75:25
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`would consist of 30 mg doxycycline in the IR portion and 10 mg doxycycline in
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`the DR portion. (Id.) A POSA would have understood that all of these IR:DR
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`ratios are disclosed in the
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`'932 publication because these are common,
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`immediately-envisaged increments of ratios for drug formulations. (Id.)
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`But even if a POSA would not have immediately envisaged the claimed
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`ratio, the '932 publication still renders claim 1 prima facie obvious because the
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`claimed ratio would have been arrived at using routine experimentation. (Id., ¶76.)
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`As explained, the '932 discloses a range of IR:DR ratios, i.e., 50:50 to 95:5,
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`and the claimed IR:DR ratio lies within that ratio range. In the case where the
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`claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima
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`facie case of obviousness exists. In re Wertheim, 541 F.2d 257 (CCPA 1976); In re
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`Woodruff, 919 F.2d 1575 (Fed. Cir. 1990) (The prior art taught carbon monoxide
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`IPR of USPN 8,206,740
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`concentrations of "about 1-5%" while the claim was limited to "more than 5%."
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`The court held that "about 1-5%" allowed for concentrations slightly above 5% and
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`thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71 (Fed. Cir.
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`1997) (Claim reciting thickness of a protective layer as falling within a range of
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`"50 to 100 Angstroms" considered prima facie obvious in view of prior art
`
`reference teaching that "for suitable protection, the thickness of the protective layer
`
`should be not less than about 10 nm [i.e., 100 Angstroms]." The court reasoned
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`that "by stating that 'suitable protection' is provided if the protective layer is 'about'
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`100 Angstroms thick, [the prior art reference] directly teaches the use of a
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`thickness within [applicant's] claimed range.").
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`Using similar reasoning, the CAFC invalidated a claim reciting a specific
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`ratio of two compounds. Merck v. Biocraft, 874 F.2d 804 (Fed Cir. 1989). In
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`Merck, the claim recited a composition for oral administration which comprises 5
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`mg of compound A, and 50 mg of compound B. Id. at 807. Although the art taught
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`"a multitude of effective compound combinations," the CAFC found that such
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`disclosure does not render any particular formulation less obvious. Id. Merck (the
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`patent holder) argued, unsuccessfully, that the claimed invention as a whole was
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`not obvious because of the recited dosage limitations. Id. at 809. The CAFC
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`found that only routine experimentation was needed to arrive at the claimed
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`dosages: "[r]eached by means of routine procedures, and producing only
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`IPR of USPN 8,206,740
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`predictable results, the recited dosages therefore do not distinguish the claims of
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`the [patent at issue]" from the prior art combination." Id.
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`Similarly, the '932 publication discloses an oral composition having
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`doxycycline in an IR portion and a DR portion. And the '932 publication discloses
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`ratio ranges that encompass the claimed ratio, which is even more than the
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`invalidating art disclosed in Merck. Controlling case law therefore dictates a
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`finding of prima facie obviousness of claim 1 based on the '932 publication.
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`A finding of obviousness might be avoided by showing the criticality of the
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`claimed ratio, i.e., that the ratio is "unexpectedly good." Id. But there is no
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`evidence in the '740 patent or its file history of any criticality of an IR portion
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`comprising 30 mg doxycycline and a DR portion comprising 10 mg doxycycline as
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`claimed. (AMN 1022, ¶77.) In fact, the '740 patent supports a finding that the
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`claimed doxycycline ratio is not critical. (AMN 1022, ¶77.) In the '740 patent
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`specification, Supernus admits that formulations that fall outside of claim 1
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`provide blood levels within the recited range. (AMN 1001, Fig. 4.) For example,
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`all of the following formulations provide blood levels within the recited range: (a)
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`40 mg once-a-day IR formula, (b) IR:DR combinations at 70:30 and 80:20 ratios,
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`and (c) 20 mg IR twice daily. (Id.) So a variety of compositions achieve the blood
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`levels recited in the claims, and there is no evidence of the criticality of the
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`claimed formulation.
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`IPR of USPN 8,206,740
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`As confirmed by Dr. Van Buskirk, a POSA would have had a reasonable
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`expectation of success in formulating doxycycline as claimed. (AMN 1022, ¶79.)
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`A POSA would have had a reasonable expectation of success in preparing and
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`using the claimed doxycycline formulation using the doxycycline formulations of
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`the '932 publication because the '932 publication discloses formulations that (i) are
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`oral, once-daily dosages; (ii) achieve the desired steady state blood levels for sub-
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`antimicrobial beneficial effects; (iii) comprise IR and DR portions (each containing
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`doxycycline) in an IR:DR ratio that falls within the claim; and (iv) include
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`pharmaceutically acceptable excipients. (Id.) Therefore, Petitioner has made a
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`prima facie showing of obviousness of claim 1 with respect to Ground 1.
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`Claim 19: Independent claim 19 is directed to a method for treating rosacea
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`by administering an oral composition of doxycycline having the features of the
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`composition of claim 1. The '932 publication would have rendered such a method
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`prima facie obvious.
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`The oral pharmaceutical composition recited in claim 19 has the same
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`limitations as the oral pharmaceutical composition of claim 1. And, as detailed
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`below, the '932 publication discloses a method of administering 40 mg of
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`doxycycline once-daily for the treatment of rosacea. (AMN 1022, ¶130). Thus, the
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`analysis of claim 1 also applies to claim 19.
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`Claim 19 contains the following additional claim element compared to
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`claim 1:
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`IPR of USPN 8,206,740
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` A method for treating rosacea in a mammal in need thereof,
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`comprising administering an oral pharmaceutical composition of
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`doxycycline.
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`The '932 publication, which incorporates the '854 application, discloses this
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`claim element and renders claim 19 obvious:
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` “A method of treating acne in a human in need thereof comprising
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`adminestering [sic] systemically
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`to said human a
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`tetracycline
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`compound.…" (AMN 1002, Abstract.) Doxycycline is a preferred
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`tetracycline. (AMN 1002, 7:27-28.)
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` "The present invention provides methods of treating acne…. For the
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`purposes of this specification, acne includes all known types of
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`acne. Some types of acne include, for example…acne rosacea."
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`(AMN 1002, 6:34 to 7:4.)
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` Example 38 of the '932 patent discloses the effects of doxycycline
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`hyclate 20 mg (Dermastat) tablets administered twice daily for the
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`treatment of moderate acne. (AMN 1002, 33:1.)
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`The '932 publication discloses methods of treating acne rosacea with
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`doxycycline. (AMN 1002, 6:34 – 7:4; AMN 1022, ¶135.) As explained above, the
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`'932 publication also discloses oral pharmaceutical compositions of doxycycline
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`IPR of USPN 8,206,740
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`that achieve steady state blood levels of a minimum of 0.1 µg/ml and a maximum
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`of 1.0 µg/ml. (AMN 1002, 10:27-29; AMN 1022, ¶135.) The '932 publication
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`discloses that doxycycline dosages achieving such steady state blood levels of
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`doxycycline provide beneficial sub-antimicrobial effects, e.g., an effective amount
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`of drug to treat rosacea. (AMN 1002, 5:17-21; AMN 1022, ¶137.) As discussed
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`above, a POSA would have understood that the 40 mg dose disclosed in the '932
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`publication is an effective amount to achieve steady state blood levels of a
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`minimum of 0.1 µg/ml and a maximum of 1.0 µg/ml of doxycycline.
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`A POSA would have had a reasonable expectation of success in practicing
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`the claimed method of treating rosacea because the '932 publication discloses
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`formulations that (i) are oral, once-daily dosages; (ii) achieve the desired steady
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`state blood levels; (iii) comprise IR and DR portions (each containing doxycycline)
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`in an IR:DR ratio that falls within the claim; (iv) include pharmaceutically
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`acceptable excipients; and (v) are useful for the treatment of rosacea in mammals.
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`(AMN 1022, ¶147.)
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`B.
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`10BGround 2: Independent Claims 1 and 19 Would Have Been
`Obvious Over the '932 publication in View of the '748 Patent
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`Even if a POSA would not have immediately envisaged claim 1's IR:DR
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`ratio, or arrived at it through routine experimentation based on the '932 publication
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`alone, claim 1 is nonetheless unpatentable for obviousness over the '932
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`publication in view of the '748 patent. The '748 patent is directed to once-daily
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`