UNITED STATES PATENT AND TRADEMARK OFFICE
`________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________
`
`AGILA SPECIALTIES INC. and MYLAN PHARMACEUTICALS INC.
`Petitioners
`
`v.
`
`CUBIST PHARMACEUTICALS, INC.
`Patent Owner
`
`________________________
`
`Case IPR 2015-00132
`________________________
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 6,852,689
`
`
`________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________
`
`AGILA SPECIALTIES INC. and MYLAN PHARMACEUTICALS INC.
`Petitioners
`
`v.
`
`CUBIST PHARMACEUTICALS, INC.
`Patent Owner
`
`________________________
`
`Case IPR 2015-00132
`________________________
`
`PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 6,852,689
`
`
`
`TABLE OF CONTENTS
`I.
`INTRODUCTION .......................................................................................... 1
`
`A.
`
`B.
`
`Overview of the ʼ689 Patent ................................................................. 1
`
`Brief Overview of the Prosecution History.......................................... 2
`
`II.
`
`GROUNDS FOR STANDING - § 42.104(a)................................................. 3
`
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8.................................. 4
`
`A.
`
`B.
`
`C.
`
`Real Party in Interest ............................................................................ 4
`
`Related Matters..................................................................................... 4
`
`Lead and Backup Counsel and Service Information............................ 4
`
`IV.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED FOR
`
`EACH CLAIM CHALLENGED.................................................................... 5
`
`A.
`
`B.
`
`Identification of the Challenge - § 42.104(b)....................................... 5
`
`Statement of Non-Redundancy ............................................................ 6
`
`V.
`
`LEVEL OF ORDINARY SKILL IN THE ART............................................ 7
`
`VI. CLAIM CONSTRUCTION ........................................................................... 7
`
`VII. SCOPE AND CONTENT OF THE PRIOR ART........................................ 10
`
`A.
`
`B.
`
`U.S. Patent No. 5,912,226 to Baker (“Baker ʼ226,” Ex. 1006) ......... 10
`
`Kennedy, Antimicrob. Agents and Chemother. 1989 Sept. p.
`
`1522-1525 (Ex. 1007) ........................................................................ 12
`
`i
`
`
`
`A. Woodworth et al, Antimicrob Agent Chemother. 1992, 36:318-
`
`25 (Ex. 1009)...................................................................................... 12
`
`C.
`
`Rybak et al, Antimicrob. Agent Chem. 1992, 36:1109-14 (Ex.
`
`1008)................................................................................................... 13
`
`D.
`
`Van der Auwera, Antimicrob. Agents Chemother. 1992 Oct.
`
`33:1783-90 (Ex. 1010) ....................................................................... 13
`
`VIII. EACH GROUND OF UNPATENTABILITY DEMONSTRATES A
`
`REASONABLE LIKELIHOOD OF PREVAILING AGAINST THE
`
`CHALLENGED CLAIMS OF THE ‘689 PATENT ................................... 14
`
`A.
`
`B.
`
`State of the Art Prior to September 1998........................................... 14
`
`Ground 1: Claims 1-5, 10-12, 14-18, 21-30, 32, 33 and 36-57
`
`of the ʼ689 patent are obvious in view of Baker (Ex. 1006),
`
`Kennedy (Ex. 1007), and Woodworth (Ex. 1009) ............................. 19
`
`C.
`
`Ground 2: Claims 6-9 of the ʼ689 patent are obvious in view of
`
`Baker (Ex. 1006), Kennedy (Ex. 1007), Woodworth (Ex. 1009)
`
`and Van der Auwera (Ex. 1010)......................................................... 36
`
`D.
`
`Ground 3: Claims 1-5, 10-12, 14-18, 21-30, 32, 33 and 36-57
`
`of the ʼ689 patent are obvious in view of Baker (Ex. 1006),
`
`Kennedy (Ex. 1007), and Rybak (Ex. 1008)...................................... 38
`
`ii
`
`
`
`E.
`
`Ground 4: Claims 6-9 of the ʼ689 patent are obvious in view of
`
`Baker (Ex. 1006), Kennedy (Ex. 1007), Rybak (Ex. 1008) and
`
`Van der Auwera (Ex. 1010) ............................................................... 51
`
`IX. CONCLUSION............................................................................................. 54
`
`X.
`
`PAYMENT OF FEES UNDER 37 C.F.R. §§ 42.15(a) AND 42.103.......... 55
`
`iii
`
`
`
`I.
`
`INTRODUCTION
`Pursuant to the provisions of 35 U.S.C. § 311, § 6 of the Leahy-Smith
`
`America Invents Act (“AIA”), and 37 C.F.R. Part 42, Agila Specialties Inc. (f/k/a
`
`Strides, Inc.) and Mylan Pharmaceuticals Inc. (collectively, “Petitioners”)
`
`respectfully request inter partes review of claims 1-12, 14-18, 21-30, 32, 33, 36-57
`
`(“the challenged claims”) of U.S. Patent No. 6,852,689 (“the ʼ689 patent,” Ex.
`
`1001) to Cubist Pharmaceuticals, Inc. Through this Petition, Petitioners
`
`demonstrate that, by a preponderance of the evidence, there is a reasonable
`
`likelihood that the challenged claims of the ʼ689 patent are unpatentable over the
`
`prior art. The challenged claims should be found unpatentable and canceled.
`Concurrently herewith Petitioners are filing a Petition for Inter Partes review of
`
`Patent No. 6,468,967 (“the ʼ967 patent,” Ex. 1002), from which the ʼ689 is a
`
`continuation, and over which the ʼ689 is terminally disclaimed.
`
`Overview of the ʼ689 Patent
`A.
`Daptomycin is an antibiotic that was discovered in the early 1980s by
`
`scientists at Eli Lilly and Company (Lilly). It was developed by Lilly as a drug for
`
`intravenous injection for the treatment of serious Gram-positive bacterial
`
`infections. Ex. 1001. Phase I and II clinical studies involving several hundred
`
`humans were conducted by Lilly in the 1980s and early 1990s. The results were
`
`regarded as highly encouraging, particularly with serious skin and soft tissue
`
`infections. A variety of dosing protocols were employed, and the drug was
`
`considered well tolerated when given intravenously to individuals at 1 or 2 mg/kg
`
`every 24 hours. Ex. 1001, col. 1, ll. 65 to col. 2, l. 3, citing Ex. 1009. The ʼ689
`
`1
`
`
`
`reports that doses even higher than those of the Phase II clinical trials were
`
`conducted, though in some cases a mild reversible skeletal muscle effect was
`
`reported. Ex. 1001, col. 1, ll. 4-8.
`
`In September, 1999, Cubist filed the application which matured into the ʼ967
`
`patent, serial no. 09/406,568 (“the ʼ568 application”). The ʼ967 patent claimed the
`
`benefit of provisional applications filed in September, 1998, and March, 1999.
`
`Although the presently challenged claims are not believed to be entitled to the
`
`benefit of the provisional applications, for the present Petition a challenge to
`
`benefit is not necessary to establish the obviousness of the claims. Petitioner
`
`reserves the right to do so if benefit becomes relevant in a subsequent aspect of this
`
`proceeding.
`
`The ʼ689 patent claims recite methods of administering daptomycin to a
`
`human patient. The claims recite particular terms for practicing the methods, such
`
`as a dose of 3 to 75 mg/kg where the dose is repeated once every 48 hours to once
`
`weekly (independent claims 1 and 27), or every 48 hours (independent claim 47).
`
`The three independent claims also recite an intended result of those terms, such as
`
`intervals that “minimize skeletal muscle toxicity,” but this intended result is non-
`
`limiting and does not result in a manipulative difference in the steps of the claims.
`
`See Ex. 1003, ¶¶9-16.
`
`Brief Overview of the Prosecution History
`B.
`The ʼ689 patent, entitled Methods for Administration of Antibiotics,
`
`resulting from Application No. 10/082,544, was filed February 20, 2002, as a
`
`continuation from application 09/406,568, which matured into the ʼ967 patent.
`
`2
`
`
`
`The ʼ689 patent was assigned on its face to Cubist Pharmaceuticals, Inc. As with
`
`the ʼ967 patent, prosecution was relatively compact – a first Office action (Ex.
`
`1005, pp.0119-0128), which included an obviousness-type double patenting
`
`rejection over the ‘967 patent, responded to by an amendment. Ex. 1005, pp.0096-
`
`0117. Arguments made accompanying the amendment included efforts to
`
`distinguish the Kennedy reference (Ex. 1007). These arguments included an
`
`interpretation of Kennedy’s dosage in the rabbit model (Ex. 1005, p. 0104), which
`
`interpretation had also been argued during prosecution of the ‘967 patent. During
`
`prosecution of the ‘967 patent, the arguments were supported by a self-serving
`
`declaration from inventor Oleson under Rule 1.132 (Oleson being a senior
`
`executive of the assignee at the time). See Ex. 1023, at pp. 0121-0131; see also
`
`Ex. 1003, ¶¶29-30. A second (final) Office action (Ex.1005, pp.0091-0095)
`
`followed, with a Request for Continued Examination and an amendment of the
`claims. Id., 0082-0090. Shortly thereafter another non-final Office action issued.
`
`Id., pp. 0073-0076. In response, a Terminal Disclaimer was filed (Id., p. 0070),
`
`then an Amendment (Ex. 1005, pp.0058-0068). Notices of Allowability and
`
`Allowance ensued. Ex. 1005, p. 0030-0036. The ʼ689 patent issued Feb. 8, 2005.
`
`II. GROUNDS FOR STANDING - § 42.104(a)
`Petitioner certifies pursuant to 37 C.F.R. § 42.104(a) that the patent for
`which review is sought is available for inter partes review and that the Petitioner is
`
`not barred or estopped from requesting an inter partes review challenging the
`
`patent claims on the grounds identified in this Petition.
`
`3
`
`
`
`III. MANDATORY NOTICES UNDER 37 C.F.R. § 42.8
`A.
`Real Party in Interest
`In accordance with 37 C.F.R. § 42.8(b)(1), Petitioners identify Agila
`
`Specialties Inc. (f/k/a Strides, Inc.) and Mylan Pharmaceuticals Inc. as both
`
`Petitioners and Real Parties-in-Interest. Additionally, Agila Specialties Private
`
`Limited, Mylan Laboratories Limited, Mylan Institutional Inc., and Mylan Inc. are
`
`Real Parties-in-Interest.
`
`Related Matters
`B.
`In accordance with 37 C.F.R. § 42.8(b)(2), Petitioners identify the pending
`action styled Cubist Pharmaceuticals, Inc. v. Strides, Inc. and Agila Specialties
`Private Limited, Case No. 13-cv-1679-GMS, filed by Cubist Pharmaceuticals, Inc.
`
`on October 9, 2013, D.I. 1, Delaware Complaint, Ex. 1024, served on Strides, Inc.
`
`and Agila Specialties Private Limited on October 23, 2013, D.I. 6,Service of
`
`Strides, Inc., Ex. 1025, D.I. 7, Service of Agila Specialties Private Limited, Ex.
`
`1026, in the United States District for the District of Delaware; and the dismissed
`action styled Cubist Pharmaceuticals, Inc. v. Strides, Inc. and Agila Specialties
`Private Limited, Case No. 13-cv-06016-NLH, filed by Cubist Pharmaceuticals,
`
`Inc. on October 9, 2013, D.I. 1, New Jersey Complaint, Ex. 1027, in the United
`
`States District for the District of New Jersey, and voluntarily dismissed without
`
`prejudice on October 24, 2013, D.I. 8, New Jersey Dismissal, Ex. 1028.
`
`Lead and Backup Counsel and Service Information
`C.
`The service information requested under 37 C.F.R. § 42.8(b)(4) is identified
`
`below. Petitioners hereby consent to electronic service.
`
`4
`
`
`
`Lead Counsel
`
`Backup Counsel
`
`Backup Counsel
`
`Steven W. Parmelee
`
`Peter R. Munson, Esq.
`
`Lori P. Westin
`
`USPTO Reg. No. 31,990
`
`USPTO Reg. No. 43,821
`
`USPTO Reg. No. 52,353
`
`Tel.: 206- 883-2542
`
`Tel.: 858-350-2312
`
`Tel.: 858-350-2225
`
`Fax: 206- 883-2699
`
`Fax: 858-350-2399
`
`Fax: 858-350-2399
`
`Wilson Sonsini Goodrich
`
`Wilson Sonsini Goodrich
`
`Wilson Sonsini Goodrich
`
`& Rosati PC
`
`& Rosati PC
`
`& Rosati PC
`
`701 Fifth Avenue
`
`12235 El Camino Real
`
`12235 El Camino Real
`
`Suite 5100
`
`Suite 200
`
`Suite 200
`
`Seattle, WA 98104-7036
`
`San Diego, CA 92130
`
`San Diego, CA 92130
`
`Email:
`
`Email:
`
`Email:
`
`sparmelee@wsgr.com
`
`pmunson@wsgr.com
`
`lwestin@wsgr.com
`
`IV.
`
`STATEMENT OF THE PRECISE RELIEF REQUESTED FOR EACH
`CLAIM CHALLENGED
`A.
`Identification of the Challenge - § 42.104(b)
`
`Petitioner challenges claims 1-12, 14-18, 21-30, 32, 33, 36-57 of the ʼ689
`
`patent, and requests review of those claims under 35 U.S.C. § 311 and AIA § 6.
`
`Petitioner’s grounds of challenge are that each of the claims 1-12, 14-18, 21-30,
`
`32, 33, 36-57 should be canceled as invalid and unpatentable as follows:
`
`Ground Claims
`
`Description
`
`1
`
`1-5, 10-12, 14-18,
`
`§103(a) Obvious over Baker ʼ226, Kennedy and
`
`21-30, 32, 33 and
`
`Woodworth
`
`36-57
`
`5
`
`
`
`2
`
`3
`
`4
`
`6-9
`
`§103(a) Obvious over Baker ʼ226, Kennedy,
`
`Woodworth and Van der Auwera
`
`1-5, 10-12, 14-18,
`
`§103(a) Obvious over Baker ʼ226, Kennedy and
`
`21-30, 32, 33 and
`
`Rybak
`
`36-57
`
`6-9
`
`§103(a) Obvious Baker ʼ226, Kennedy, Rybak
`
`and Van der Auwera
`
`In further support of these grounds of unpatentability, this Petition is
`
`accompanied by explanation of the applied references (Ex. 1003, ¶¶69-90), the
`
`state of the art at the time the earliest claimed priority application for the ʼ689
`
`patent was filed (September 1998) (Ex. 1003, ¶¶31-68), and the expert declaration
`of Dr. George Grass (Ex. 1003) (Dr. Grass’ curriculum vitae is provided as Ex.
`
`1004).
`
`Statement of Non-Redundancy
`B.
`To the extent the Board evaluates the exercise of its discretion under 35
`
`U.S.C. § 325(d), the grounds herein warrant full consideration. None of the
`
`grounds herein has been previously brought. Each ground differs significantly from
`
`each other ground herein because of additional features and elements included in
`
`the asserted prior art. For example, even though references Baker ʼ226, Kennedy,
`
`Woodworth Freeman and Van der Auwera were applied by the Examiner during
`
`prosecution, it was in a different context and in different combinations. For
`
`example, during prosecution Kennedy and Van der Auwera were cited under §
`
`6
`
`
`
`102(b) against claims, whereas here Baker ʼ226 is combined with Kennedy, and
`
`further with Woodworth or Rybak under § 103 as to most claims, with Van der
`
`Auwera applied in Grounds 2 and 4 to co-administration elements found in
`
`dependent claims 6-9. Thus, the instant Petition is not duplicative of grounds
`
`advanced during prosecution.
`
`V.
`
`LEVEL OF ORDINARY SKILL IN THE ART
`A person of ordinary skill in the relevant field in September 1998 would
`
`have an advanced degree (e.g., an M.D., Ph.D., or a Pharm. D.), or less education
`
`with considerable experience. Ex. 1003, ¶26. In particular, one of ordinary skill in
`
`the art would likely have some combination of the following skills and experience:
`
`a) experience with and/or knowledge of pharmacology and pharmacokinetics,
`
`particularly with respect to effective drug dosages and dosing intervals; b) the
`
`ability to contemplate dosage and dosing intervals for treating bacterial infections;
`
`and c) the ability to understand work presented or published by others in the field,
`
`including the state of the art as discussed by Dr. Grass in Ex. 1003 (¶27), as well as
`
`the references applied herein against the challenged claims. See Ex. 1003, ¶¶25-
`
`27.
`
`VI. CLAIM CONSTRUCTION
`Claim terms not defined in the specification “are generally given their
`
`ordinary and customary meaning,” which is “the meaning that the term would have
`
`to a person of ordinary skill in the art in question at the time of the invention.”
`Phillips v. AWH Corp., 415 F.3d 1303, 1312-13 (Fed. Cir. 2005). Here, the
`
`undefined claim terms should be given their plain and ordinary meaning. See Ex.
`
`7
`
`
`
`1003, ¶28.
`
`It should be noted that a phrase appears in claims 1, 27 and 47 that does not
`
`require construction because it fails to limit the scope of the claims. Specifically,
`
`the phrase “at a dosage interval that minimizes skeletal muscle toxicity” is non-
`
`limiting and does not require construction. It is a phrase directed to an intended
`
`result or treatment goal, and does not alter any aspect of the claimed method of
`
`administration. Indeed, the minimum interval of 48 hours is already recited in each
`
`of the claims. As such, the phrase is non-limiting, directed to an intended result
`
`and should be given no patentable weight.
`
`More specifically, claims 1, 27 and 47 are directed to methods for
`
`administering daptomycin to a human patient in need thereof. Each of these
`
`independent claims addresses the parameters of administration. First, the method
`
`of administration is performed on “a human patient in need thereof.” Second, the
`
`amount of drug per dose is recited as “a therapeutically effective amount of
`
`daptomycin in a dose of 3 to 75 mg/kg of daptomycin.” Third, each of claims 1,
`
`27 and 47 defines the interval for administration, “wherein the daptomycin dose is
`
`repeatedly administered” and “at a dosage interval of once every 48 hours to once
`
`weekly” (claims 1 and 27) or “once every 48 hours” (claim 47). Some claims
`
`specify the overall length of treatment, e.g., claim 27 (“until said bacterial infection
`
`is treated or eradicated”) or as a range of days, weeks or months (e.g., claims 25,
`
`26, 39, 40, 42-46 and 55-57).
`In Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368 (Fed.
`
`Cir. 2001), the Federal Circuit considered whether similar result-specifying phrases
`
`8
`
`
`
`were non-limiting. In particular, the phrase “an antineoplastically effective
`
`amount” recited in the body of the claims was found to be an expression of
`
`intended result that “essentially duplicates the dosage amounts recited in the
`claims.” Id. at 1375. The Court found that while the express dosage amounts were
`
`material claim limitations, the “statement of the intended result of administering
`
`those amounts [did] not change the amounts or otherwise limit the claim.” Id. The
`
`Court further noted that the phrase at issue was not added to the claims to
`
`overcome the prior art, and instead found that the patentee’s “unsolicited assertions
`
`of patentability made during prosecution do not create a material limitation where
`we have determined that language does not create one.” Id. Likewise, the phrase
`
`“at a dosage interval that minimizes skeletal muscle toxicity” in claims 1, 27 and
`
`47 was added for reasons other than to overcome the prior art, and thus any
`
`unsolicited assertions of patentability of this element do not create a material
`
`limitation in this phrase.
`
`Moreover, the Federal Circuit has consistently ruled that claim elements
`
`doing nothing more than describing an intended result are non-limiting. For
`example, in Syntex (U.S.A.) LLC v. Apotex, Inc. 407 F.3d 1371, 1378 (Fed. Cir.
`
`2005) (claim construction later upheld in Roche Palo Alto LLC v. Apotex, Inc., 531
`
`F.3d 1372, 1378 (Fed. Cir. 2008)), the Federal Circuit found that the phrase “in a
`
`stabilizing amount”, as recited in the claim body, did not further limit the scope of
`
`the claim, and instead “simply describe[d] the intended result of using the weight
`to volume ratios recited in the claims.” See also Texas Instruments Inc. v. U.S.
`Int’l. Trade Comm’n, 988 F.2d 1165, 1171-1172 (Fed. Cir. 1993) (finding that the
`
`9
`
`
`
`phrase “to preclude direct high velocity engagement between the fluid and the
`
`device and the electrical connections thereto” in the claim body did nothing more
`
`than “describe the result of arranging the components of the claims in the manner
`
`recited in the claims”).
`
`Like the claim elements at issue in these decisions, the phrase “at a dosage
`
`interval that minimizes skeletal muscle toxicity” in claims 1, 27 and 47 does
`
`nothing more than recite an intended result achievable by the other claim elements.
`
`Therefore, the phrase is non-limiting and should be given no patentable weight.
`
`VII. SCOPE AND CONTENT OF THE PRIOR ART
`A.
`U.S. Patent No. 5,912,226 to Baker (“Baker ʼ226,” Ex.
`
`1006)
`Baker ʼ226 has a priority date of no later than December 16, 1991. Ex.
`
`1006. Baker ʼ226 is one of several daptomycin patents obtained by Eli Lilly and
`
`Company, the original developers of daptomycin. Ex. 1003, ¶71. Baker ʼ226 is
`
`directed to and describes compositions containing, and methods of using,
`daptomycin and other antibacterial compounds containing cyclic peptides. Id.
`
`Importantly, Baker ʼ226 describes methods for treating bacterial infections in
`
`humans. See Ex. 1003, ¶¶70-76, describing Ex. 1006.
`
`The methods disclosed by Baker ʼ226 include administering daptomycin in
`
`effective doses “between about 0.1 mg/kg and about 100 mg/kg.” Ex. 1006, col.
`
`10, ll. 53-54. Baker ʼ226 describes that a preferred dose of daptomycin is “from
`about 1 to about 30 mg/kg” of daptomycin. Id. at col. 10, l. 55. These ranges of
`
`doses, including what are characterized as preferred, overlap substantially with
`
`10
`
`
`
`doses recited in the claims of the ʼ967 patent. Ex. 1003, ¶72. The dose of 30
`
`mg/kg is specifically identified as one point at the end of the “preferred” dose
`
`range. Id., citing Ex. 1006, col. 10, l. 55.
`
`Baker ʼ226 also teaches that a “typical daily dose for an adult human is from
`
`about 100 mg to about 1.0 g.” Ex. 1006, col. 10, l. 56-57. An average adult
`
`human has a body weight of 70 kg (154 lbs) . See, e.g., Ex. 1019, discussed at Ex.
`
`1003, ¶¶73-74.
`
`Thus, when a typical daily dose of daptomycin for an adult human is from
`
`about 100 mg to about 1.0 gram, as specified in the Baker ʼ226, based on Ex. 1019
`
`this corresponds to a typical daily dose from about 1.43 mg/kg to about 14.3
`
`mg/kg. Ex. 1003, ¶74. This range also overlaps with doses recited in claims of the
`
`ʼ689 patent. Id. Baker ʼ226 also describes that daptomycin can be administered as
`
`“a single daily dose or in multiple doses per day.” Ex.1006, col.10, l.59-60. Baker
`
`therefore teaches a dosage interval of once every 24 hours. Ex. 1003, ¶75. Baker
`
`ʼ226 also describes repeated administration, stating that the “treatment regime may
`
`require administration over extended periods of time, e.g., for several days or for
`
`from two to four weeks.” Ex. 1006, col. 10, l. 60-62; Ex. 1003 ¶75. Baker ʼ226
`
`also describes oral and intravenous methods of administration, stating that “[a]
`
`convenient method of practicing the treatment method is to administer the
`
`antibiotic orally, using tablets, capsules, suspensions, syrups and the like. The
`
`antibiotic may also be administered by other methods, e.g. as a suppository or
`
`parenterally via IV infusion.” Ex. 1006, col. 11, ll. 3-7; Ex. 1003, ¶75.
`
`11
`
`
`
`Kennedy, Antimicrob. Agents and Chemother. 1989
`B.
`Sept. p. 1522-1525 (Ex. 1007)
`
`Kennedy describes using daptomycin to treat rabbits following experimental
`
`induction of endocarditis of the aortic valve. Ex. 1003, ¶75. Daptomycin was
`
`given intravenously every 24 hours at a dose of 10 mg/kg for two days or four
`
`days: “[D]aptomycin (10 mg/kg i.v. every 24 h).” Ex. 1007, p. 1522, right col., ¶3.
`
`As described above, a declaration of co-inventor Dr. Frederick Oleson was
`
`submitted during prosecution of the parent ‘967 patent. Ex. 1023, pp. 0121-0131,
`
`discussed at Ex. 1003, ¶¶29-30. Oleson’s declaration stated that administering
`
`daptomycin to a rabbit with a dose of 10 mg/kg every 24 hours “is equivalent to a
`
`2.97 mg/kg dose in humans every 85 hours.” Ex. 1023, p. 0127, ¶12; emphasis
`
`added. Ex. 1023, p. 0127. Based on the Patentee’s own admission, Kennedy
`
`therefore teaches a dosage interval (85 hours) and duration of administration (7
`
`days or 14 days) falling in the ranges recited in the ʼ689 claims. Kennedy’s dose is
`
`functionally indistinguishable from a dose of 3 mg/kg. Ex. 1003, ¶79.
`
`A. Woodworth et al, Antimicrob Agent Chemother. 1992, 36:318-25
`(Ex. 1009)
`
`Woodworth describes administering daptomycin to humans at progressively
`
`increasing doses of 2, 3, 4 and 6 mg/kg, with an interval between doses of at least
`
`72 hours: “[V]olunteers were administered daptomycin in successive single doses
`
`of 2, 3, 4 and 6 mg/kg.” Ex. 1009, p. 319, left col., ¶4. “At least 72 hours separated
`each dose.” Id. Daptomycin was administered to these subjects for at least 9 days
`
`in total (3 dosage intervals separated by at least 72 hours each). See Ex. 1003, ¶82.
`
`12
`
`
`
`Woodworth therefore teaches doses, dosage intervals, and total durations of
`administration as recited in the ʼ689 claims. Id.
`
`Rybak et al, Antimicrob. Agent Chem. 1992, 36:1109-14
`
`C.
`(Ex. 1008)
`
`Rybak (Ex. 1008) describes a clinical study in which daptomycin was
`
`administered intravenously to humans as a first (loading) dose of 6 mg/kg,
`
`followed by doses of 3 mg/kg every 12 hours for the purpose of “examining the
`
`efficacy of daptomycin at an increased dosage.” Ex. 1009, p. 1109, left col., ¶1.
`
`Rybak also states that “[e]arly clinical trials utilizing 2 mg/kg of body weight per
`
`day were suspended because of unexplained treatment failures . . . daptomycin’s
`high degree of binding to serum proteins may have been a contributing factor.” Id.
`
`Thus a multicenter trial to administer daptomycin at 6 mg/kg/day was motivated by
`
`the conclusion that the dose of 2 mg/kg used previously mayhave been too low to
`
`provide therapeutic benefit. Ex. 1003, ¶85.
`
`Rybak does not report any toxic or other adverse effects of administering
`
`daptomycin at 6 mg/kg followed by 3 mg/kg every 12 hours. Ex. 1003, ¶86. Thus
`
`Rybak teaches doses of daptomycin as high as 6 mg/kg, and repeated doses of 3
`mg/kg after the loading dose, were feasible. Id. Rybak notes that daptomycin
`
`exhibits concentration-dependent killing and “[t]herefore, it is plausible that higher
`
`serum concentrations may have resulted in higher clinical efficacy in serious
`
`infections.” Ex. 1009, p.1114, left col., discussed at Ex. 1003, ¶¶84-97.
`
`Van der Auwera, Antimicrob. Agents Chemother. 1992
`D.
`Oct. 33:1783-90 (Ex. 1010)
`
`13
`
`
`
`Van der Auwera describes co-administering daptomycin and the
`
`aminoglycoside amikacin (also known as amikin) “to evaluate the efficacy of
`
`daptomycin alone and in combination with amikacin against gram-positive
`
`bacteria.” Ex. 1010, p. 1783, left col., ¶1. Van der Auwera also states that it “has
`
`been suggested that the combination of daptomycin with an aminoglycoside is
`
`synergistic against staphylococci and enterococci.” Id. Van der Auwera reports
`
`that tolerance of the co-administered antibiotics “was excellent; no side effects
`were observed in the 12 volunteers tested.” Id. Thus the study of Van der Auwera
`
`demonstrates that daptomycin can be safely co-administered to humans with other
`
`antibiotics, such as the aminoglycoside antibiotic, amikacin. Ex. 1003, ¶¶88-90.
`
`VIII. EACH GROUND OF UNPATENTABILITY DEMONSTRATES A
`REASONABLE LIKELIHOOD OF PREVAILING AGAINST THE
`CHALLENGED CLAIMS OF THE ‘689 PATENT
`A.
`State of the Art Prior to September 1998
`
`Prior to September 25, 1998, the earliest priority date claimed by the ʼ689
`
`patent, it was known that the therapeutic efficacy and potential toxicity of
`
`antibiotic treatment regimens can be influenced by the dose administered (e.g.,
`
`mg/kg), the dosage interval (e.g., hours or days between doses), and the overall
`
`duration of a treatment regimen, e.g., for days, weeks or months. Ex. 1003, ¶32.
`
`In the case of daptomycin, also known by the Eli Lilly designation “LY 146032,” a
`
`variety of combinations of doses, dosage intervals, and treatment durations had
`
`been disclosed in the literature prior to September 1998. Id. at ¶¶31-32.
`
`The benefits of using higher doses of antibiotics given at longer dosage
`
`intervals, thereby minimizing toxicity, were well known prior to September of
`
`14
`
`
`
`1998. Id. at ¶¶34. For example, extensive studies with aminoglycoside antibiotics
`
`in both animal models and human patients established numerous benefits
`
`associated with administering a higher dose at an interval of 24 hours, rather than
`smaller doses given at intervals of 8 or 12 hours. Id., citing Ex. 1011. For
`
`example, the benefits of using higher doses and longer dosage intervals included
`
`(1) improved therapeutic efficacy, (2) reduced toxicity and (3) reduced cost. Id.
`
`It was also known in the art, well prior to September of 1998, that the
`
`therapeutic efficacy of daptomycin (i.e., its ability to kill bacteria) is related to its
`
`peak blood concentration (maximum concentration, Cmax), not the duration of
`
`time that its blood concentration is above a minimum level of activity (minimum
`
`inhibitory concentration, MIC). Ex. 1003, ¶35, citing Ex. 1012. This informed
`
`workers in the field that greater therapeutic efficacy could be achieved by
`
`administering larger doses of daptomycin less frequently than could be achieved by
`administering smaller doses of daptomycin more frequently. Id.
`
`It was also well known prior to September of 1998 that daptomycin was an
`
`antibiotic having a prolonged post-antibiotic effect (PAE). Ex. 1003, ¶¶36-37,
`
`citing Ex. 1013. The PAE refers to a suppression of bacterial growth that persists
`
`after even a brief exposure to antibiotics. Id. at ¶36. Bush states that “the
`
`relevance of the PAE pertains to its effect on the dosing regimen.” Ex. 1013, p.
`
`1199. Bush discloses that such an effect can allow a greater period of time for
`
`drug level below the MIC (minimum inhibitor concentration) without loss of
`efficacy. Id. at ¶39, citing Ex. 1013, p. 1199. In addition, Bush also suggests that
`
`this observed PAE is more likely to occur in vivo at a high free drug level in
`
`15
`
`
`
`serum. Id. at ¶39. One who is skilled in the art would recognize that one way to
`achieve higher free drug levels is by administration of higher doses. Id.
`
`Aminoglycoside antibiotics also have a prolonged PAE. Id. ¶40, citing Ex. 1011, p.
`
`1030.
`
`The art prior to September of 1998 had also reported that daptomycin has
`
`nephrotoxic properties, similar to aminoglycosides. Ex. 1003, ¶41, discussing
`
`Kreft, Ex. 1014. The minimum threshold dose of daptomycin found to have
`
`nephrotoxic effects was comparable to that of gentamicin and tobramycin, both
`
`aminoglycoside antibiotics. Id. It was also known that the nephrotoxicity of
`
`daptomycin, like that of aminoglycosides, was not directly related to drug
`concentration in the kidney. See Id. One of ordinary skill prior to September of
`
`1998 would have understood, when there is no observed relationship between
`
`nephrotoxicity and renal concentrations, nephrotoxicity is likely due to the duration
`of exposure. Id. at ¶45. Further, Kreft expressly states that “[t]he similarities in
`
`nephroprotection between LY 146032 [daptomycin] and aminoglycosides could
`
`indicate that renal handling and the mechanisms of nephrotoxicity of LY 146032
`
`are similar to that of aminoglycosides, glycopeptide and lipopeptide antibiotics.”
`
`Ex. 1014, p. 642.
`
`By June 1997, Dr. Grass notes, an evolution in aminoglycoside dosing
`regimens had occurred. See Ex. 1003, ¶¶48-51, citing Anaizi, Ex. 1015.
`
`Previously, multiple daily dosings were assumed to be necessary for efficacy, “the
`
`validity of this assumption for aminoglycosides has been strongly challenged
`
`during the past decade. [...] The primary aim of these changes is not only to
`
`16
`
`
`
`minimize toxicity but also reduce treatment failure, morbidity, and mortality.” Ex.
`
`1015, p. 223.
`
`As Anaizi describes, the rationale for the once-daily dosing of
`
`aminoglycosides is rooted in observations that aminoglycosides exhibit a
`significant post antibiotic effect (PAE), which daptomycin exhibits. See Ex. 1003,
`
`¶¶50-51, citing Ex. 1015, p. 224; Ex. 1013. As with daptomycin, the bactericidal
`
`action of aminoglycosides is concentration dependent, i.e. the higher the peak/MIC
`ratio, the higher the kill rate. Id at ¶51, citing Rybak, Ex. 1009. Higher peak
`
`concentrations do not necessarily result in greater risk of toxicity, found to be the
`case with daptomycin. Id., citing Kreft, Ex. 1014.
`
`In the ’689 patent (Ex. 1001), it is impled that one should ignore some very
`
`important commonalities between daptomycin and aminoglycosides. See Ex.
`
`1001, col. 3, ll. 9-11. This assertion overlooks numerous functional similarities
`
`that had been observed between daptomycin and aminoglycosides with respect to
`
`toxicity, post-antibiotic effects, pharmacokinetics and the relationship between
`
`peak drug concentration and bacterial killing efficacy, as mentioned above. Ex.
`
`1003, ¶58.
`
`It was also well known in the art that when administering renally excreted
`
`drugs, as daptomycin is, dosage intervals must be adjusted to compensate for
`
`reduced rates of drug clearance in renally compromised patients. Van Scoy, 1983,
`
`Ex. 1021, abst., discussed in Ex. 1003, ¶64.
`
`With respect to aminoglycosides in particular, Freeman et al. (J Antimicrob
`
`Chemother. 1997 Jun;39:677-86; Ex. 1022) discloses “[i]f one is to adhere to the
`
`17
`
`
`
`principles of high-dose, less frequent aminoglycoside dosing therapy, it would
`
`seem more logical to maintain a fixed dose and lengthen the interval for patients
`
`with decreased renal function. This second method would continue to optimize the
`
`peak:MIC ratio while allowing for the necessary drug-free period which is
`
`postulated to lead to a lower incidence of aminoglycoside toxicity and adaptive
`
`resistance.” Freeman. pp. 681-682, spanning ¶(Ex. 1022). Ex. 1003, ¶65.
`
`Freeman further discloses “[t]he recommended regimen should employ an
`
`optimal individualized dose (e.g., 5-7 mg/kg for gentamicin, tobramycin or
`
`netilmicin) every 24 h. We also advocate that the dosing interval should be
`
`lengthened (e.g., 26, 48 h, etc.) in patients with decreased renal function.”
`
`Freeman, p. 683, ¶3, emphasis added. Freeman provides an example of an
`
`aminoglycoside dosing regimen used clinically, in which patients with reduced
`
`creatinine clearance
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