UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD. FRESENIUS-KABI USA LLC Petitioner

Transcription

1 UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD FRESENIUS-KABI USA LLC Petitioner v. CUBIST PHARMACEUTICALS, INC. Patent Owner CASE IPR: UNASSIGNED PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 6,468,967 CLAIMS 1-7, 12-28, AND UNDER 35 U.S.C AND 37 C.F.R , Mail Stop PATENT BOARD Patent Trial and Appeal Board U.S. Patent and Trademark Office P.O. Box 1450 Alexandria, VA

2 TABLE OF CONTENTS Page TABLE OF ABBREVIATIONS... i EXHIBIT LIST... ii RULE 42.8 MANDATORY NOTICES... 1 I. Statement of the Precise Relief Requested and the Reasons Therefor (37 C.F.R (a))... 2 II. The 967 Patent... 3 A. The Technology... 3 B. Claims... 3 C. Priority Date... 5 D. Prosecution History... 7 III. A Person of Ordinary Skill in the Art... 9 IV. Claim Construction V. Identification of Challenge (37 C.F.R (b)) A. Ground 1: Claims 1-7, 12-17, 20-28, and are anticipated by the 226 patent Claim a. The 226 patent anticipates the claimed dose ranges and amounts b. The 226 patent anticipates the claimed dosing intervals c. The 226 patent inherently discloses skeletal muscle toxicity d. The 226 patent discloses repeated administration The 226 patent also anticipates claims 2-7, 12-17, 20-28, and Claim chart i-

3 TABLE OF CONTENTS Page B. Ground 2: Woodworth anticipates Claims 1-5, 12-17, 22, 26-28, 32-35, and Claim a. Woodworth anticipates the claimed dose ranges and amounts b. Woodworth anticipates the claimed dosing intervals c. Woodworth inherently discloses minimized skeletal muscle toxicity d. Woodworth discloses repeated administration Woodworth anticipates 967 patent claims 2-5, 12-17, 22, 26-28, 32-35, and Claim Chart C. Ground 3: Claims 1-7, 12-28, and would have been obvious over the 226 patent alone Claim a. The claimed dose amounts and dosing intervals would have been obvious b. A person of skill would have been motivated to use the claimed dosing regimen in light of other prior art antibiotic dosing regimens c. Minimizing muscle toxicity adds nothing to the claims Claim Claim Dependent claims 2, 16, 17, and 33 directed to a dosing interval are also obvious Claims 2, 3, 4, 5, 6, 7, 13, 14, 15, 16, 17, 18, 19, 20, 21, 27, 28, 34, and 35 directed to dosing ranges and amounts are also obvious ii-

4 TABLE OF CONTENTS Page 6. Claims 22, 32 and directed to methods of administration are also obvious Claims 24, 25, and directed to duration of treatment are also obvious D. Ground 4: Claims 1-7, 12-28, and would have been obvious over the 226 patent in view of Woodworth Claim a. The claimed dose amounts would have been obvious b. The claimed dose intervals would have been obvious Claim Claim Dependent claims 2, 16, 17, and 33 directed to dosing interval are also obvious Claims 2, 3, 4, 5, 6, 7, 13, 14, 15, 16, 17, 18, 19, 20, 21, 27, 28, 34, and 35 directed to dosing ranges and amounts are also obvious Claims 22, 32 and directed to methods of administration are also obvious Claims 24, 25, and directed to duration of treatment are also obvious E. The Challenges Based on the 226 Patent and Woodworth are not Redundant F. Secondary Considerations of Non-Obviousness do not Negate Obviousness VI. Conclusion iii-

5 TABLE OF ABBREVIATIONS Abbreviation Explanation 967 patent U.S. Patent No. 6,468, application File history of U.S. Patent Application No. 09/406, application U.S. Provisional Patent Application No. 60/101, application U.S. Provisional Patent Application No. 60/125, patent United States Patent No. 5,912,226 Woodworth Woodworth et al., Antimicrob. Agents Chemotherapy (1992), Sexton Sexton et al., Abstracts of the 28 th ICAAC (1988), Abstract 932, p. 275 Lee Lee et al., Abstract 885, Program and Abstracts of the Thirty-First Interscience Conference on Antimicrobial Agents and Chemotherapy, 246 Tally declaration Tally Declaration from 967 prosecution history Petitioner Fresenius Kabi USA LLC Patentee Cubist Pharmaceuticals MIC Minimum inhibitory concentration Exh. : This refers to the indicated exhibit This refers to the indicated column or page and lines of the patent or patent publication -i-

6 EXHIBIT LIST Exhibit Number Exhibit 1001 U.S. Patent No. 6,468, File history of U.S. Patent Application No. 09/406, U.S. Provisional Patent Application No. 60/101, U.S. Provisional Patent Application No. 60/125, Declaration of Alexander Shepherd 1006 Cubist v. Hospira claim construction ruling 1007 Cubist v. Teva claim construction ruling 1008 United States Patent No. 5,912, Woodworth et al., Antimicrob. Agents Chemotherapy (1992), Freeman et al., J. of Antimicrobial Chemotherapy (1997) 39, Sexton et al., Abstracts of the 28 th ICAAC (1988), Abstract 932, p Lee et al., Abstract 885, Program and Abstracts of the Thirty-First Interscience Conference on Antimicrobial Agents and Chemotherapy, Tally et al., J. of Antimicrobial Chemotherapy (2000) 46, D. McKindley and E. Maderazo, Drug Use in the Critically Ill Patient with Renal Dysfunction, Application of the DREM system, in Infectious Diseases in Critical Care Medicine at (B. A. Cunha ed., 1998) Shepherd CV 1016 Claim chart 1017 H. Ansel and M. Stoklosa, -ii-

7 Pharmaceutical Calculation, 11 th ed., 2001, pp Tally, et al., Exp. Opin. Invest. Drugs (1999), 8(8): Casarett and Doull s Toxicology, The Basic Science of Poisons, Fifth Edition, Chapter 2: Principles of Toxicology, pp Baltz, Biotechnology of Antibiotics (1997), iii-

8 RULE 42.8 MANDATORY NOTICES Real Party-In-Interest (37 C.F.R. 42.8(b)(1)): The real party-in-interest is Fresenius-Kabi USA LLC ( Fresenius or Petitioner ). Fresenius is not barred by operation of estoppel to submit this petition for inter partes review. Related Matters (37 C.F.R. 42.8(b)(2)): The 967 patent is being asserted in co-pending litigations captioned as: Del.) Cubist Pharmaceuticals, Inc. v. Hospira, Inc., 1:12-cv GMS (D. Cubist Pharmaceuticals, Inc. v. Fresenius-Kabi USA LLC, 1:14-cv GMS (D.Del.) Cubist Pharmaceuticals, Inc. v. Strides Inc. and Agila Specialties Private Ltd., 1:13-cv GMS (D.Del.) The 967 patent was asserted in terminated litigation captioned as: Cubist Pharmaceuticals, Inc. v. Teva Parenteral Medicines, Inc., et al., 1:09-cv GMS (D. Del) Designation of Lead and Back-Up Counsel (37 C.F.R. 42.8(b)(3)): Lead counsel is Imron T. Aly (Reg. No. 48,706) and back-up counsel is Jason G. Harp (Reg. No. 42,634). Grounds for Standing (37 C.F.R (a)): Petitioner hereby certifies that the patent for which review is sought is available for inter partes review and that Petitioner is not barred or estopped from requesting inter partes review challenging the patent claims on the grounds identified in the petition. Petitioner -1-

9 was served with a complaint asserting the 967 patent no earlier than July 11, 2014, and this petition is being filed on November 3, Service Information (37 C.F.R. 42.8(b)(4)): Papers concerning this matter should be served on the following: Mail and hand-delivery address: Imron T. Aly Schiff Hardin LLP 233 S. Wacker Dr., Suite 6600 Chicago, Illinois ialy@schiffhardin.com jharp@schiffhardin.com Telephone: (312) Facsimile: (312) I. STATEMENT OF THE PRECISE RELIEF REQUESTED AND THE REASONS THEREFOR (37 C.F.R (A)) Petitioner requests inter partes review and cancellation of independent claims 1, 12, and 16, and dependent claims 2-7, 13-25, 27-28, and of the 967 patent (Exh. 1001) based on one or more of the grounds under 35 U.S.C. 102 or 103 set forth herein. Petitioner s detailed statement of the reasons for relief requested is set for in V, below. II. THE 967 PATENT A. The Technology Researchers at Eli Lilly and Company ( Lilly ) discovered daptomycin 30 years ago in the early 1980s. (Exh. 1013, p. 523). Daptomycin is an antibiotic -2-

10 that was known to kill Gram-positive bacteria, and Lilly even worked on an intravenous version but chose not to market it. (Exh. 1013, p. 523). In 1997, Lilly licensed daptomycin to Cubist Pharmaceuticals Inc. ( Cubist ). (Exh. 1013, p. 523). Lilly s original patent covering the daptomycin product was granted in 1980 and is long expired. (Exh. 1002, p. 139). Petitioner is challenging the 967 patent, a follow-on patent directed to a dosing regimen for daptomycin. B. Claims The 967 patent, entitled "Methods for Administration of Antibiotics", issued on October 22, 2002 from U.S. Application No. 09/406,568 filed on September 24, The application claims priority to U.S. Provisional Patent Application Nos. 60/101,828, filed on September 25, 1998 and 60/125,750 filed on March 24, The 967 patent is assigned on its face to Cubist Pharmaceuticals Inc., and the listed inventors are Frederick B. Oleson, Jr., and Francis P. Tally. The claims of the 967 patent are directed to a particular dosing regimen of daptomycin characterized by repeated administration at least once every 24 hours. Independent claim 1 recites: A method for administering daptomycin, comprising the stop of administering to a human patient in need thereof a therapeutically effective amount of daptomycin in a dose of 3 to 75 mg/kg of daptomycin at a dosage interval that minimizes skeletal muscle toxicity, wherein the -3-

11 daptomycin dose is repeatedly administered at a dosage interval of once every 24 hours to once every 48 hours. Independent claim 12 is directed to the same method requiring however that the dosage interval in once every 24 hours. Independent claim 26 is directed to a method for treating or eradicating a bacterial infection in a human patient comprising administering daptomycin in the manner as in claim 1. The independent claims of the 967 patent all require administering daptomycin to a human patient at a dose of 3 to 75 mg/kg at a dosage interval that minimizes skeletal muscle toxicity and is administered repeatedly at a dose interval of either once every 24 hours to once every 48 hours (claim 1 and 26) or once every 24 hours (claim 12). Claim 2 further limits the dosage interval to once every 24 hours or once every 48 hours and claim 33 limits the dosage interval to once every 24 hours. Dependent claims 3-7, 13-21, 27, 28, 34, and 35 further limit the dose within the range of 3 to 75 mg/kg. Claims 8-11 and require the co-administration with another antibiotic. Claims 22, 32, and are limited to a route of administration, either oral, subcutaneous or intravenous. Claims and are directed to a specified period in which the daptomycin is repeatedly administered, ranging from 3 days to 6 months. -4-

12 C. Priority Date The 967 patent issued from U.S. Application Serial No. 09/406,568 ( the 568 application ) (Exh. 1002) which was filed on September 24, 1999 and claims priority to U.S. Provisional Patent Application Nos. 60/101,828 (Exh. 1003), filed on September 25, 1998 and 60/125,750 (Exh. 1004), filed on March 24, The disclosures of the two provisional applications are limited to methods of administering daptomycin in which the dosing interval is from once every 12 hours to once every 24 hours. Provisional application 60/101,828 ( the 828 application ) reports two studies on dogs comparing the administration of daptomycin once every 8 hours to once every 24 hours. (Exh. 1003, pp. 4-5). It concludes that [t]he findings described above suggest that longer intervals between doses of daptomycin (i.e., once every 12 hours to 24 hours) will minimize the possibility of muscle toxicity in the clinical setting and may permit the use of higher doses than have been possible so far. (See, Exh. 1003, p. 5). The 828 application discloses a method of administering daptomycin to a patient in need of such treatment at a dose of between 2 and 10 mg/kg and subsequently, readministering that same dose at intervals between 12 and 24 hours. (See, Exh. 1003, p. 5). The only claim attached to the provisional application recites the same method. -5-

13 Provisional application 60/125,750 ( the 750 application ) also describes only two studies, those conducted on dogs. (Exh. 1004). The 750 application hypothesizes that administration of daptomycin once every 12 hours to once every 24 hours minimizes muscle toxicity. (Exh. 1004, p. 5). The main difference between the disclosure of the 750 application and 828 application is that the dose is changed from 2 to 10 mg/kg to a dose of 2 to 75 mg/kg once every 12 to 24 hours. (See Exh. 1004, p. 5; Exh. 1003, p. 5). Examples 1 and 2 in the 750 application described the same two dog studies disclosed in the 568 application. (Exh. 1004, pp. 6-10; Exh. 1002, pp ). The claims are limited to a dosing regimen of 2 to 75 mg/kg once every 12 hours to once every 24 hours. (Exh. 1004, pp ). In contrast to the provisional applications, the specification of the 967 patent discloses a dosage of 3 to 75 mg/kg and a dosage interval of once every 24 hours to once weekly. (Exh. 1001, 5:50-62). This includes, according to the specification once every 48 hours, once every 72 hours, and once every 96 hours. (Exh. 1001, 5:45-6:28). In addition to the dog studies in Examples 1 and 2, the 967 specification discloses studies with daptomycin in humans in Examples 4 and 5. (Exh. 1001, 12:63-14:27). The dose intervals for administering daptomycin in Example 4 were once every 12 hours and once every 24 hours. (Exh. 1001, 13:7-21). In Example 5, the dose interval was varied to once every 24 hours, once -6-

14 every 48 hours, once every 72 hours, once every 96 hours, or once weekly. (Exh. 1001, 14:4-7). Neither of the provisional applications provides written description support for any claims wherein the dosage interval for administering daptomycin is longer than 24 hours. Specifically, claims of administering daptomycin at a dose of 3-75 mg/kg once every 24 hours to once weekly are supported, if at all, by the filing of the 568 application. Therefore, the effective filing date for claims directed to a dosage interval for administering daptomycin longer than 24 hours is September 24, D. Prosecution History The Patentee attempted to avoid the prior art by claiming that none of the cited prior art teaches or suggests administration of daptomycin at a dosage interval that minimizes skeletal muscle toxicity. (See, e.g., Exh. 1002, p. 203). However, the Federal Circuit has held that the discovery of a previously unappreciated property of a prior art composition, or a scientific explanation for the prior art s functioning, does not render the old composition patentably new to the discoverer. Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1347 (Fed. Cir. 1999). In addition, minimizing skeletal muscle toxicity is nothing more than the intended result of the claimed method and therefore does not render a known -7-

15 composition patentable. 1 MPEP 2145, discussing In re Sullivan, 498 F.3d 1345 (Fed. Cir. 2007) (a statement of intended use may not render a known composition patentable). The Examiner failed to recognize these principles and mistakenly allowed the claims. As Petitioner s expert, Dr. Alexander Shepherd, describes in his declaration (Exh. 1005), 2 the prior art disclose the same dosing amounts and intervals that are recited in the 967 patent claims. These prior art dosing regimens would have inherently minimized skeletal muscle toxicity, and the 967 patent claims should not have been allowed. The Patentee also attempted to avoid the prior art by arguing that it was unexpected that a higher dose of daptomycin did not result in increased toxicity. The Examiner s Reasons for Allowance indicate that he accepted that argument. (Exh. 1002, p. 221). However, as Dr. Shepherd explains, it would not have been unexpected that the dosing regimen recited in the claims had acceptable toxicity. 1 As described in detail in Section IV., it is Petitioner s position not only that minimizing skeletal muscle toxicity is not an independent claim limitation but also that, in any event, minimizing toxicity would be an inherent result of the recited dose amounts and dosing interval. (See also Sections V.A.1.c. and V.B.2.c.). 2 In support of this petition, Fresenius files herewith the declaration of technical expert Dr. Alexander Shepherd M.D., Ph.D., Professor of Medicine and Pharmacology at the University of Texas San Antonio Health Centers. ( Shepherd Dec. ) (Exh. 1005). -8-

16 The prior art dosing regimens, the properties of daptomycin and basic strategies used to develop dosing regimens would have readily led a person of skill to the claimed dosing regimen. In view of the foregoing and for the reasons discussed herein, inter partes review of the 967 patent is warranted to give the PTO an opportunity to consider the validity of the 967 patent claims in view of the prior art reference discussed below. III. A PERSON OF ORDINARY SKILL IN THE ART As confirmed in Dr. Shepherd s declaration the art of the 967 patent relates generally to the dosing regimen of a drug, in particular the dosing regimen of daptomycin. A person of ordinary skill in this art would have an advanced degree in pharmacology, pharmaceutical sciences, pharmacokinetics, medicine or related discipline, as well as several years of experience designing or evaluating drug treatment regimens. (Exh. 1005, 9). IV. CLAIM CONSTRUCTION Pursuant to 37 C.F.R (b), a challenged claim must be given its broadest reasonable construction in light of the specification of the 967 patent. Courts have addressed claim construction issues related to the 967 patent in two cases: Cubist v. Hospira (12-cv-367; 12-cv-859; 12-cv-1142) and Cubist v. Teva (09-cv-189). In the Hospira litigation, the court defined daptomycin to mean -9-

17 the cyclic lipopeptide antibiotic derived from the fermentation of Streptomyces roseosporus, comprised of decanoyl side chain linked to the N-terminal tryptophan of a cyclic 13-amino acid peptide having the chemical formula that corresponds to LY (Exh. 1006, claim construction ruling). The active ingredient in Cubicin is daptomycin as the Hospira court has defined it. In the Teva litigation, the court decided that the phrases a therapeutically effective amount of daptomycin and at a dosage interval that minimizes skeletal muscle toxicity should be construed to have their plain and ordinary meaning, which is to be determined based on the understanding of a person of ordinary skill in the art. (Exh. 1007, claim construction ruling). Dr. Shepherd explains that a person of ordinary skill would understand a therapeutically effective amount of daptomycin to be an amount of daptomycin that produces a desired therapeutic response or desired effect in the patient. (Exh. 1005, 20). Dr. Shepherd also opines in his declaration that a person of ordinary skill in the art would have understood that the claim language at a dosage interval that minimizes skeletal muscle toxicity would be linked to the dosing interval set forth in the claims, i.e., once every 24 hours to once every 48 hours. In other words, a person of skill would have understood that the dosage interval was defined to be once every 24 to 48 hours and that the intended result minimized skeletal toxicity would have inherently been the result of the claimed dosing regimen. -10-

18 Accordingly, a person of skill would have understood that the language minimizing skeletal muscle toxicity does not modify dosage interval of once every 24 to 48 hours set forth in the claims. (Exh. 1005, 21 and 42). Put another way, the dosing interval recited in the claims provides a specific quantitative limit on the dosage interval which effectively supersedes the qualitative requirement that the dosage interval minimizes skeletal muscle toxicity. Minimizing muscle toxicity is nothing more than the intended result of the claimed method and recited dosage interval. Accordingly, the intended result recited in the 967 patent provides no patentable distinction over the prior art. See MPEP 2145, discussing In re Sullivan, 498 F.3d 1345 (Fed. Cir. 2007) (a statement of intended use may not render a known composition patentable). Any disclosure or teaching in the prior art of a dose within the recited range administered at the recited dosage interval achieves the same intended result recited in the claims of the 967 patent. The parties in the Teva litigation agreed to the following definitions: Claim Term administering to a human patient in need thereof wherein the daptomycin dose is repeatedly administered at a dosage interval of once every 24 hours to once every 48 hours wherein the daptomycin dose is repeatedly administered at a dosage Agreed definition administering daptomycin to a human patient in need of daptomycin to treat a gram-positive bacterial infection the daptomycin dose is administered more than once at an interval of once every 24 hours, i.e., daily, to once every 48 hours, i.e., once every other day the daptomycin dose is administered more than once at an interval of once -11-

19 interval of once every 24 hours until said bacterial infection is treated or eradicated every 24 hours, i.e., daily until effective to reduce or eliminate bacterial infection Dr. Shepherd confirms that the definitions set forth in the table above are consistent with how a person of skill in the art would understand those phrases. (Exh. 1005, 23). V. IDENTIFICATION OF CHALLENGE (37 C.F.R (B)) Inter partes review of claims 1-7, 12-28, and of the 967 patent is requested based on the following grounds for unpatentability. Pursuant to 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 Alexander Shepherd M.D., Ph.D. (Exh. 1005) which explains what the art would have conveyed to a person of ordinary skill in the art. Ground 1: Claims 1-7, 12-17, 20-28, and are anticipated by United States Patent No. 5,912,226 ( the 226 patent ). (Exh. 1008) Ground 2: Claims 1-5, 12-17, 22, 26-28, 32-35, and are anticipated by Woodworth et al., Antimicrob. Agents Chemotherapy (1992), ( Woodworth ). (Exh. 1009). Ground 3: Claims 1-7, 12-28, and would have been obvious over the 226 patent alone. -12-

20 Ground 4: Claims 1-7, 12-28, and would have been obvious over the 226 patent in view of Woodworth. Petitioner is aware that Agila Specialties Inc. ( Agila ) and Mylan Pharmaceuticals Inc. ( Mylan ) filed a Petition for Inter Partes Review of United States Patent No. 6,468,967 on October 23, 2014 (IPR ). Fresenius- Kabi s petition was developed independently and relies on different grounds for unpatentability. Fresenius-Kabi s petition includes a ground for unpatentability under 35 U.S.C. 102(b) based on the Woodworth article (Exh. 1009) that is not included in the Agila/Mylan petition. Fresenius-Kabi s obviousness challenges are based on the 226 patent alone or in combination with Woodworth. On the other hand, the Agila/Mylan petition relies only on the 226 patent in combination with other secondary references. As explained in Section V.E. below, Woodworth and the 226 patent references are not cumulative. When compared to the 226 patent, Woodworth provides unique prior art disclosures that are relevant to different claims of the 967 patent. A. Ground 1: Claims 1-7, 12-17, 20-28, and are anticipated by the 226 patent. The 226 patent was filed by inventors other than those of the 967 patent and is directed to lipopetide antibiotics that are anhydro- and isomer-forms of A C Cyclic peptides, including LY which is daptomycin. The

21 patent issued on June 15, 1999 from an application filed on December 16, 1991 and is therefore prior art under 35 U.S.C. 102(e). The 226 patent is also prior art under 35 U.S.C. 102(a) for those claims directed to a dosage interval for administering daptomycin which is longer than 24 hours for the reasons discussed above in Section II.C. The publication of the 226 patent is a little more than three months before the September 24, 1999 priority date for those claims. (See Section II.C.). All the limitations of the challenged 967 patent claims are disclosed in the 226 patent. As confirmed by Dr. Shepherd, the 226 patent discloses that daptomycin is useful for treating infectious disease, including those caused by Gram-positive bacteria. (Exh. 1005, 40). Dr. Shepherd has also confirmed that the compound designated LY in the 226 patent is daptomycin. (Exh. 1005, 40) Claim 1 a. The 226 patent anticipates the claimed dose ranges and amounts. The 226 patent discloses a typical daily dose in humans of from about 100 mg to about 1.0 g. Assuming an average adult human weighs 70 kg, this range corresponds to 1.4 mg/kg to 14 mg/kg. (Exh. 1005, 41). It is an 3 See Section V.A.3. for a claim chart detailing the disclosures of the 226 patent that anticipate the challenged claims. -14-

22 elementary principle of patent law that when as by a recitation of ranges or otherwise, a claim covers several composition, the claim is anticipated if one of them is in the prior art. Titanium Metals Corp. v. Banner, 778 F.2d 775, 782 (Fed. Cir. 1985). And in the absence of extenuating circumstances, a prior art range that overlaps a claimed range anticipated that claimed range. See Titanium Metals, 778 F.2d at 782. The Federal Circuit has found extenuating circumstances if the claimed range was critical to the invention and there was a considerable difference between the range taught in the prior art and the claimed range. See ClearValue v. Pearl River Polymer, 668 F.3d 1340, (Fed. Cir. 2012) citing Atofina v. Great Lakes Chem. Corp., 441 F.3d 991 (Fed. Cir. 2006). There are no extenuating circumstances here that would render the recited dosage amounts patentable. None of the dose amounts or ranges recited in the claims is identified in the 967 patent as being critical to the invention. The broadest dosing range 3mg/kg to 75mg/kg is recited in independent claims 1, 12, and 26. Narrower ranges and specific doses are recited in the independent claims. For example, claims 3, 13, and 27 recite 3 to 12 mg/kg. Claims 6 and 20 recite 10 to 25 mg/kg. Claim 18 recites 25 to 75 mg/kg, and claims 4, 5, 7, 14, 15, 16, 17, 19, 21, 28, 34, and 35 recite specific dose amounts between 3 and 25 mg/kg Examples 4 and 5 disclose administering daptomycin to humans. Example 4 discloses 3, 4 and 6 mg/kg doses without identifying any particular dose as being -15-

23 particularly safe, effective or otherwise beneficial. (Exh. 1001, 12:64-13:55). Example 5 states that [d]osage levels that may be used include 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, or 25 mg/kg. Other dosage levels that are lower than, intermediate to, or higher than these dosage levels also may be used. (Exh. 1001, 14:9-11). Accordingly, the specification itself teaches that the claimed ranges or dose amounts are not critical to the claimed invention. (Exh. 1005, 41). The purported ability of the claimed invention to minimize skeletal muscle toxicity also does not create any extenuating circumstances that would overcome the anticipating disclosures of the 226 patent. The only examples in the 967 patent of daptomycin being administered to humans are in Example 4. (Exh. 1001, 12:64-13:60). Example 4 discloses administration of 4 and 6 mg/kg every 24 hours and the administration of 6 mg/kg followed by 3 mg/kg every 12 hours. (Id.) It was reported that these dosing regimens did not cause an increase in serum CPK levels above the normal range ( U/L) in a majority of patients. (Exh. 1001, 13:8-11). In the very next example, the 967 discloses that a broad range of doses from 7 to 25 mg/kg may be used. (Exh. 1001, 14:8-10). Similarly, the claims themselves teach that the ranges and doses recited therein minimize muscle toxicity. In other words, according to the specification itself, administration of any recited dose would allegedly minimize muscle toxicity. The patentee s own statements concede that minimizing muscle toxicity is not linked to a particular -16-

24 dose or dose range and does not create an extenuating circumstance that overcomes anticipation by the 226 patent. The range disclosed in the 226 patent substantially overlaps with the broadest range recited in claims 1, 12, and 26 (3-75 mg/kg) and with the range recited in claims 6 and 20 (10 to 25 mg/kg) and therefore anticipates those recited ranges. The range of 3 to 12 mg/kg recited in claims 3, 13, and 27 is subsumed within the range disclosed in the 226 patent, 1.4 to 14 mg/kg. Like overlapping ranges, a claimed range that is subsumed within a prior art range is anticipated absent extenuating circumstances, which are not present here. ClearValue v. Pearl River Polymers, 668 F.3d 1340, 1345 (Fed. Cir. 2012). Even if the 226 patent does not expressly disclose the specific dosage amounts recited in claims 4, 5, 7, 14, 15, 16, 17, 19, 21, 28, 34, and 35, those claims are still anticipated by the range of doses 1.4 to 14 mg/kg disclosed in the 226 patent. The prior art need not disclose the precise number within the disclosed range. The Federal Circuit recently described as silly the notion that [a] reference to 5-15 mg did not disclose all dosages between 5 and 15 mg. Tyco Healthcare Grp. v. Mutual Pharm., 642 F.3d 1370, 1373, n.3 (Fed. Cir. 2011). The issue is whether the genus was of such a defined and limited class that one of ordinary skill in the art could at once envisage each member of the genus. Wm. Wrigley Jr. Co. v. Cadbury Adams USA, 683 F.3d 1356, 1361 (Fed. Cir. 2012). It -17-

25 is apparent here that the disclosed range of 1.4 to 14 mg/kg would enable a person of skill in the art to envisage all the likely doses in that relatively narrow range, including the 13 integers between 1.4 and 14. (Exh. 1005, 46). b. The 226 patent anticipates the claimed dosing intervals. The 226 patent discloses administering daptomycin as a single daily dose. (Exh.1008, 10:59-60; Exh. 1005, 44). A person of skill in the art would have understood that a single daily dose is equivalent to once every 24 hours which is recited in the 967 patent claims. (See Exh. 1005, 42). The 967 patent claims all recite dosage intervals that include every 24 hours. Therefore, the 226 anticipates the recited dosing interval limitations. See Titanium Metals Corp., 778 F.2d at 782 (Fed. Cir. 1985) (It is an elementary principle of patent law that when as by a recitation of ranges or otherwise, a claim covers several composition, the claim is anticipated if one of them is in the prior art. ). c. The 226 patent inherently discloses skeletal muscle toxicity While it may be true the 226 patent does not expressly refer to minimizing skeletal muscle toxicity, the toxicity is an inherent property of the recited dose and dose interval. In other words, the toxicity of the prior art regimens with the same doses and dosing intervals recited in the claims will inherently possess the claimed toxicity profile. (Exh. 1005, 21, 42). It is well established that an inherent -18-

26 disclosure occurs when the prior art necessarily functions in accordance with the disputed claimed limitation. Leggett & Platt, Inc. v. Butek, Inc., 537 F.3d 1349, 1354 (Fed. Cir. 2008). A person of ordinary skill need not have full recognition of those benefits. Perricone, 432 F.3d at As discussed in Section V.A.1.a., above, the 226 patent discloses a dosing range of 1.4 to 14 mg/kg. (Exh. 1005, 41). Dr. Shepherd confirms that a person of skill in the art would be able to envisage all the likely doses in that relatively narrow range, including the 13 integers between 1.4 and 14. (Exh 1005, 41 and 46). Accordingly, the 226 patent s disclosure of certain doses 4 or 6 mg/kg, for example administered daily would inherently possess the recited muscle toxicity properties. This conclusion is supported by the 967 patent itself which discloses broadly that doses of from 7-25 mg/kg may be used and specifically that doses of 4 or 6 mg/kg administered every 24 hours did not result in skeletal muscle toxicity. (Exh. 1001, 14:8-10; 13:8-18). d. The 226 patent discloses repeated administration. The 226 patent discloses that the treatment regime may require administration over extended periods of time, e.g., for several days or from two to four weeks (Exh. 1008, 10:61-62) and that the drug may be administered as a single daily dose. (Exh. 1008, 10:60-61). A dose administered once a day for several days or from two to four weeks will necessarily be administered -19-

27 repeatedly. Accordingly, the 226 patent s description of a daptomycin dosing regimen includes repeatedly administering the drug. (Exh. 1005, 43). 2. The 226 patent also anticipates claims 2-7, 12-17, 20-28, and As indicated in the chart below and confirmed by Dr. Shepherd, claims 2-7, 12-17, 20-28, and are anticipated by the 226 patent. (Exh. 1005, 45-55). 3. Claim chart As shown in the following chart, all the limitations of the challenged claims are disclosed in the 226 patent, arranged as claimed, so as to enable a person of ordinary skill in the art to make and use the invention claimed in the 967 claims without the need for undue experimentation in light of the general knowledge available in the art. Claim 1 A method for administering daptomycin, 6,468, patent In the parent group described by Abbott et al., one particular compound has been found to have especially outstanding activity, i.e., the compound wherein the reacylated side chain is n-decanoyl. This compound has been given the designation LY (7:61-65). In a further aspect, this invention provides a method for treating infectious diseases, especially those caused by Gram-positive bacteria, in animals.... The method comprises administering to the animal an effective dose of a compound of this invention. (10:46-51). comprising the step of administering to a human The method comprises administering to the animal an effective dose... (10:51-52). -20-

28 patient in need thereof a therapeutically effective amount of daptomycin in a dose of 3 to 75 mg/kg of daptomycin A typical daily dose for an adult human is from about 100 mg to about 1.0 g (10:57-58). A typical daily dose for an adult human is from about 100 mg to about 1.0 g. (10:57-58). at a dosage interval that minimizes skeletal muscle toxicity, wherein the daptomycin dose is repeatedly administered at a dosage interval of once every 24 hour to once every 48 hours. Claim 2 claim 1, wherein daptomycin is administered at a dosage interval of once every 24 hours or once every 48 hours. Claim 3 claim 1, wherein the dose is 3 to 12 mg/kg Claim 4 claim 3, wherein the dose is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg/kg. This range corresponds to a range of 1.4 mg/kg to 14 mg/kg for an average adult human who weighs 70 kg. (Exh ). In practicing this method, the antibiotic compound can be administered as a single daily does or in multiple doses per day. The treatment regime may require administration over extended periods of time, e.g., for several days or from two to four weeks. (10:59-64). In practicing this method, the antibiotic compound can be administered as a single daily does or in multiple doses per day. (10:60-61). A typical daily dose for an adult human is from about 100 mg to about 1.0 g. (10:57-58). This range corresponds to a range of 1.4 mg/kg to 14 mg/kg for an average adult human who weighs 70 kg. (Exh. 1005, 41). See claim 3. Claim 5 See claim

29 claim 4 wherein the dose is 4, 6, 8 or 10 mg/kg Claim 6 claim 1, wherein the dose is 10 to 25 mg/kg Claim 7 claim 6, wherein the dose is 10, 11, 12, 13, 14, 15, 16, 20 or 25 mg/kg. Claim 12 A method for administering daptomycin, See claim 3. See claim 3. In the parent group described by Abbott et al., one particular compound has been found to have especially outstanding activity, i.e., the compound wherein the reacylated side chain is n-decanoyl. This compound has been given the designation LY (7:61-65). In a further aspect, this invention provides a method for treating infectious diseases, especially those caused by Gram-positive bacteria, in animals.... The method comprises administering to the animal an effective dose of a compound of this invention. (10:46-51). comprising the step of administering to a human patient in need thereof a therapeutically effective amount of daptomycin at a dose of 3 to 75 mg/kg of daptomycin at a dosage interval that minimizes skeletal The method comprises administering to the animal an effective dose... (10:51-52). A typical daily dose for an adult human is from about 100 mg to about 1.0 g (10:57-58). A typical daily dose for an adult human is from about 100 mg to about 1.0 g. (10:57-58). This range corresponds to a range of 1.4 mg/kg to 14 mg/kg for an average adult human who weighs 70 kg. (Exh. 1005, 41). In practicing this method, the antibiotic compound can be administered as a single daily does or in multiple -22-

30 muscle toxicity, wherein the daptomycin dose repeatedly administered at a dosage interval of once every 24 hours. Claim 13 claim 12, wherein the dose is 3 to 12 mg/kg Claim 14 claim 13, wherein the dose is 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg/kg. Claim 15 claim 14, wherein the dose is 4, 6, 8 or 10 mg/kg. Claim 16 claim 14, wherein the dose is 4 mg/kg administered once every 24 hours. Claim 17 claim 14, wherein the dose is 6 mg/kg administered once every 24 hours. Claim 18 claim 13, wherein the dose is 25 to 75 mg/kg. Claim 19 claim 18, wherein the dose is 25, 50 or 75 doses per day. The treatment regime may require administration over extended periods of time, e.g., for several days or from two to four weeks. (10:59-64). See claim 3. See claim 3. See claim 3. See claim 3. See claim 2. See claim 3. See claim 2. See claim 3. See claim

31 mg/kg. Claim 20 claim 12, wherein the dose is 10 to 25 mg/kg. Claim 21 claim 20, wherein the dose is 10, 11, 12, 13, 14, 15, 16, 20 or 25 mg/kg. Claim 22 either of claim 1 or 12, wherein said administering is via oral, subcutaneous or intravenous administration. See claim 3. See claim 3. Pharmaceutical formulations of... [daptomycin] or its salts are also part of this invention. The compounds, preferably as a pharmaceutically acceptable salts, can be formulated for oral or parenteral administration... (9:51-55). For intravenous (IV) use, a water soluble form of the compound can be dissolved in one of the commonly used intravenous fluid and administered by infusion. (10:19-21). Claim 23 either of claim 1 or 12, wherein the daptomycin is administered for 3 days to 6 months. Claim 24 either of claims 1 or 12, wherein the daptomycin is administered for 7 to For oral use, solid formulations such as tablets and capsules are particularly useful. (10:33-34). The treatment regime may require administration over extended periods of time, e.g., for several days or for from two to four weeks. (10:61-63). See claim days. Claim 25 See claim

32 either of claims 1 or 12, wherein the daptomycin is administered for 7 to 14 days. Claim 26 A method for treating or eradicating a bacterial infection in a human patient in need thereof, In the parent group described by Abbott et al., one particular compound has been found to have especially outstanding activity, i.e., the compound wherein the reacylated side chain is n-decanoyl. This compound has been given the designation LY (7:61-65). In a further aspect, this invention provides a method for treating infectious diseases, especially those caused by Gram-positive bacteria, in animals.... The method comprises administering to the animal an effective dose of a compound of this invention. (10:46-51). comprising the step of administering a therapeutically effective amount of daptomycin in a dose of 3 to 75 mg/kg to the patient at a dosage interval that minimizes skeletal muscle toxicity, wherein the daptomycin dose is repeatedly administered at the dosage interval of once every 24 hours to once every 48 hours until said bacterial infection is treated or eradicated. The method comprises administering to the animal an effective dose... (10:51-52). A typical daily dose for an adult human is from about 100 mg to about 1.0 g (10:57-58). A typical daily dose for an adult human is from about 100 mg to about 1.0 g. (10:57-58). This range corresponds to a range of 1.4 mg/kg to 14 mg/kg for an average adult human who weighs 70 kg. (Exh. 1005, 41). In practicing this method, the antibiotic compound can be administered as a single daily does or in multiple doses per day. The treatment regime may require administration over extended periods of time, e.g., for several days or from two to four weeks. (10:59-64). In a further aspect, this invention provides a method for treating infectious diseases, especially those caused by Gram-positive bacteria, in animals.... The method -25-

33 Claim 27 claim 26, wherein the dose is 3 to 12 mg/kg. Claim 28 claim 26 wherein the dose is 3, 4, 5, 6, 7, 8, 9, 20, 11 or 12 mg/kg. Claim 32 any one of claims 26 or 29, wherein said administering is via oral, subcutaneous or intravenous administration. Claim 33 any one of claims 26 or 29, wherein said administering is once every 24 hours. Claim 34 claim 33, wherein the dose is 4 mg/kg Claim 35 claim 33, wherein the dose is 6 mg/kg Claim 36 claim 33, wherein the daptomycin is administered for 3 days to 6 months. comprises administering to the animal an effective dose of a compound of this invention. (10:46-51). See claim 3. See claim 3. See claim 22. See claim 2. See claim 3. See claim 3. See claim

34 Claim 37 claim 33, wherein the daptomycin is administered for 7 to 28 days. Claim 38 claim 33, wherein the daptomycin is administered for 7 to 14 days. Claim 39 either of claim 26 or 29, wherein the daptomycin is administered for 3days to 6 days. Claim 40 either of claims 26 or 29, wherein the daptomycin is administered for 7 to 28 days. Claim 41 either of claims 26 or 29, wherein the daptomycin is administered for 7 to 14 days. Claim 42 claim 16, wherein said administering is via intravenous administration Claim 43 claim 17, wherein said See claim 23. See claim 23. See claim 23. See claim 23. See claim 23. See claim 22. See claim

35 administering is via intravenous administration. Claim 44. claim 34, wherein said administering is via intravenous administration. Claim 45 claim 35, wherein said administering is via intravenous administration. See claim 22. See claim 22. B. Ground 2: Woodworth anticipates Claims 1-5, 12-17, 22, 26-28, 32-35, and The Woodworth article is entitled Single-Dose Pharmacokinetics and Antibacterial Activity of Daptomycin, a New Lipopeptide Antibiotic in Healthy Volunteers. (Exh. 1009). Woodworth was published in 1992 and is prior art under 35 U.S.C. 102(b) because it was published more than one year before the earliest priority date. As detailed below, all the limitations of the challenged 967 patent claims are disclosed in Woodworth Claim 1 4 See Section V.B.3. for a claim chart detailing the disclosures in Woodworth that anticipate the challenged claims. -28-

36 a. Woodworth anticipates the claimed dose ranges and amounts. Woodworth administered single doses of 2, 3, 4, and 6 mg/kg and concluded that good antibacterial activity would be produced from single doses of 4 to 6 mg/kg. (Exh. 1009, 319 and 324; Exh. 1005, 26)). The disclosed doses in Woodworth fall within the ranges cited in claims 1, 3, 12, 13, 26, and 27. Accordingly, the recited dose range limitations are anticipated. See Titanium Metals Corp. v. Banner, 778 F.2d 775, 782 (Fed. Cir. 1985) (It is an elementary principle of patent law that when as by a recitation of ranges or otherwise, a claim covers several composition, the claim is anticipated if one of them is in the prior art ). Similarly, one or more of the specific doses recited in claims 4, 5, 14, 15, 16, 17, 28, 34, and 35 are disclosed in Woodworth. Accordingly, the specific dose amounts disclosed in these claims are also anticipated. See Titanium Metals Corp. v. Banner, 778 F.2d 775, 782 (Fed. Cir. 1985). b. Woodworth anticipates the claimed dosing intervals. Woodworth twice discloses dosing daptomycin once daily. (See Exh. 1009, Abstract) ( On the basis of the drug s pharmacokinetics and antibacterial activity, doses of 4 to 6 mg/kg/day, possibly in divided doses, are predicted effective. ); p. 324 (... allowing once- or twice-daily administration with the proper doses. ); Exh. 1005, 29). A person of skill in the art would have understood that a single -29-

37 daily dose is equivalent to once every 24 hours which is recited in the 967 patent claims. (See Exh. 1005, 29). The 967 patent claims all recite dosage intervals that include every 24 hours. Therefore, Woodworth anticipates the recited dosing interval limitations. See Titanium Metals Corp. v. Banner, 778 F.2d 775, 782 (Fed. Cir. 1985) (It is an elementary principle of patent law that when as by a recitation of ranges or otherwise, a claim covers several composition, the claim is anticipated if one of them is in the prior art. ) The fact that Woodworth discloses twice-daily administration along with once-daily dosing does not change the conclusion that Woodworth anticipates. (Exh. 1009, 324). The Federal Circuit has rejected the erroneous assumption that the disclosure of multiple examples renders one example less anticipatory. Leggett, 537 F.3d at Indeed, in Perricone, the prior art reference taught fourteen skin benefit ingredients. Perricone v. Medicis Pharmaceutical Corp., 432 F.3d 1368, 1376 (Fed. Cir. 2005). Yet the use of one... anticipate[d] [the patentee s] claims. Id. at c. Woodworth inherently discloses minimized skeletal muscle toxicity. Even if Woodworth does not expressly refer to minimizing skeletal muscle toxicity, the article does state that [n]o adverse events were reported or observed during the course of these studies. All doses were well tolerated. (Exh. 1009, 321). In any event, the toxicity is an inherent property of the recited dose and dose -30-

38 interval. (Exh. 1005, 21, 27). In other words, the toxicity of the prior art regimens with the same doses and dosing intervals recited in the claims will inherently possess the claimed toxicity profile. (Exh. 1005, 21, 27). It is well established that an inherent disclosure occurs when the prior art necessarily functions in accordance with the disputed claimed limitation. Leggett, 537 F.3d at A person of skill need not have had full recognition of those benefits. Perricone, 432 F.3d at In addition, it is not necessary that the prior art actually have administered the dosing regimen which it suggests. See Bristol- Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368, 1379 (Fed. Cir. 2001). ( Furthermore, although he did not actually premedicate the patients himself, anticipation does not require actual performance of suggestions in a disclosure. ). Accordingly, the dosing regimen Woodworth suggests 4 to 6 mg/kg/day inherently anticipates the minimizing skeletal muscle toxicity limitation. This conclusion is supported by the 967 patent itself which discloses, broadly, that doses of from 7-25 mg/kg may be used and, specifically, that doses of 4 or 6 mg/kg administered every 24 hours did not result in skeletal muscle toxicity. (Exh. 1001, 14:8-10; 13:8-18). d. Woodworth discloses repeated administration. Woodworth suggests once- or twice-daily administration with the proper doses. (Exh.1009, 324). Dr. Shepherd confirms that a person of skill would have -31-

39 understood that this conclusion indicated that daptomycin was intended to be dosed repeatedly. (Exh. 1005, 28). Not only does Woodworth refer to doses, i.e., more than one dose, but administering repeated doses would also have been apparent to a person of skill in order to effectively treat a gram-positive bacterial infection. (Exh. 1005, 28). 2. Woodworth anticipates 967 patent claims 2-5, 12-17, 22, 26-28, 32-35, and As indicated in the chart above and confirmed by Dr. Shepherd, claims 2-5, 12-17, 22, 26-28, 32-35, and are anticipated by the 226 patent. (Exh. 1005, 30-38). 3. Claim Chart As shown in the following chart, all the limitations of the challenged claims are disclosed in Woodworth, arranged as claimed, so as to enable a person of ordinary skill in the art to make and use the invention claimed in the 967 claims without the need for undue experimentation in light of the general knowledge available in the art. Claim 1 A method for administering daptomycin, 6,468,967 Woodworth Three separate single-dose studies were performed to define the disposition and pharmacokinetics of daptomycin in healthy volunteers. (Abstract). On the basis of the drug s pharmacokinetics and antibacterial activity, doses of 4 to 6 mg/kg/day, possibly in divided doses, are predicted to be -32-

40 comprising the step of administering to a human patient in need thereof a therapeutically effective amount of daptomycin in a dose of 3 to 75 mg/kg of daptomycin effective. (Abstract). Three separate single-dose studies were performed to define the disposition and pharmacokinetics of daptomycin in healthy volunteers. (Abstract). On the basis of the drug s pharmacokinetics and antibacterial activity, doses of 4 to 6 mg/kg/day, possibly in divided doses, are predicted to be effective. (Abstract) In conclusion, our data suggests that good antibacterial activity would be produced from single doses of 4 to 6 mg/kg. (p. 324) On the basis of the drug s pharmacokinetics and antibacterial activity, doses of 4 to 6 mg/kg/day, possibly in divided doses, are predicted to be effective. (Abstract). Six volunteers were administered daptomycin in successive single doses of 2, 3, 4, and 6 mg/kg. (p. 319). at a dosage interval that minimizes skeletal muscle toxicity, wherein the daptomycin dose is repeatedly administered at a dosage interval of once every 24 hour to once every 48 hours. Claim 2 In conclusion, our data suggests that good antibacterial activity would be produced from single doses of 4 to 6 mg/kg. (p. 324). On the basis of the drug s pharmacokinetics and antibacterial activity, doses of 4 to 6 mg/kg/day, possibly in divided doses, are predicted to be effective. (Abstract). No adverse events were reported or observed during the course of these studies. All doses were well tolerated. (p. 321).... allowing one- or twice-daily administration with the proper doses. In conclusion, our data suggests that good antibacterial activity would be produced from single doses of 4 to 6 mg/kg. (p. 324). -33-