Paper No Entered: May 14, 2015 UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD

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1 Paper No Entered: May 14, 2015 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 Before LORA M. GREEN, TINA E. HULSE, and CHRISTOPHER G. PAULRAJ, Administrative Patent Judges. PAULRAJ, Administrative Patent Judge. DECISION Institution of Inter Partes Review 37 C.F.R

2 I. INTRODUCTION Fresenius-Kabi USA LLC ( Petitioner ) filed a Petition requesting an inter partes review of claims 1 7, 12 28, and of U.S. Patent No. 6,468,967 B1 (Ex. 1001, the 967 patent ). Paper 1 ( Pet. ). Cubist Pharmaceuticals, Inc. ( Patent Owner ) filed a Preliminary Response to the Petition. Paper 10 ( Prelim. Resp. ). We have jurisdiction under 35 U.S.C. 314, which provides that an inter partes review may not be instituted unless... there is a reasonable likelihood that the petitioner would prevail with respect to at least 1 of the claims challenged in the petition. 35 U.S.C. 314(a). Upon considering the Petition and Preliminary Response, we determine that Petitioner has shown a reasonable likelihood that it would prevail in showing the unpatentability of claims 1 7, 12 28, and Accordingly, we institute an inter partes review of those claims. A. Related Proceedings The parties identify several related matters, including the co-pending district court case, Cubist Pharms., Inc. v. Fresenius-Kabi USA LLC, 1:14- cv gms (D.Del.). Pet. 1; Paper 3, 2; Paper 6, 2. Petitioner also filed a petition for inter partes review of related U.S. Patent No. 6,852,689 B2 (IPR ). B. The 967 Patent (Ex. 1001) The 967 patent relates to methods for administering a therapeutically effective amount of the antibiotic daptomycin in a manner that minimizes skeletal muscle toxicity. Ex. 1001, 3: Daptomycin has potent bactericidal activity against gram-positive bacteria that cause serious and life-threatening diseases. Id. at 1: Prior clinical trials and toxicology studies in animals found that skeletal muscle was the primary target tissue of 2

3 daptomycin toxicity. Id. at 2: Although low doses of daptomycin do not cause muscle toxicity, certain types of gram-positive bactericidal infections, such as deep-seated infections, or those caused by antibioticresistant bacterial strains, may require higher doses of daptomycin for effective treatment. Id. at 2: Thus, according to the Specification, there is a great need to develop methods for administration of effective amounts of daptomycin that will also minimize adverse skeletal muscle effects. Id. at 2: The Specification discloses the results of several studies that suggest that daptomycin-associated skeletal muscle toxicity is not related to the peak concentration of drug that occurs in the bloodstream after administration. Id. at 4: Nor does toxicity appear to relate to the total concentration of daptomycin in the bloodstream for 24 hours (i.e., the AUC24h). Id. at 4: Instead, the Specification states that the data suggest that the dosing interval is the key determinant of muscle toxicity, rather than just the magnitude of the dose itself. Id. at 4: Accordingly, the Specification discloses methods of providing daptomycin at a dosing interval of 24 hours or greater to minimize skeletal muscle toxicity and allow for higher peak concentrations of daptomycin. Id. at Abstract. C. Illustrative Claim Petitioner challenges claims 1 7, 12 28, and of the 967 patent. Claims 1, 12, and 26 are independent claims. Claim 1 is illustrative and is reproduced below: 1. A method for administering daptomycin, 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 at a dosage interval that minimizes skeletal muscle toxicity, wherein the daptomycin dose is 3

4 repeatedly administered at a dosage interval of once every 24 hours to once every 48 hours. D. The Asserted Grounds of Unpatentability Petitioner challenges the patentability of the claims of the 967 patent on the following grounds (Pet ): References Basis Claims challenged The 226 patent 1 102(e), (a) 1 7, 12 17, 20 28, and Woodworth 2 102(b) 1 5, 12 17, 22, 26 28, 32 35, and The 226 patent , 12 28, and The 226 patent and Woodworth , 12 28, and II. ANALYSIS A. Definition of One of Ordinary Skill in the Art According to Petitioner, a person of ordinary skill in the 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. Pet. 9 (citing Ex ). Patent Owner, on the other hand, asserts that a person of ordinary skill in the art would be familiar with methods for administering 1 Baker et al., US 5,912,226, issued June 15, 1999 (Ex. 1008). We refer to this reference as the 226 patent because that is how it is identified by both Petitioner and Patent Owner. 2 J. R. Woodworth et al., Single-dose Pharmacokinetics and Antibacterial Activity of Daptomycin, a New Lipopeptide Antibiotic, in Healthy Volunteers, 36 ANTIMICROB. AGENTS & CHEMOTHER (1992) (Ex. 1009). 4

5 antibiotics, and [t]hat person would typically hold a degree in pharmacy, medicine, chemistry, biochemistry, physiology, or a complementary discipline relevant to pharmacology, and have experience evaluating information concerning the safety and/or efficacy of drugs in mammals. Prelim. Resp. 11. We find the parties respective definitions of the person of ordinary skill in the art to be substantially similar in terms of education and experience requirements. We agree with Patent Owner, however, that a person of ordinary skill in the art would be familiar with methods for administering antibiotics, the relevant class of drugs for daptomycin, and we therefore incorporate that understanding as part of the level of ordinary skill in the art in our analysis. B. Claim Construction In an inter partes review, the Board interprets claim terms in an unexpired patent according to the broadest reasonable construction in light of the specification of the patent in which they appear. See In re Cuozzo Speed Techs., LLC, 778 F.3d 1271, (Fed. Cir. 2015); 37 C.F.R (b). Under that standard, and absent any special definitions, we give claim terms their ordinary and customary meaning, as would be understood by one of ordinary skill in the art at the time of the invention. See In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007). Any special definitions for claim terms must be set forth with reasonable clarity, deliberateness, and precision. See In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994). 1. at a dosage interval that minimizes skeletal muscle toxicity The term at a dosage interval that minimizes skeletal muscle toxicity appears in independent claims 1, 12, and 26. Petitioner argues that this term is directed to an intended result and, therefore, does not modify the 5

6 dosage interval of once every 24 to 48 hours set forth in the claims. Pet In other words, Petitioner argues that 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. Id. at 11. Patent Owner argues that the term is limiting, and should be construed as at a dosage interval that reduces skeletal muscle toxicity in comparison to dosing more than once every 24 hours. Prelim. Resp. 12. We are not persuaded based on the current record that the claim language suggests that the term at issue requires anything beyond administering daptomycin at the express dosage intervals recited in the claims. For example, claim 1 recites that daptomycin is administered in a dose of 3 to 75 mg/kg of daptomycin at a dosage interval that minimizes skeletal muscle toxicity, wherein the daptomycin dose is repeatedly administered at a dosage interval of once every 24 hours to once every 48 hours. The most natural reading of this language is that the wherein clause equates the dosage interval that minimizes skeletal muscle toxicity with a dosage interval of once every 24 hours to once every 48 hours. As such, the requirement of minimiz[ing] skeletal muscle toxicity would be understood as nothing more than the intended result or consequence of administering daptomycin at the specifically recited dosage interval. Our interpretation is consistent with the Specification, which repeatedly indicates that lengthening the dosing interval is what minimizes skeletal muscle toxicity. For example, the Abstract states that [t]he methods provide daptomycin administration at a dosing interval of 24 hours or greater. This long dosing interval minimizes skeletal muscle toxicity and allows for higher peak concentrations of daptomycin, which is related to 6

7 daptomycin s efficacy. Ex. 1001, Abstract (emphasis added). The Specification further presents data suggesting that the dosing interval is the key determinant of muscle toxicity. Id. at 4: The Specification also hypothesizes that skeletal muscle toxicity is related to time between doses for repair of skeletal muscle damage. Id. at 5: The Specification does not indicate that the minimization of skeletal muscle toxicity is due to any variable other than extending the dosage interval to once every 24 hours or more. Id. at 5: Patent Owner argues that the minimizes skeletal muscle toxicity claim language is limiting because it allegedly describes an essential part of the invention and was relied upon during prosecution to distinguish the claimed invention from the prior art. Prelim. Resp On the current record, we are unpersuaded by these contentions. To the extent that minimizing skeletal muscle toxicity is an essential part of the invention, it already is encompassed in the claims by the express dosage interval of once every 24 hours to once every 48 hours. Furthermore, we do not discern anything in the prosecution history that suggests that a dosage interval that minimizes skeletal muscle toxicity requires anything more than a lengthened dosage interval. Finally, none of the case law cited by Patent Owner precedential or otherwise addresses the issue of essentiality or prosecution history where the claim term at issue was defined further by additional language in the claim, particularly under the broadest reasonable interpretation standard. Accordingly, at this stage of the proceeding, we determine that the term at a dosage interval that minimizes skeletal muscle toxicity does not require anything beyond administering daptomycin at the express dosage intervals recited in the claims. 7

8 2. Remaining Claim Terms We determine that, for purposes of this Decision, none of the other terms in the challenged claims requires express construction. C. Anticipation by the 226 Patent Petitioner asserts that the 226 patent anticipates claims 1 7, 12 17, 20 28, and of the 967 patent. Pet As support, Petitioner submits the testimony of Dr. Alexander Shepherd. Ex We determine, on the current record, that Petitioner has established a reasonable likelihood that it would prevail in showing that the 226 patent anticipates claims 1 7, 12 17, 20 28, and The 226 Patent (Ex. 1008) The 226 patent relates to an antibacterial drug LY (i.e., daptomycin). Ex. 1008, Abstract; Ex The 226 patent discloses methods of treating infections caused by gram-positive bacteria by administering an effective dose of daptomycin. Ex. 1008, 10: The 226 patent states an effective dose is generally between about 0.1 and about 100 mg/kg of the drug, with the preferred dose from about 1 to about 30 mg/kg. Id. at 10: The 226 patent also states that a typical daily dose for an adult human is from about 100 mg to about 1.0 g. Id. at 10: In practicing the method, the 226 patent discloses that the antibiotic compound can be administered as a single daily dose or in multiple doses per day. Id. at 10: The 226 patent further discloses that the treatment regime may require administration over extended periods of time, such as for several days or two to four weeks. Id. at 10: According to the 226 patent, [t]he amount per administered dose or the total amount administered will depend on such factors as the nature and severity of the infection, the age and general health of the patient, the tolerance of the 8

9 patient to the antibiotic and the microorganism or microorganisms involved in the infection. Id. at 10:64 11:2. 2. Analysis Claim 1 requires administering to a human patient in need thereof daptomycin in a dose of 3 to 75 mg/kg, repeatedly at a dosage interval of once every 24 hours to once every 48 hours. Independent claim 12 is similar to claim 1, but recites that the dose is administered repeatedly once every 24 hours. Independent claim 26 is also similar to claim 1, but expressly recites treating or eradicating a bacterial infection. Each of these claims, as mentioned above, also requires administration at a dosage interval that minimizes skeletal muscle toxicity. Petitioner asserts that the 226 patent discloses the use of daptomycin at a typical daily dose in humans of from about 100 mg to about 1.0 g, and [a]ssuming an average adult human weighs 70 kg, this range corresponds to 1.4 mg/kg to 14 mg/kg. Pet Petitioner argues also that the 226 discloses that daptomycin can be administered as a single daily dose, which satisfies the requirement for a dosing interval of once every 24 hours. Id. at 18 (quoting Ex. 1008, 10:59 60). Petitioner argues further that the 226 patent teaches repeated administration of daptomycin by its disclosure that a dose may be administered once a day for several days or from two to four weeks. Id. at 19; Ex. 1008, 10: Finally, Petitioner notes that the recitation of a dosage interval that minimizes skeletal muscle toxicity is inherently satisfied by the 226 patent s disclosure of a dosing range 1.4 to 14 mg/kg that may be administered once every 24 hours. Pet. 19; Ex , 46. Based on the current record, we are persuaded that Petitioner has shown sufficiently that claims 1, 12, and 26 are anticipated by the 226 9

10 patent. In particular, we find that the 226 patent s disclosure of administering daptomycin at a dosage level between 1.4 mg/kg and 14 mg/kg provides sufficient specificity to anticipate the claimed range of 3 to 75 mg/kg. See Ineos USA LLC v. Berry Plastics Corp., No , 2015 WL , at *3 (Fed. Cir. Apr. 16, 2015) ( If the prior art discloses its own range, rather than a specific point, then the prior art is only anticipatory if it describes the claimed range with sufficient specificity such that a reasonable fact finder could conclude that there is no reasonable difference in how the invention operates over the ranges. ). Additionally, for the reasons discussed in the claim construction section above, we find based on the present record that the 226 patent s disclosure of a dosage interval of once every 24 hours necessarily satisfies the claim requirement of a dosage interval that minimizes skeletal muscle toxicity. We also have considered the arguments and evidence with respect to dependent claims 2 7, 13 17, 20 25, 27, 28, and 32 45, and determine that Petitioner has made a sufficient showing as to those claims, as well. Pet ; Ex , , 52 55; see infra (addressing Patent Owner s arguments). Accordingly, based on the record, we conclude that Petitioner has established a reasonable likelihood that it would prevail in showing that the 226 patent anticipates claims 1 7, 12 17, 20 28, and of the 967 patent. D. Anticipation by Woodworth Petitioner asserts that claims 1 5, 12 17, 22, 26 28, 32 35, and also are anticipated by Woodworth. Pet ; Ex We determine, based on the current record, that Petitioner has established a reasonable likelihood that it would prevail on this assertion. 10

11 1. Woodworth (Ex. 1009) Woodworth describes three studies to define the disposition and pharmacokinetics of daptomycin in healthy volunteers. Ex. 1009, Abstract. Woodworth generally discloses that [o]n 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. Id. In one study, Woodworth administered successive single doses of 2, 3, 4, and 6 mg/kg intravenously with at least 72 hours separating each dose. Id. at 319. Woodworth found that daptomycin exhibits extensive protein binding. Id. at 320. Woodworth also found that [n]o adverse events were reported or observed during the course of these studies. All doses were well tolerated. Id. at Analysis Petitioner argues that Woodworth s disclosure of that good antibacterial activity would be produced from single doses of 4 to 6 mg/kg satisfies the claimed dosage requirements of 3 mg/kg to 75 mg/kg recited in the independent claims as well as one or more of the specific doses recited in claims 4, 5, 14, 15, 16, 17, 28, 34, and 35. Pet. 29; Ex We are persuaded by this contention as the specifically disclosed doses of Woodworth fall within the broader range that is claimed. See Titanium Metals Corp. v. Banner, 778 F.2d 775, 782 (Fed. Cir. 1985). Petitioner also argues that a person of ordinary skill in the art would understand that Woodworth s disclosure of once daily dosing for daptomycin anticipates the claimed dosing intervals. Pet ; Ex. 1009, Abstract, 324 (allowing once-or twice-daily administration with the proper doses ); Ex We determine based on the current record that Woodworth teaches repeated administration of daptomycin once every 24 11

12 hours, and this disclosed dosing regimen would also necessarily satisfy the claim requirement of a dosing interval that minimizes skeletal muscle toxicity. We are, therefore, persuaded that Petitioner has shown sufficiently that claims 1, 12, and 26 are anticipated by Woodworth. We also have considered the arguments and evidence with respect to dependent claims 2 5, 13 17, 22, 27, 28, 32 35, and 42 45, and determine that Petitioner has made a sufficient showing as to those claims, as well. Pet ; Ex , 31, 33, 34, 36 38; see infra (addressing Patent Owner s arguments). Accordingly, based on the record, we conclude that Petitioner has established a reasonable likelihood that it would prevail in showing that Woodworth anticipates claims 1 5, 12 17, 22, 26 28, 32 35, and of the 967 patent. E. Obviousness over the 226 Patent and Woodworth Relying on the testimony of Dr. Shepherd, Petitioner asserts that claims 1 7, 12 28, and are unpatentable as obvious over the combination of the 226 patent and Woodworth. Pet ; Ex For the reasons discussed above, we find that either the 226 patent or Woodworth individually anticipate claims 1 7, 12 17, 20 28, and For the same reasons, we find those claims also rendered obvious by the combination of the 226 patent and Woodworth. Claims 18 and 19 recite a daptomycin dose between 25 mg/kg and 75 mg/kg, which falls outside the dosage range disclosed by the 226 patent and Woodworth. Nonetheless, we determine based on the current record that it would have been obvious to use a larger dose of daptomycin to treat more severe infections. Pet. 46; Ex ,

13 We, therefore, determine, on the current record, that Petitioner has established a reasonable likelihood that it would prevail on this assertion. F. Patent Owner s Arguments In response, Patent Owner raises four primary arguments for why we should deny the Petition. At this stage of the proceeding, we are not persuaded by any of the arguments. We address each in turn below. 1. Failure to Address the Minimizes Skeletal Muscle Toxicity Limitation Patent Owner contends that the Petition should be denied because it does not specify where the prior art discloses at a dosage interval that minimizes skeletal muscle toxicity. Prelim. Resp. 23. As explained above, at this stage of the proceeding, we determine that this claim element does not require anything beyond a dosage interval of once every 24 hours, or once every 24 hours to once every 48 hours, as further recited in the claims. Accordingly, we determine that the Petition has addressed this element of the claims adequately. 2. Improper Reliance on Additional References to Supply Teachings for Petitioner s Obviousness Analysis Patent Owner argues that the obviousness grounds are deficient under 37 C.F.R (b) because the Petition improperly relies on additional information and references that are not cited in the grounds in order to establish the claim elements. Prelim. Resp. 27. Specifically, Patent Owner complains that the Petition and Shepherd Declaration relies improperly on additional references in an attempt to establish that a person of ordinary skill in the art would have identified the claimed dosing amounts and intervals, and been motivated to administer daptomycin at larger doses and longer 13

14 intervals with a reasonable expectation of success in obtaining a safe and effective dosing regimen as claimed. Id. at 28. We are not persuaded that the Petition has violated our Rules. As explained above, we are persuaded that Petitioner has demonstrated a reasonable likelihood that the claims are obvious over the prior art relied upon in challenging the claims. That showing included a limitation-bylimitation analysis from Petitioner s Declarant, Dr. Shepherd, and detailed claim charts identifying where each limitation of the claims is disclosed in the cited prior art. Under the circumstances of this case, we do not find it improper to cite to other prior art references as support for Petitioner s assertions regarding the state of the art at the time of the claimed invention. Indeed, we require such support for any opinions rendered by alleged expert witnesses. See 37 C.F.R (a) ( Expert testimony that does not disclose the underlying facts or data on which the opinion is based is entitled to little or no weight. ). Thus, we reject Patent Owner s suggestion to penalize Petitioner for citing additional prior art references that support the reasoning of its declarant. 14

15 3. 35 U.S.C. 325(d) Patent Owner argues that we should deny the Petition because it relies on prior art presented previously to the PTO during prosecution. Prelim. Resp As Patent Owner recognizes, however, rejecting a petition under 35 U.S.C. 325(d) is discretionary. Here, we decline to exercise our discretion to deny the Petition, particularly in light of the foregoing determination that Petitioner has established a reasonable likelihood of prevailing on its patentability challenges. 4. Duplicative Grounds Finally, Patent Owner argues that the Petition s Ground 1, i.e., anticipation by the 226 patent, should be denied because it relies on the same prior art as Ground 1 of Agila Specialties Inc. and Mylan Pharmaceuticals Inc. s ( Agila s ) inter partes review petition against the same patent. See Agila Specialties Inc. and Mylan Pharms. Inc. v. Cubist Pharms., Inc., IPR , Paper 4, at (P.T.A.B.) ( IPR Petition ). Prelim. Resp. 43. We find this argument moot in view of the recent termination of IPR prior to institution. See IPR , slip op. at 2 (PTAB Apr. 28, 1015) (Paper 17). G. Remaining Challenge Petitioner also asserts that the challenged claims of the 967 patent are unpatentable as obvious over the 226 patent alone. Pet Because this ground relies upon the same teachings of the 226 patent that are relied upon with respect to the obviousness ground based on the combination of the 226 patent and Woodworth, we exercise our discretion not to institute an inter partes review on this asserted ground. See 37 C.F.R (a). 15

16 III. CONCLUSION We conclude that Petitioner has demonstrated a reasonable likelihood of prevailing on its assertion that claims 1 7, 12 28, and of the 967 patent are unpatentable. At this stage of the proceeding, the Board has not made a final determination as to the construction of any claim term or the patentability of any challenged claim. IV. ORDER In consideration of the foregoing, it is hereby: ORDERED that pursuant to 35 U.S.C. 314(a), an inter partes review is hereby instituted on the following grounds: I. Claims 1 7, 12 17, 20 28, and as anticipated by II. III. the 226 patent; Claims 1 5, 12 17, 22, 26 28, 32 35, and as anticipated by Woodworth; and Claims 1 7, 12 28, and as obvious over the combination of the 226 patent and Woodworth. FURTHER ORDERED that no other proposed grounds of unpatentability are authorized; and FURTHER ORDERED that pursuant to 35 U.S.C. 314(c) and 37 C.F.R. 42.4, notice is hereby given of the institution of a trial commencing on the entry date of this decision. 16

17 PETITIONER: Imron T. Aly Jason G. Harp Schiff Hardin LLP PATENT OWNER: Emily R. Whelan Jane M. Love Heather M. Petruzzi Wilmer Cutler Pickering Hale and Dorr LLP Gerard M. Devlin 17