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

Transcription

1 UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD FRESENIUS KABI USA, LLC, Petitioner v. CEPHALON, INC., Patent Owner Case IPR Patent No. 8,791,270 PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,791,270 UNDER 35 U.S.C AND 37 C.F.R ET SEQ. Mail Stop: Patent Board Patent Trial and Appeal Board United States Patent and Trademark Office P.O. Box 1450 Alexandria, VA

2 TABLE OF CONTENTS I. INTRODUCTION AND BACKGROUND... 1 II. NOTICES, STATEMENTS AND PAYMENT OF FEES... 7 A. Real Party In Interest Under 37 C.F.R. 42.8(b)(1)... 7 B. Related Matters Under 37 C.F.R. 42.8(b)(2)... 7 C. Lead and Back-Up Counsel Under 37 C.F.R. 42.8(b)(3)... 8 D. Service Information Under 37 C.F.R. 42.8(b)(4)... 9 E. Grounds for Standing Under 37 C.F.R (a)... 9 F. Fees Under 37 C.F.R III. IDENTIFICATION OF CHALLENGE UNDER 37 C.F.R (B)... 9 IV. FRESENIUS KABI S GROUNDS OF UNPATENTABILITY ARE NOT CUMULATIVE OF THOSE PRESENTED BY MYLAN...11 V. OVERVIEW OF THE 270 PATENT, PROSECUTION HISTORY, AND THE BOARD S RELEVANT INSTITUTION DECISIONS...12 A. The Alleged Invention of the 270 Patent B. The Prosecution History of the 190 and 270 Patents Prosecution History of the 190 Patent Prosecution History of the 270 Patent...15 C. The Mylan Inter Partes Review of the 190 Patent VI. LEVEL OF ORDINARY SKILL IN THE ART...18 VII. HOW THE CHALLENGED CLAIMS ARE TO BE CONSTRUED UNDER 37 C.F.R (B)(3)...18 A. Pharmaceutical Composition B. Pharmaceutical Composition That Has Been Reconstituted...20 C. Area Percent of Bendamustine...21 D. Bendamustine Degradants...22 i

3 E. Time Zero After Reconstitution VIII. DETAILED EXPLANATION AND SUPPORTING EVIDENCE UNDER 37 C.F.R (B)(4) AND (B)(5)...23 IX. A. Ground 1: Claims 1-20 Are Obvious Over Maas in View of Teagarden Scope and Content of the Prior Art A Person of Ordinary Skill in the Art Would Have Been Motivated to Combine Maas and Teagarden A Person of Ordinary Skill in the Art Would Have A Reasonable Expectation of Success in Reducing Degradant Levels The Combination of Maas and Teagarden Discloses Each and Every Claim Limitation B. Ground 2: Claims 13 and 19 Are Obvious Over Maas, Teagarden, and Gust C. Ground 3: Claims Are Obvious Over Maas, Teagarden, and the Ribomustin Product Monograph D. Ground 4: Claims 1-23 Are Obvious Over The Admitted Prior Art In The 270 Patent In View of Teagarden SECONDARY CONSIDERATIONS, EVEN IF CONSIDERED, FAIL TO OVERCOME THE EVIDENCE OF OBVIOUSNESS X. CONCLUSION...60 ii

4 TABLE OF AUTHORITIES Page(s) FEDERAL CASES AstraZeneca LP v. Breath Ltd., 603 F. App x 999 (Fed. Cir. 2015) Aventis Pharmaceuticals S.A. v. Hospira, Inc., 743 F. Supp. 2d 305 (D. Del. 2010) Bayer Healthcare Pharmaceuticals, Inc. v. Watson Pharmaceuticals, Inc., 713 F.3d 1369 (Fed. Cir. 2013) In re Bendamustine Consolidated Cases, Case No. 1:13-cv-2046 (D. Del. Dec. 19, 2013)...passim Bristol-Myers Squibb Co. v. Ben Venue Labs., Inc., 246 F.3d 1368 (Fed. Cir. 2001) Cephalon, Inc. v. Apotex, Inc., Case No. 1:5-cv-404 (D. Del. May 19, 2015)... 7 Cephalon, Inc. v. Nang Kuang Pharmaceuticals Company, Ltd., Case No. 1:4-cv-5180 (E.D.N.Y. Sept. 3, 2014)... 7 Cephalon, Inc. v. Panacea Biotec, Ltd., Case No. 1:5-cv-735 (D. Del. Aug. 25, 2015)... 7 Ex Parte Fyke, No , 2015 WL (P.T.A.B. June 22, 2015) Ex Parte Trans Tex. Holdings Corp., No , 2006 WL (B.P.A.I. Jan. 24, 2006) Goldenberg v. Cytogen, Inc., 373 F.3d 1158 (Fed. Cir. 2004)..14 In re Huai-Hung Kao, 639 F.3d 1057 (Fed. Cir. 2011) iii

5 In re Huang, 100 F.3d 135 (Fed. Cir. 1996) Par Pharmaceuticals, Inc. v. TWi Pharmaceuticals, Inc., 773 F.3d 1186 (Fed. Cir. 2014) In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003) Randall Mfg. v. Rea, 733 F.3d 1355 (Fed. Cir. 2013) Riverwood Internatinal Corp. v. R.A. Jones & Co., Inc., 324 F.3d 1346 (Fed. Cir. 2003) Teva Pharmaceuticals. USA, Inc. v. Sandoz, Inc., 789 F.3d 1335 (Fed. Cir. 2015) Wyers v. Master Lock Co., 616 F.3d 1231 (Fed. Cir. 2010) FEDERAL STATUTES 35 U.S.C , U.S.C , U.S.C U.S.C iv

6 PETITIONERS EXHIBIT LIST Exhibit No. Exhibit 1001 Exhibit 1002 Description U.S. Patent No. 8,791,270 ( the 270 patent ) Amended Complaint filed in Cephalon, Inc. v. Hetero Labs Ltd. v. Hetero USA, Inc., Case No. 13-cv-2046 (D. Del.) Exhibit 1003 Copy of Prosecution History for the U.S. Patent No. 8,791,270 (downloaded from PAIR) Exhibit 1004 Exhibit 1005 Exhibit 1006 Birgit Maas et al., Stability of Bendamustine Hydrochloride in Infusions, 49 PHARMAZIE 775 (1994) (German language original and certified English translation) ( Maas ) Dirk L. Teagarden & David S. Baker, Practical Aspects of Lyophilization using Non-Aqueous Co-Solvent Systems, 15 EUR. J. PHARM. SCI. 115 (March 2002) ( Teagarden ) R. Gust et al. Investigations on the Stability of Bendamustin, A Cytostatic Agent of the Nitrogen Mustard Type, I. Synthesis, Isolation, and Characterization of Reference Substances, 128 MONATSHEFT FÜR CHEMIE 291 (1997) ( Gust ) Exhibit 1007 The Ribomustin Product Monograph, 2002 ( Ribomustin Product Monograph ) Exhibit 1008 Exhibit 1009 The Rote Liste 2003 (German language original and certified English translation) ( Rote Liste ) Robert Thornton Morrison & Robert Neilson Boyd, Organic Chemistry 798 (4th ed. 1983) ( Thornton ) Exhibit 1010 V. Scasnar et al., Radiochemical Assay of Stability of C- Cytostasan Solutions During Preparation and Storage, 121 J. RADIOANAL. NUCL. CHEM. 489 (1988) ( Scasnar ) v

7 Exhibit 1011 Exhibit 1012 Exhibit 1013 Guidance for Industry Q3B(R) Impurities in New Drug Products, November USDHHS, Food and Drug Administration Institution Decision in Agila Specialties Inc. and Mylan Labs. Ltd. v. Cephalon, Inc., Paper No. 11, IPR (P.T.A.B. July 20, 2015) Declaration of Michael J. Akers, Ph.D. and Accompanying Exhibits Exhibit 1014 Copy of Prosecution History for the U.S. Patent No. 8,436,190 (downloaded from PAIR) Exhibit 1015 Exhibit 1016 Exhibit 1017 Exhibit 1018 Exhibit 1019 Exhibit 1020 Exhibit 1021 Dkt. No. 85, Case No. 1:13-cv-2046, In re Bendamustine Consolidated Cases Dkt. No. 360, Case No. 1:13-cv-2046, In re Bendamustine Consolidated Cases Declaration of Bernard Olsen, Ph.D. and Accompanying Exhibits Exhibit Comparing Specification of 270 Patent With Disclosure of Teagarden Dkt. No. 349, Case No. 1:13-cv-2046, In Re Bendamustine Consolidated Cases Dkt. No. 138, Case No. 1:13-cv-2046, In Re Bendamustine Consolidated Cases Thomas Beesley and Benjamin Buglio, Quantitative Chromatographic Analysis (2000) Exhibit 1022 Marvin C. McMaster, HPLC: A Practical User s Guide (1994) Exhibit 1023 R.J. Hamilton and P.A. Sewell, Introduction to High Performance Liquid Chromatography (1977) vi

8 Exhibit 1024 Raymond P.W. Scott, Liquid Chromatography for the Analyst (1994) Exhibit 1025 W. Furst et al., On the Hydrolytic Decomposition of IMET 3393, 108 PHARMAZEUTISCHE ZENTRALHALLE 489 (1969) ( Furst ) Exhibit 1026 Exhibit 1027 Exhibit 1028 Inspection Guides, Lyophilization of Parenterals (1993), Food and Drug Administration B. Nuijen et al., Pharmaceutical Development of a Parenteral Lyophilized Formulation of the Novel Antitumor Agent Aplidine, 54 PDA J. PHARM. SCI. TECH. 193 (2000) ( Nuijen ) Patent Owner Response in Agila Specialties Inc. and Mylan Labs. Ltd. v. Cephalon, Inc., Paper No. 9, IPR (P.T.A.B. April 21, 2015) Exhibit 1029 Norbert W. Tietz, Textbook of Clinical Chemistry (1986) Exhibit 1030 Exhibit 1031 Final Written Decision in Intri-Plex Techs., Inc. et al. v. Saint- Gobain Performance Plastics Rencol Ltd., Paper No. 83, IPR (P.T.A.B. March 23, 2015) Phyllis R. Brown, High Pressure Liquid Chromatography: Biochemical and Biomedical Applications (1973) Exhibit 1032 Colin F. Poole, The Essence of Chromatography (2003) Exhibit 1033 Exhibit 1034 Exhibit 1035 Alfonso R. Gennaro, Remington: The Science and Practice of Pharmacy (1885) Reinhard Klette, Combinatorial Image Analysis: 10th International Workshop, IWCIA 2004 Auckland, New Zealand, December 1-3, 2004 Proceedings (2004) The United States Pharmacopeia (USP29-NF24), General Tests and Assays (2006) vii

9 Petitioner Fresenius Kabi USA, LLC ( Petitioner ) requests inter partes review of claims 1-23 ( the challenged claims ) of U.S. Patent No. 8,791,270 ( the 270 patent ) (Exhibit 1001) pursuant to 35 U.S.C and 37 C.F.R et seq. I. INTRODUCTION AND BACKGROUND The challenged claims should never have been issued. They are drawn to pharmaceutical compositions of bendamustine hydrochloride a compound that has been in the public domain for more than 50 years having specified levels of known bendamustine degradants. Neither the compositions nor these degradant levels are novel or nonobvious. In fact, a number of the challenged claims directly read on Cephalon, Inc. s ( Cephalon ) own description and analysis of admitted prior art in the 270 patent specification. See Exhibit 1001 at Table 13. Because Petitioner is, at a minimum, reasonably likely to prevail in showing unpatentability of at least one challenged claim, this Petition should be granted and trial instituted on all of the challenged claims. The analysis relevant to this Petition is straightforward. There can be no reasonable dispute that pharmaceutical compositions of bendamustine hydrochloride such as Cytostasan and Ribomustin have been known, described, and widely used in Europe since at least 1971 to treat chronic lymphocytic leukemia ( CLL ) and non-hodgkin s lymphoma ( NHL ) the same indications 1

10 that Cephalon now purports to claim. See Exhibit 1001 at 2:1-8. Nor can there be any reasonable dispute that, many years before Cephalon s earliest claimed priority date, bendamustine hydrochloride was known to degrade in aqueous (water) solutions and yield certain hydrolysis degradants. See, e.g., Exhibit 1025 at 0001 (describing hydrolysis degradation in 1969). These hydrolysis degradants were described by their structure and termed HP1 (hydrolysis product 1) and HP2 (hydrolysis product 2) by German researchers long before Cephalon ever used that terminology in its claims. See, e.g., Exhibit 1006 at 0001 (using terminology and providing chemical structure in 1997). This prior knowledge of bendamustine hydrochloride degradation was not limited to just hydrolysis degradation. As the Board has already found in related proceedings, the same bendamustine ethyl ester ( BM1EE ) degradant that Cephalon now claims was actually reported in the literature by Gust approximately seven years before the earliest priority date. Exhibit 1012 at There will also not be any reasonable dispute that the degradation of bendamustine pharmaceutical compositions had been assessed using highperformance liquid chromatography ( HPLC ) the same analytical method that Cephalon discusses in the 270 patent specification nearly ten years before the earliest priority date. Indeed, in 1994, a team of researchers led by Birgit Maas published an HPLC chromatogram showing the degradation of Ribomustin and 2

11 formation of the HP1 degradant that Cephalon now claims: bendamustine HP1 Exhibit 1004 at As discussed in detail below, the degradants in the Maas HPLC chromatogram can be readily quantified Given the extensive overlap between the prior art and the alleged invention, Cephalon asserted that the crux of its alleged invention was a better impurity profile than Ribomustin with respect to certain impurities, in particular HP1... and bendamustine ethylester.... Exhibit 1001 at 12: According to Cephalon, it achieved this better impurity profile by lyophilizing bendamustine with tertiary-butyl alcohol ( TBA ) rather than ethanol, which was used in the 3

12 lyophilization procedure for the Ribomustin formulation. Exhibit 1014 at Cephalon s arguments fail to impart patentability for at least two independent reasons. First, Cephalon s purported basis of novelty does not square with and is expressly contradicted by the 270 patent specification. Indeed, a number of Cephalon s claims reciting an alleged improved impurity profile actually read on the very Ribomustin formulation that Cephalon purported to distinguish. See Exhibit 1001 at Table 13. According to Cephalon s own testing, Ribomustin had the following degradant profile (annotations in table by counsel): As shown in Table 13, every Ribomustin batch tested by Cephalon had BM1EE levels (calculated as area percent of bendamustine ) below 0.5%, thus readily meeting the degradant levels recited in claims 13 and 19 ( containing not more than about 0.5% (area percent of bendamustine) of [BM1EE] ). Similarly, every Ribomustin batch had a total degradant level of less than 4.0%, thus meeting the 4

13 degradant levels recited in claims 7 and Thus, Cephalon s own specification contradicts the purported point of novelty of several challenged claims. Second, beyond Cephalon s own description of the anticipatory nature of Ribomustin, others in the art had solved the same problem (i.e., purportedly high impurity levels) using the exact same solution that Cephalon later claimed. As a threshold matter, the motivation for lowering impurities in a pharmaceutical composition cannot reasonably be disputed. As Cephalon itself admitted, [t]he desirability of keeping the amount of impurities low in a pharmaceutical composition is well known in the art. Exhibit 1014 at In light of this established motivation, a number of researchers studied the effect of alcohols in the lyophilization process on the degradation rate of a drug product well before Cephalon s earliest priority date. See generally Exhibit 1027; Exhibit In particular, in 2001, a researcher named Teagarden published a review article on the effect of utilizing TBA in the lyophilization process. Exhibit 1005 at Teagarden reported that the use of TBA in the lyophilization 1 As explained in further detail below, the level of BM1EE (expressed as area percent of bendamustine ) for each of these lots would be: 0.21%, 0.20%, 0.30%, and 0.19%. The amount of total degradants (expressed as area percent of bendamustine ) for each of these lots would be: 1.86%, 2.33%, 3.07%, and 2.39%. 5

14 process significantly reduced the degradation rate for lyophilized drugs by a factor of approximately 4-5. Id. at Teagarden further noted [t]his type of effect would be expected to be observed for many other drug products [that] are degraded in the presence of water. Id. at As the Board has recognized, bendamustine is precisely such a drug. Exhibit 1012 at Thus, as the Board has already found in related proceedings, there was ample motivation before the priority date to improve the stability of existing bendamustine hydrochloride formulations such as Ribomustin by applying Teagarden s teaching of the benefits of TBA. Id. at Cephalon appears to have done exactly that, as portions of the 270 patent specification relating to solvent selection appear to be identical to the disclosure of Teagarden. Exhibit 1018 (comparing Teagarden with portions of specification). As detailed below, Maas and Teagarden render obvious claims Additionally, claims 13 and 19 are rendered obvious over Maas, Teagarden, and Gust. Claims are obvious over Maas, Teagarden, and the Ribomustin Product Monograph, which teaches that Ribomustin was utilized for the same indications that Cephalon now claims. Finally, claims 1-23 are obvious over the admitted prior art in the 270 patent in view of Teagarden. The Board has recognized that admitted prior art rejections even if the admitted prior art is in the challenged patent itself are appropriate in an IPR. Exhibit 1030 at

15 II. NOTICES, STATEMENTS AND PAYMENT OF FEES A. Real Party In Interest Under 37 C.F.R. 42.8(b)(1) Fresenius Kabi USA, LLC is the real-party-in-interest. No other entity is funding, controlling, or otherwise has an opportunity to control or direct this Petition or Fresenius Kabi USA, LLC s participation in any resulting IPR. Fresenius Kabi USA, LLC has numerous affiliated and/or related entities including: Fresenius Kabi USA, Inc., Fresenius Kabi Pharmaceuticals Holding, Inc., Fresenius Kabi AG, and Fresenius SE & Co. KGaA. Fresenius Kabi USA, LLC is also contractual partners with Hetero Labs, Ltd. and Hetero USA, Inc. Out of an abundance of caution, Fresenius Kabi USA, LLC identifies the foregoing entities, each of which agrees to be estopped under the provisions of 35 U.S.C. 315 and/or 325 as a result of any final written decision in the requested IPR to the same extent as Fresenius Kabi USA, LLC, as real-parties-in-interest solely to avoid disputes related to this Petition. B. Related Matters Under 37 C.F.R. 42.8(b)(2) Cephalon has asserted the 270 patent in co-pending litigations captioned In re Bendamustine Consolidated Cases, Case No. 1:13-cv-2046 (D. Del. Dec. 19, 2013) ( the Consolidated Bendamustine Action ), Cephalon, Inc. v. Apotex, Inc., Case No. 1:5-cv-404 (D. Del. May 19, 2015), Cephalon, Inc. v. Panacea Biotec, Ltd., Case No. 1:5-cv-735 (D. Del. Aug. 25, 2015), and Cephalon, Inc. v. Nang 7

16 Kuang Pharm. Co., Ltd., Case No. 1:4-cv-5180 (E.D.N.Y. Sept. 3, 2014) (collectively, the 270 Bendamustine Actions ). Petitioner is not a party to any of the 270 Bendamustine Actions, and Cephalon has never asserted the 270 patent against Petitioner. Petitioner s contractual partners, Hetero Labs, Ltd. and Hetero USA, Inc., are parties to the Consolidated Bendamustine Action. The first Complaint asserting the 270 patent against Hetero Labs, Ltd. and Hetero USA, Inc. was served no earlier than November 6, Exhibit On December 24, 2014, Agila Specialties f/k/a Strides Inc. and Mylan Laboratories Limited (collectively, Mylan ) filed a petition for inter partes review of U.S. Patent No. 8,436,190 ( the 190 patent ), from which the 270 patent claims priority. See IPR Trial was instituted by the Board on July 20, Exhibit On October 9, 2015, Mylan filed a petition for inter partes review of claims 1-23 of the 270 patent. The Board has not decided whether or not to institute the Mylan 270 petition. See IPR C. Lead and Back-Up Counsel Under 37 C.F.R. 42.8(b)(3) Petitioner designates lead and back-up counsel as noted below. Powers of attorney pursuant to 37 C.F.R (b) accompany this Petition. Lead Counsel Backup Counsel Lawrence Sung, Reg. No. 38,330 Neal Seth, Reg. No. 67,075 8

17 WILEY REIN LLP ATTN: Patent Administration 1776 K Street NW Washington, DC 20006, Phone: / Fax: D. Service Information Under 37 C.F.R. 42.8(b)(4) Please address all correspondence to counsel at the addresses above. Petitioner consents to electronic service by at: lsung@wileyrein.com and nseth@wileyrein.com. E. Grounds for Standing Under 37 C.F.R (a) Pursuant to 37 C.F.R (a), Petitioner certifies that the 270 patent is available for inter partes review, and that Petitioner is not barred or estopped from requesting inter partes review based on the grounds herein. F. Fees Under 37 C.F.R Petitioner concurrently submits fees of $26,800. If more fees are necessary to accord this Petition a filing date, authorization is granted to charge the same to Deposit Account No with reference to Attorney Docket No III. IDENTIFICATION OF CHALLENGE UNDER 37 C.F.R (b) Petitioner requests cancellation of claims 1-23 of the 270 patent as unpatentable under 35 U.S.C. 102 and 103. This Petition, supported by the accompanying Declarations of Dr. Bernard Olsen ( Olsen Decl. ) (Exhibit 1017) and Dr. Michael J. Akers ( Akers Decl. ) (Exhibit 1013), demonstrates that there 9

18 is a reasonable likelihood that the challenged claims are not patentable and that Petitioners will prevail with respect to at least one challenged claim. Pursuant to 37 C.F.R (a) and (b)(1)-(2), Petitioner s challenge is based on the following references, all of which are prior art pursuant to 35 U.S.C. 102(b): 1. Maas (Exhibit 1004), Stability of Bendamustine Hydrochloride in Infusions, 49 PHARMAZIE 775, published in German in 1994 nearly 10 years before the priority date of the 270 patent. Maas is cited on the face of the 270 patent, although it was not used during prosecution to substantively reject the claims. 2. Teagarden (Exhibit 1005), Practical Aspects of Lyophilization Using Non- Aqueous Co-Solvent Systems, 15 EUR. J. PHARM. SCI. 115, published in March Teagarden is cited on the face of the 270 patent, although it was not used during prosecution to substantively reject the claims. 3. Gust (Exhibit 1006), Investigations on the Stability of Bendamustin, a Cytostatic Agent of the Nitrogen Mustard Type, I. Synthesis, Isolation, and Characterization of Reference Substances, 128 MONATSHEFTE FÜR CHEMIE 291, published in Gust is cited on the face of the 270 patent, although it was not used during prosecution to substantively reject the claims. 4. Ribomustin Product Monograph (Exhibit 1007), Ribosepharm GmbH, München, Germany, published in January Exhibit 1003 at 0101, The 10

19 Ribomustin Product Monograph is cited on the face of the 270 patent, although it was not used during prosecution to substantively reject the claims. 5. Admitted Prior Art in the 270 Specification (Exhibit 1001). As noted above, the Board has held that admitted prior art in the challenged patent itself can serve as a basis for rejection. Exhibit 1030 at As explained in further detail below, Petitioner respectfully requests that the Board cancel claims 1-23 based on the following grounds of unpatentability: Ground 1: Claims 1-20 are invalid under 35 U.S.C. 103 as obvious over Maas in view of Teagarden; Ground 2: Claims 13 and 19 are invalid under 35 U.S.C. 103 as obvious over Maas in view of Teagarden and Gust; Ground 3: Claims are invalid under 35 U.S.C. 103 as obvious over Maas in view of Teagarden and the Ribomustin Product Monograph. Ground 4: Claims 1-23 are invalid under 35 U.S.C. 103 as obvious over the admitted prior art in the 270 specification in view of Teagarden. IV. FRESENIUS KABI S GROUNDS OF UNPATENTABILITY ARE NOT CUMULATIVE OF THOSE PRESENTED BY MYLAN As noted above, Mylan filed IPR on October 9, The instant petition was developed independently and relies on different grounds for unpatentability. In particular, the instant petition relies on different grounds, 11

20 references, interpretations of references, and claim constructions. For example, the instant petition relies on a different interpretation of the Maas reference, different claim constructions with respect to at least the pharmaceutical composition, bendamustine degradants, and time zero after reconstitution terms, and at least three distinct grounds. Specifically, the instant petition quantifies the level of degradants in Maas using accepted methodology, whereas Mylan s petition does not make an assessment of the degradant content in Maas. This quantification of degradant content impacts almost all of the grounds presented in the instant petition. For all these reasons, the grounds of unpatentability in the instant petition are not cumulative of Mylan s grounds. V. OVERVIEW OF THE 270 PATENT, PROSECUTION HISTORY, AND THE BOARD S RELEVANT INSTITUTION DECISIONS A. The Alleged Invention of the 270 Patent The application that matured into the 270 patent was filed on August 19, 2013, and purports to claim priority through a series of applications to a January 14, 2005 provisional application. Exhibit 1001 at 1:7-16. At a high level, the 270 patent relates to bendamustine hydrochloride pharmaceutical compositions, but it does not claim the bendamustine hydrochloride active ingredient itself. Id. at 2:1-2. As the 270 patent concedes, bendamustine hydrochloride has long been in the public domain for treating certain blood cancers, and is not subject to patent 12

21 protection. Id. at 2:1-8. Given bendamustine hydrochloride s established history in the public domain, companies have developed bendamustine hydrochloride pharmaceutical formulations since the 1970s. For example, the 270 specification acknowledges that, as early as 1971, German companies marketed bendamustine hydrochloride pharmaceutical compositions under the trade name Cytostasan and, later, Ribomustin. Id. The 270 specification further concedes that Ribomustin was lyophilized (freeze-dried) the same formulation technique that Cephalon now claims given bendamustine hydrochloride s known instability. Id. at 2: As noted above, Cephalon s purported point of novelty over these prior formulations was an alleged improvement in the profile of various degradants such as the hydrolysis degradant (HP1). Id. at 12: In particular, Cephalon submitted claims reciting HP1 levels of not more than 0.4% to 0.9% (area percent of bendamustine), BM1EE levels of not more than 0.5% (area percent of bendamustine) of BM1EE, and total degradant levels of not more than 4.0% (area percent of bendamustine). As discussed below, however, Cephalon s claims read directly on the very Ribomustin prior art it sought to distinguish. B. The Prosecution History of the 190 and 270 Patents The application that matured into the 270 patent was filed as a continuation of the 190 patent. Prosecution of the 190 patent is relevant to the issues 13

22 presented in his Petition because Cephalon made several key concessions with respect to the scope and content of the prior art. See Goldenberg v. Cytogen, Inc., 373 F.3d 1158, 1167 (Fed. Cir. 2004) (explaining that response that constitute[d] part of the prosecution history of the... parent application to the [patent-at-issue]... [was] therefore part of the [patent-at-issue s] prosecution history ). 1. Prosecution History of the 190 Patent On January 12, 2006, Cephalon filed the application that eventually matured into the 190 patent. Although the entire prosecution history of the 190 patent is attached as Exhibit 1014, two Patent Owner Responses (dated November 17, 2009 and November 19, 2010) are particularly germane to the issues presented here. In its November 17, 2009 Response, Cephalon expressly conceded in response to an obviousness rejection that [t]he desirability of keeping the amount of impurities low in a pharmaceutical composition is well known in the art. Exhibit 1014 at Cephalon further conceded that [l]yophilization is a known technique in the art. Id. Cephalon alleged that what was unknown in the art was that the amount of HP1 formed... c[ould] be reduced by using... solvents set forth in the present specification. Id. Cephalon did not inform the Examiner that Teagarden taught that reduction, nor did it disclose the Teagarden review article during the prosecution of the 190 patent (despite the overlap between Teagarden and the specification of the 190 patent). 14

23 In its November 19, 2010 Response, Cephalon specifically characterized Ribomustin in arguing why the claims were nonobvious, explaining that: Prior to the invention, bendamustine was historically lyophilized from a solution of ethanol, water, mannitol, and bendamustine... The present inventors discovered that the amount of bendamustine ethyl ester in the lyophilized preparation could be minimized by creating an entirely new pre-lyophilization procedure. Id. at Based on Cephalon s representation, the Patent Office allowed the claims, noting that Applicant has unexpectedly found that the addition of tertiarybutyl alcohol stabilizes the formulation such that bendamustine degradation is negligible (no more than 0.5% formation of bendamustine ethyl ester.) Id. at As discussed below, Cephalon never informed the Examiner that the 270 patent specification itself undercuts this conclusion. 2. Prosecution History of the 270 Patent On August 19, 2013, Cephalon filed the application that matured into the 270 patent. Cephalon received accelerated review via Track One. Despite the substantial body of prior art relating to bendamustine hydrochloride s instability, the claims that ultimately issued as claims 1-23 received only a restriction requirement, and were never substantively rejected over any prior art. See generally Exhibit Moreover, although there is no record 15

24 in the prosecution of Cephalon arguing unexpected results, the Patent Office provided the following reasons for allowance: The prior art suggests using a combination of mannitol and tertiarybutyl alcohol with bendamustine to produce a formulation to be lyophilized. However, Applicant has unexpectedly found that the addition of a solvent stabilizes the formulation such that bendamustine degradation is negligible (no more than 0.5% formation of bendamustine ethyl ester). Id. at Beyond the fact that the stated basis for allowance only applies to 2 out of the 23 claims, the basis is contradicted by the 270 patent specification. Indeed, Table 13 of the 270 specification clearly discloses Ribomustin lots having BM1EE levels below 0.5%. Exhibit 1001 at Table 13. C. The Mylan Inter Partes Review of the 190 Patent As noted above, Mylan filed a petition for inter partes review of the 190 patent ( the Mylan 190 IPR ). See IPR The Board instituted trial on July 20, In its institution decision, the Board made a number of findings relevant to the instant petition. First, the Board concluded that it was persuaded that, at the time of the [ 190/ 270] patent invention, one of ordinary skill in the art would have been motivated to improve the stability of Ribomustin, the bendamustine drug on the market. Exhibit 1012 at The Board reached this 16

25 conclusion based on Maas s disclosure of Ribomustin stability data. Id. Second, the Board noted that it was persuaded that an ordinary artisan, motivated to improve the stability of Ribomustin, would have looked to Teagarden s teaching of the benefits of TBA. Id. at With respect to Teagarden, the Board specifically observed that Teagarden describes that freezedrying unstable drugs from a TBA/water solution significantly reduced the degradation rate, sometimes by a factor of approximately 4-5. Id. Third, the Board found that Cephalon s attempts to distance itself from its prior admissions concerning Ribomustin during the 190 prosecution were not persuasive, explaining that Cephalon could not take an inconsistent position without presenting persuasive evidence. Id. at Fourth, the Board was persua[ded] by Mylan s argument that the BM1EE claims were obvious because one of skill in the art would expect that the BM1EE levels reported in Table 13 would be lowered even further through the use of TBA. Id. at Fifth, the Board rejected Cephalon s secondary considerations arguments, explaining that Patent Owner has not established sufficiently a nexus between the addition of TBA, and the regulatory approval, the alleged acclaim and copying by others, as well as the asserted commercial success of TREANDA. Id. at Each of these findings applies with equal force to the instant Petition, and confirm various aspects of Petitioner s arguments, set forth below. 17

26 VI. LEVEL OF ORDINARY SKILL IN THE ART A person of ordinary skill in the art is a hypothetical person presumed to be aware of all pertinent art. A person of ordinary skill in the art thinks along conventional wisdom in the art, and is a person of ordinary creativity. A person of ordinary skill in the art as of January 2005, the filing date of the 270 patent, would have a Ph.D. in pharmaceutics, analytical chemistry, or a related field, with at least three years of practical experience in the formulating and/or analytically characterizing pharmaceutical compositions. Exhibit 1013, Akers Decl. 22; Exhibit 1017, Olsen Decl VII. HOW THE CHALLENGED CLAIMS ARE TO BE CONSTRUED UNDER 37 C.F.R (b)(3) A claim subject to inter partes review receives the broadest reasonable construction in light of the specification of the patent in which it appears. 37 C.F.R (b). Throughout this Petition, Petitioner applies the broadest reasonable construction of claim terms appropriate for these proceedings, including claim terms for which a claim construction is not explicitly discussed. Claim constructions appropriate for these proceedings may be different than those appropriate in district courts. Thus, the constructions relied upon in this Petition do not necessarily reflect the constructions that Petitioner believes should be adopted by a district court. Any term not construed below should be interpreted 18

27 in accordance with its plain meaning under the broadest reasonable construction. A. Pharmaceutical Composition Claims 1-23 recite the phrase pharmaceutical composition. According to the 270 patent specification, pharmaceutical composition means: a composition that is made under conditions such that it is suitable for administration to humans, e.g., it is made under GMP conditions and contains pharmaceutically acceptable excipients, e.g., without limitation, stabilizers, bulking agents, buffers, carriers, diluents, vehicles, solubilizers, and binders. As used herein pharmaceutical composition includes but is not limited to a pre-lyophilization solution or dispersion as well as a liquid form ready for injection or infusion after reconstitution of a lyophilized preparation. Exhibit 1001 at 11:7-15. In the Consolidated Bendamustine Action, Cephalon asserted that both sentences of this definition should be adopted as part of the construction an approach that the district court rejected. Exhibit 1015 at 0015; Exhibit 1016 at The district court explained that, while pharmaceutical composition was clearly defined in the specification, it was not necessary to name particular embodiments. Exhibit 1016 at Accordingly, the district court construed pharmaceutical composition to mean a composition that is made under conditions such that it is suitable for administration to humans. Id. 19

28 The Board should take the same approach. Indeed, the Board has stated that [i]n giving claims their broadest reasonable construction, the Board takes into account definitions in the written description, but is not permitted to read limitations from the disclosed embodiments or examples into the claims. Ex Parte Trans Tex. Holdings Corp., , 2006 WL , at *4 (B.P.A.I. Jan. 24, 2006). Accordingly, for purposes of this proceeding, pharmaceutical composition should be construed to mean a composition that is made under conditions such that it is suitable for administration to humans. Nevertheless, the second sentence of the 270 specification definition provides context to the construction. In particular, the second sentence confirms that, under a broadest reasonable construction, a composition need not be immediately administrable to a human to qualify as a pharmaceutical composition. For example, the pre-lyophilized pharmaceutical compositions described in the 270 patent contain, at times, high levels of alcohols that would be toxic to humans. Exhibit 1001 at 8: Thus, under the broadest reasonable construction, so long as the composition is prepared under appropriate conditions, it is a pharmaceutical composition even if it cannot be directly administered. B. Pharmaceutical Composition That Has Been Reconstituted Claims 1-6 and 9-13 recite the phrase pharmaceutical composition that has been reconstituted. For purposes of this proceeding, pharmaceutical composition 20

29 that has been reconstituted should be construed to mean [pharmaceutical composition] (as construed above) that has been dissolved in a solvent or diluent. This construction comports with the plain meaning of reconstituted. See, e.g., Exhibit 1026 at 0020 ( reconstitute means [t]he dissolving of the dried product into a solvent or diluent ); Exhibit 1035 at In the Consolidated Bendamustine Action, the parties agreed to a construction of pharmaceutical composition that has been dissolved in a solvent and that is suitable for medical administration. Exhibit 1019 at The addition of the suitable for medical administration is inconsistent with the plain language of the claim. Moreover, this additional language is superfluous because pharmaceutical composition already recites this limitation. Prior to agreeing to the construction above in the Consolidated Bendamustine Action, Cephalon proposed a construction of pharmaceutical composition that has been dissolved in a solvent. Exhibit 1015 at This construction omits dissolution in a diluent, and thus is not the broadest reasonable construction. Nevertheless, Petitioner will analyze the references below under all three constructions. As shown below, the prior art meets this claim limitation regardless of which construction is adopted. C. Area Percent of Bendamustine Claims 1-23 recite the phrase area percent of bendamustine. According to 21

30 the 270 specification, area percent of bendamustine means the amount of a specified degradant, e.g., HP1, relative to the amount of bendamustine as determined, e.g., by HPLC. Exhibit 1001 at 12: Because the broadest reasonable construction would not be limited by any exemplary measurement (e.g., HPLC), area percent of bendamustine should be construed to mean the amount of a specified degradant relative to the amount of bendamustine. D. Bendamustine Degradants Claims 7-23 recite the phase bendamustine degradants. For purposes of this proceeding, bendamustine degradants should be construed to mean chemical compounds resulting from a change in chemical structure of bendamustine. This construction is consistent with the 270 patent specification. See Exhibit 1001 at 9:56-57 ( [D]egraded... mean[s] that the active has undergone a change in chemical structure ). E. Time Zero After Reconstitution Claims 2, 4, 6, and recite the phrase time zero after reconstitution. Time zero after reconstitution is not defined or described with any objective criteria in the intrinsic record, and is the type of term that the Federal Circuit has found indefinite. See Teva Pharms. USA, Inc. v. Sandoz, Inc., 789 F.3d 1335 (Fed. Cir. 2015). For purposes of this Petition, however, this Board does not apply the strict Markman rules, but instead uses the broadest reasonable interpretation. 22

31 In the Consolidated Bendamustine Actions, Cephalon proposed that this term be construed as soon after dissolution in a solvent. Exhibit 1015 at In other words, it refers to the first measurement taken as soon as reasonably practicable after reconstitution. Exhibit 1020 at In the Mylan 270 IPR, Mylan proposed that this term be construed as 30 minutes or less after reconstitution. Although Petitioner believes that Cephalon s construction is inappropriate for a district court proceeding, Petitioner will adopt Cephalon s construction of soon after dissolution in a solvent or diluent 2 solely for purposes of this Petition, where soon after is understood to refer to the first measurement taken as soon as reasonably practicable. Petitioner will analyze the references below under all constructions. The prior art meets this claim limitation regardless of the construction. VIII. DETAILED EXPLANATION AND SUPPORTING EVIDENCE UNDER 37 C.F.R (b)(4) AND (b)(5) Pursuant to 37 C.F.R (b)(4) and (b)(5), Petitioner sets forth an 2 Petitioner slightly modified Cephalon s construction to include a diluent based on the record evidence concerning the broadest reasonable meaning of reconstitution. Exhibit Petitioner will separately analyze the references under Cephalon s construction of soon after dissolution in a solvent. As set forth below, all references meet the claims regardless of the construction. 23

32 explanation below of why claims 1-23 are unpatentable under the statutory grounds identified above, including the identification of where each element is found in the prior art. The claim charts identify the supporting evidence relied upon to support the challenge by exhibit number and set forth the relevance of the evidence to the challenge raised, including an identification of those specific portions of the evidence that support the challenge. An Exhibit List (see 37 C.F.R (e)) identifying the exhibits is also included, supra, at p. v. A. Ground 1: Claims 1-20 Are Obvious Over Maas in View of Teagarden. Each and every limitation of claims 1-20 is taught by Maas in view of Teagarden, which are fully combinable for the reasons discussed below and in the declarations of Bernard Olsen (Exhibit 1017) and Michael Akers (Exhibit 1013). 1. Scope and Content of the Prior Art Nearly ten years before Cephalon s earliest priority date, Maas described the degradation of Ribomustin including formation of the HP1 degradant in significant detail. Exhibit 1004 at Indeed, Maas ran HPLC analyses the very technique cited in the 270 specification to assess that degradation, and published an HPLC chromatograph showing the levels of bendamustine hydrochloride and the HP1 degradant immediately after dilution. Id. at Teagarden was published approximately four years before the priority date 24

33 of the 270 patent, and specifically teaches using TBA in the pre-lyophilization solution for water-unstable drugs. Exhibit 1005 at Teagarden teaches that utilizing TBA in the pre-lyophilization process can have a number of beneficial effects, decreasing the product s drying time, decreasing reconstitution time, and increasing the shelf-life of the product. Id. at 0001, Importantly, Teagarden discloses that the use of organic solvents such as TBA can have a profound effect on the chemical stability of the drug. Id. at Specifically, Teagarden teaches that freeze-drying unstable drugs from a TBA/water solution significantly reduced the degradation rate of the drug, sometimes by a factor of approximately 4 5. Id. at 0003, Teagarden observed that [t]his type of effect would be expected to be observed for many other drug products which are degraded in the presence of water. Id. at A Person of Ordinary Skill in the Art Would Have Been Motivated to Combine Maas and Teagarden. As the Board has already recognized, and for the reasons discussed below, one of skill in the art would have been motivated to improve the stability of Ribomustin. Exhibit 1012 at 0011 ( [W]e are persuaded that, at the time of the... patent invention, one of ordinary skill in the art would have been motivated to improve the stability of Ribomustin, the bendamustine drug on the market ); Exhibit 1017, Olsen Decl ; Exhibit 1013, Akers Decl

34 Significantly, Cephalon itself has conceded that [t]he desirability of keeping the amount of impurities low in a pharmaceutical composition is well known in the art. Exhibit 1014 at This rationale alone would have prompted one of skill in the art to improve Maas, as the Maas chromatogram reflects significant degradation immediately after dilution. Exhibit 1004 at ; Exhibit 1017, Olsen Decl. 49, 70. Additionally, one of skill in the art would have been motivated to lower the degradants taught in the Maas chromatogram to comply with FDA guidelines concerning impurities, and deliver the maximum dose of drug. Id. 51. Moreover, the t 90 data from Maas (10% degradation in 9 hours at 23 C) would have suggested to one of skill in the art that further refinement to the stability profile would be beneficial. Exhibit 1017, Olsen Decl ; Exhibit 1013, Akers Decl. 44. In particular, one of skill in the art would recognize that the instability issues reported in Maas would constrain the flexibility for manufacturing operations and the use of bendamustine solutions in clinical practice. Exhibit 1017, Olsen Decl. 50. As the Board has found and, for the reasons discussed below, one of ordinary skill in the art would have looked to the teachings of Teagarden to improve the stability of Ribomustin. Exhibit 1012 at 0012; Exhibit 1017, Olsen Decl. 52; Exhibit 1013, Akers Decl As the Board has previously 26

35 recognized, Cephalon has admitted that bendamustine was historically lyophilized from a solution of ethanol, water, mannitol, and bendamustine. Exhibit 1014 at A person of skill in the art would have been motivated to substitute TBA for ethanol to take advantage of the significant benefits of TBA disclosed in Teagarden. Exhibit 1017, Olsen Decl. 52; Exhibit 1013, Akers Decl For example, Teagarden expressly discloses that the stability of lyophilized formulations can be improved by using TBA, and that the use of TBA slowed degradation by a factor of 4-5. Exhibit 1005 at Teagarden further taught this effect would be expected to be observed for other water-unstable drugs. Id. Bendamustine hydrochloride is a prototypical example of such a drug. Id. Thus, one of skill in the art would have been motivated to utilize TBA to take advantage of these benefits. Exhibit 1017, Olsen Decl A Person of Ordinary Skill in the Art Would Have A Reasonable Expectation of Success in Reducing Degradant Levels. A person of ordinary skill in the art would have had a reasonable expectation that degradant levels reported in Maas could be reduced by applying the teachings of Teagarden. Exhibit 1017, Olsen Decl. 53; Exhibit 1013, Akers Decl Indeed, Teagarden itself expressly provides that expectation. Exhibit 1005 at 0004 (reduced degradant levels would be expected to be observed for many other drug products which are degraded in the presence of water ) (emphasis added). 27

36 Additionally, Teagarden discusses the successful use of TBA/water co-solvents for at least five different pharmaceutical compositions, including for the specific purpose of improving drug stability. Id. at 0003, 0004 ( [A]lprostadil has been successfully freeze-dried from a [TBA]/water solution. The... rate constant of alprostadil in 20% v/v [TBA]/water... was significantly reduced ). 4. The Combination of Maas and Teagarden Discloses Each and Every Claim Limitation. As set forth in further detail below, Maas and Teagarden disclose all limitations in claims Claim 1 recites [a] pharmaceutical composition that has been reconstituted from a lyophilized preparation of bendamustine or bendamustine hydrochloride, said composition containing not more than about 0.9% (area percent of bendamustine) of HP1. Maas teaches a pharmaceutical composition under the broadest reasonable construction set forth above. Indeed, Maas teaches that Ribomustin is an effective chemotherapeutic drug in the treatment of malignant diseases, and that each vial of Ribomustin contained 55 mg of dry substance [including] 25 mg of bendamustine hydrochloride (excipient: mannitol). Exhibit 1004 at 0004, Thus, Maas discloses a composition that is made under conditions such that it is suitable for administration to humans. Exhibit 1017, Olsen Decl Moreover, Maas discloses that the pharmaceutical composition has been 28

37 reconstituted under the broadest reasonable construction set forth above. In particular, Maas teaches that [e]ach ampoule of Ribomustin... was dissolved in 10 ml of water for injection and then diluted to 100 ml with NaCl solution.... prior to HPLC analysis. Exhibit 1004 at If Cephalon s narrower construction of pharmaceutical composition that has been dissolved in a solvent were adopted, Maas would similarly meet that construction given the express disclosure of dissolution in water. Exhibit 1017, Olsen Decl Even if pharmaceutical composition that has been reconstituted was construed more narrowly to require that it be suitable for administration to humans, Maas clearly meets that construction because Ribomustin is suitable for administration to humans, and was, in fact, administered to many humans over a long period of time. Exhibit 1001 at 2:5-8; Exhibit 1017, Olsen Decl. 60. Maas further teaches that the Ribomustin vials that were reconstituted were lyophilized preparations of bendamustine hydrochloride, Exhibit 1004 at 0004 ( lyophilized dry substance ), and thus fully discloses [a] pharmaceutical composition that has been reconstituted from a lyophilized preparation of bendamustine hydrochloride. Exhibit 1017, Olsen Decl The combination of Maas and Teagarden also discloses that the pharmaceutical composition contains not more than about 0.9% (area percent of bendamustine) of HP1. As shown below and explained in additional detail in the 29

38 Akers declaration, the chromatogram in Maas teaches two degradants the monohydrolysis product, and an additional unknown degradant that was a byproduct from synthesis. Exhibit 1004 at 0005; Exhibit 1017, Olsen Decl. 61. One of skill in the art would appreciate that the monohydrolysis peak in Maas corresponds to HP1. Exhibit 1017, Olsen Decl. 61. In particular, the 270 patent itself refers to HP1 as monohydroxy bendamustine. Exhibit 1001 at 21:4-5. Although Maas does not provide peak area data for these peaks, one of skill in the art would have been able to calculate peak area (and thus determine area percent bendamustine) for the two degradants in a number of different ways. In particular, one of skill in the art would know that another way of determining peak area would be to digitize the Maas chromatogram and integrate the peaks using commercial software. Exhibit 1017, Olsen Decl. 63. Digital integration has been described by the literature as the fastest and most accurate computerized method 30

39 for measuring peak area. Exhibit 1023 at 0032; Exhibit 1032 at In a similar vein, counting the number of pixels under each peak is another method for calculating peak area. Exhibit 1017, Olsen Decl. 63; Exhibit 1034 at 0012 ( In digital geometry, a common estimator of area is pixel counting.... ). Dr. Olsen utilized these methods to determine the relative peak areas in the Maas chromatogram. Id Specifically, Dr. Olsen digitized the Maas chromatogram and integrated each of the peaks using commercial software. Id The software included an integration tool that allows a user to measure the peak areas for individual peaks. Id. 64. An example integration is shown below: To check that method, Dr. Olsen transferred the digitized chromatographic data (time vs. response) to a Microsoft Excel spreadsheet. Id. 65. The peak areas 31