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St. Jude Medical, Inc. v. Access Closure, Inc.
. 24. 8. 60/560.sec.S.703 TABLE OF EXHIBITS Exhibit No.938. Formulations and Their Use in the Treatment of Neurological Diseases (filed Oct. Cross-over Study. 18. Pharmacokinetic Studies of Single and Multiple Oral Doses of Fampridine-SR (Sustained-Release 4Aminopyridine) in Patients With Chronic Spinal Cord Injury. 216 Int’l J. Pharm. 8.Patent No.440.. Description Exhibit 1001 Andrew R. Effects of 4-Aminopyridine in Patients with Multiple Sclerosis.D. Patent No. Influence of Admixed Carboxymethylcellulose on Release of 4-Aminopyridine from Hydroxypropyl Methylcellulose Matrix Tablets. Provisional Patent Application No. Patent No. at 817–21 (Apr. available at http://www. 2011) (issued May 14. 8. 2003) (“S-1”) Exhibit 1004 Rules and Related Matters. Blight & Ron Cohen. 1997) (“Schwid”) Exhibit 1010 Richard E. Jones et al.. no. Neurol. 2013) (“the ’703 Patent”) Exhibit 1002 Relevant excerpts of U. 1992) (“van Diemen”) vi . PlaceboControlled. 5. The Effect of 4-Aminopyridine on the Clinical Signs in Multiple Sclerosis: A Randomized.S. no.703 Prosecution History (“’703 prosecution history”) – Part 1 Exhibit 1003 Acorda Therapeutics. 26.. 2004) (“the Provisional”) Exhibit 1008 Masterson et al. 1994) (“Masterson”) Exhibit 1009 Schwid et al.894 (filed Apr. Sci. at 353–62 (1983) (“Jones”) Exhibit 1011 Harriët van Diemen. 2003-186 (Sept.. 2. 60 J. M. 4. U. Quantitative Assessment of Sustained Release 4Aminopyridine for Symptomatic Treatment of Multiple Sclerosis.S. Inc. 48 Neurol..703 (filed Nov. U. at 115–25 (“Juarez”) Exhibit 1007 U. 30. 2003).. Registration Statement Under the Securities Act of 1933 (Form S-1) (Sept. 9.. Patent No.txt (“S-1 Registration Statement”) Exhibit 1005 Keith C. 26 Clinical Neuropharmacology. 2003. at 185–92 (“Hayes”) Exhibit 1006 Haydee Juárez et al.S.. 32 Annals Neurol.gov/news/digest/dig093003. 2001.440.540. at 123–30 (Aug. Double-Blind. Hayes et al.440. no.. 4. et al.
1 Current Opinions in Investigational Drugs. Polman. 2003) Exhibit 1020 Goodman et al. Orally Administered 4-Aminopyridine Improves Clinical Signs in Multiple Sclerosis. at 375–79 Exhibit 1018 Porter Novelli. 18–21. at 186–92 (Feb. Placebo-Controlled Double-Blinded Dose Ranging Study of Fampridine-SR in Multiple Sclerosis.com/company_profile. Abstract. Acorda Therapeutics Begins Phase 3 Trials of Fampridine-SR for Chronic Spinal Cord Injury.org/What-is-MS/Types-of-MS (last visited Aug. MD. 11.. American Association for the Advancement of Science (AAAS) EurekAlert! (July 1. 51 Archives Neurol. 8. et al.nationalmssociety. 4-Aminopyridine Improves Clinical Signs In Multiple Sclerosis. 2015) (“NMSS”) Exhibit 1016 Declaration of Scott Bennett (“Bennett Decl. M.aspx?CompanyId=100 704 (last updated May 9. http://www. Nat. at 71–77 (1987) (“Stefoski”) Exhibit 1014 Floyd A. Multiple Sclerosis Soc’y. Darlington.Patent No.. 2002. Davis. Biospace. http://www. Nov.php Exhibit 1019 Acorda Therapeutics Company Profile. no.org/pub_releases/200207/pn-atb062802.. Fampridine Acorda Therapeutics. 2000. at 1136–39 (“Polman”) Exhibit 1013 D. http://www. Sep.. 27 Annals Neurol.703 Exhibit No.diaminopyridine in the Treatment of Patients with Multiple Sclerosis. Nov.” 21 Annals Neurol. 1. et al. 11.D. Description Exhibit 1012 Chris H.. 3.D. 1990) (“Davis”) Exhibit 1015 Types of MS. 2002).biospace. MD (“Goodman”) vii . M..eurekalert. Stefoski. Baltimore. poster presented at the 7th Annual Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis and 18th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS/ECTRIMS). PhD et al. no. no.440. 4-Aminipyridine is Superior to 3. 1994.. no.4.”) Exhibit 1017 C. 2.
54”) Exhibit 1022 Fred D.D. 1065 U. 54(1).nsf/0/4E8744EB 66E8F944C12577D600598EEF/$File/espacenet_brochure_en. European Patent No. Attachment 6 Exhibit 1036 Bennett Decl. 5.440.440. 2000). Attachment 7 Exhibit 1037 Bennett Decl.pdf (“Espacenet Brochure”) Exhibit 1028 Espacenet Bibliographic Data for US Patent No. Description Exhibit 1021 European Patent Convention art.”) Exhibit 1024 CV of Samuel J. 8. Ph.org/projects/babylon/eponet.Patent No. 8. Pleasure.T. available at http://www. M. 1 732 548 (B9) (“EP ’548”) Exhibit 1026 Excerpts from Proprietor’s Response to Opponents’ Appeals. M. http://documents. Attachment 8 Exhibit 1038 Bennett Decl. & Stephen C. Defining the Clinical Course of Multiple Sclerosis: Results of an International Survey.703 Exhibit No.. (“Pleasure CV”) Exhibit 1025 European Patent No.703 (B2) (“Espacenet 703 Data”) Exhibit 1029 CV of Scott Bennett (“Bennett CV”) Exhibit 1030 Bennett Decl. 29.html -texts/html/epc/2010/e/ar54. Reingold Ph. 1973.D.D. Ph. (2). Attachment 9 viii .epo. Attachment 1 Exhibit 1031 Bennett Decl. M. Pleasure. Attachment 3 Exhibit 1033 Bennett Decl. at 907–11 (Apr. 2004 (“Acorda EP Brief”) Exhibit 1027 European Patent Office. 4. Lublin.D..S. September 16. Espacenet Brochure. Attachment 4 Exhibit 1034 Bennett Decl.. 46 Neurology.org/law-practice/legaltexts/html/epc/2010/e/ar54. Attachment 5 Exhibit 1035 Bennett Decl. no.html (“EPC Art. Attachment 2 Exhibit 1032 Bennett Decl. 1996) (“Lublin”) Exhibit 1023 Declaration of Samuel J. 199 (as amended Nov. 1 732 548 B9. (“Pleasure Decl.D.epo.N.D. filed with the EPO. Oct.
& Donald E. Patent No. 15th ed. Nat’l Multiple Sclerosis Soc’y Website. (“Polli CV”) Exhibit 1046 Relevant excerpts of U.D. M.703 Exhibit No.D.D. Attachment 2 (Claim Charts for the ’703 Patent) Exhibit 1044 Declaration of James Polli. 343 New Eng. Hauser.440. 8. et al. Ph.. J.440. Patent No. 8.”) Exhibit 1045 CV of James Polli. 31. 2000) Exhibit 1041 Timed 25-Foot Walk (T25-FW). M. Ph. 16.S.703 Prosecution History (“’703 prosecution history”) – Part 3 ix . (“Polli Decl. 20. http://www. Goodkin. no.D. 2015) Exhibit 1042 RESERVED Exhibit 1043 Pleasure Decl. Harrison’s Principles of Internal Medicine. 2001 Exhibit 1040 Christian Confavreux.S.440.703 Prosecution History (“’703 prosecution history”) – Part 2 Exhibit 1047 Relevant excerpts of U. and Polli Decl. Med.nationalmssociety.org/ForProfessionals/Researchers/Resources-for-Researchers/ClinicalStudy-Measures/Timed-25-Foot-Walk-(T25-FW) (last visited Aug. Relapses and Progression of Disability in Multiple Sclerosis. 8. Description Exhibit 1039 Stephen L. 2452–61.Patent No. at 1430–38 (Nov.
C. (HI). Kyle Bass. and Erich Spangenberg are the real parties in interest (collectively. Hayman Investments.R.8) Real Parties-in-Interest (37 C.8(b)(1).S. MANDATORY NOTICES (37 C.100 et seq. (HCM). Credes is a limited partnership. L. 8.703 I.8(b)(1)) Pursuant to 37 C. Hayman Credes Master Fund. (HOM). requests an Inter Partes Review (“IPR”) of claims 1–52 (collectively. §§ 42.P. Hayman Offshore Management.P. RPI). HOM is the administrative general partner of Credes and HCMF.104(a).F.R.440.R. HCMF is a limited partnership. LLC (nXnP). Petitioner certifies that the ’703 Patent is available for IPR and that Petitioner is not barred or estopped from requesting IPR challenging the claims of the ’703 Patent on the grounds identified in this Petition. § 42. 1001) in accordance with 35 U. Petitioner certifies that Coalition For Affordable Drugs (ADROCA) LLC (CFAD).R. the “Challenged Claims”) of U.F. HI is 1 . (Credes). A.P.L. J. L.F.703 (the “’703 Patent”) (Ex. LLC (IPNav).440.S. HCM is the general partner and investment manager of Credes and HCMF. L. § 42. INTRODUCTION Petitioner Coalition For Affordable Drugs (ADROCA) LLC (“CFAD”). The RPI hereby certify the following information: CFAD is a wholly owned subsidiary of Credes. §§ 311–19 and 37 C.C. § 42. nXn Partners. Hayman Capital Management. IP Navigation Group.F. Inc.104(a)) Pursuant to 37 C. GROUNDS FOR STANDING (37 C. III. II.Patent No. Patent No. § 42.R. § 42. (HCMF).F. L. Hayman Capital Master Fund. 8.F.R.
8(b)(2)) Pursuant to 37 C. nXnP is a paid consultant to HCM.R. nXnP or IPNav) has authority to direct or control (i) the timing of. Inc. content of. or any decisions or other activities relating to the future proceedings related to this Petition.5% member of IPNav. 1-14-cv-00955 2 . B.. HCM. Erich Spangenberg is 98.. future filings. HCMF. Inc.440. and HCMF act. Credes and/or HCMF. directly or indirectly.Patent No.D. v. HI. § 42. Petitioner states that the ’703 Patent has been the subject of the following lawsuits: Acorda Therapeutics. No. limited partner. Erich Spangenberg is the 98. 2014). 22. 1-15-cv-00391 (D. Acorda Therapeutics. Del. HOM. v. Inc. No. filed May 15. Acorda Therapeutics.8(b)(2).703 the general partner of HCM. Other than HCM and J.F. All costs associated with this Petition will be borne by HCM. Indus. CFAD.F. Inc. through HCM as the general partner and/or investment manager of Credes and HCMF. No. CFAD.. § 42. Va. or any decisions or other activities relating to this Petition or (ii) any timing. 2015). filed Aug. 1-14-cv-00139 (N. Kyle Bass in his capacity as the Chief Investment Officer of HCM and nXnP and Erich Spangenberg in his capacity as the Manager of nXnP. or member or any other person in any of CFAD. IPNav is a paid consultant to nXnP. no other person (including any investor. W. Credes. filing of. Sun Pharm.R. J. v. Apotex Corp. Related Judicial and Administrative Matters (37 C. Kyle Bass is the sole member of HI and sole shareholder of HOM. content of. Credes. 8.5% member of nXnP. Mylan Pharm.
61. 1-14-00922 (D. filed July 16. Petitioner filed IPR2015-00720 seeking inter partes review of U. Inc.437—the parent of the presently challenged ’703 Patent. the Board issued decisions denying institution for both petitions. filed July 15. Teva Pharm. filed July 11. Parvathi Kota. Back-up counsel are Dr. Del. on February 10. No. 8. Alkem Labs. No. C.8(b)(3)) and Service Information (37 C. § 42. 8. v. Patent No. 2014). 2014). Simultaneously with this Petition. v. Inc. Ltd. Del. Accord Healthcare Inc. Patent No. Del. 2014). 1-14-cv-0082 (D. 1-14-cv-00935 (D.8(b)(4)) Lead counsel is Sarah E.. 1-14-cv-00932 (D. 2014). filed July 10. Patent No.685 Patent.685. Inc.S. 8. USA. In addition to the related judicial matters. Del.R.S. v. FL Inc.663. and U. filed July 18. Acorda Therapeutics. Petitioner filed IPR2015-00817 seeking inter partes review of U. Inc. and its child U. Acorda Therapeutics. 1-14-cv-00941 (D. Reg. Spires.501. 2015.663. Acorda Therapeutics.S. 2014). v. 2014). No. Del..826. No. Mylan Inc.. 2015.. 65. No. Petitioner is seeking IPR of U.R. Actavis Labs. No. Reg. Inc. filed July 14.S..007. Inc. filed July 17. 8. on February 27. 8. Acorda Therapeutics. Lead and Back-Up Counsel (37 C. Inc. Del. 2014.F.. Acorda Therapeutics.S. 2014). 2015. Del. v. § 42.Patent No. Skiermont (pro hac vice requested)— all at ADROCA703IPR1@skiermontpuckett. No. No.440. 3 . and Acorda Therapeutics. Patent No. No. and Paul J.703 (D. Inc. v. Acorda Therapeutics.122. filed July 7. 1-14-00917 (D.007. Inc. Aurobindo Pharma Ltd.826. v. Del. 1-14-cv-00909 (D.. On August 24.F. 8.com and of Skiermont Puckett LLP. Roxane Labs.354.
) The application. P: 214-978-6600 / F: 214-9786601.354.440. Patent App.R. Any overpayment or refund of fees may also be deposited in this Deposit Account.) These 4 . No.S.” (Ex. If any additional fees are due during this proceeding.Patent No. §§ 42. Texas 75201. 4800W. 2011. V.15(a) and 42.437).703 2200 Ross Ave. U. IDENTIFICATION OF CHALLENGE A. 8. at 3:65–4:19. filed on Apr.) 1. 2005 (now U. 506293.440. filed on Apr. 8. No. IV. 18.R. 60/560.103) The required fees are submitted herewith in accordance with 37 C. No.S.703 The ’703 Patent is titled “Methods of Using Sustained Release Aminopyridine Compositions. 9. which claims priority to Provisional App.15(A) AND § 42.103(a). 8. Ste. (Id. the Office is authorized to charge such fees to Deposit Account No.com. 13/299.S. Dallas. Patent No.559 (“’559 application”). Petitioner consents to electronic service at ADROCA703IPR1@skiermontpuckett. § 42.S. 11/102.F. 2004. The ’703 Patent Specification The ’703 Patent purports to describe methods of administering less than 15 mg of a sustained release oral dosage form of 4-aminopyridine (“SR 4-AP” or “fampridine-SR”) twice daily to patients with multiple sclerosis (“MS”) in order to improve certain aspects of lower extremity function.969 (the “’969 application”) was filed on Nov. Overview of U.894. and it is a continuation of U. (Id. Patent App. Patent No. PAYMENT OF FEES (37 C.F. 8. 1001.
8. Claims 1 and 2 are independent claims. (Id.” (Id.” as “about 15 ng/ml to about 35 ng/ml. 30–31. at 29:66.” and further requires that “the amount of said 4aminopyridine administered to said patient in each said administering step is the same over said time period.Patent No. at 29:55–67.” (Id.703 lower extremity functions are characterized by improvements in walking speed.” (Id.) The ’703 Patent further describes dispersing 4-AP “in a matrix that provides a release profile of 4-[AP] in the blood plasma of the patient extending over a period of at least 6 hours.) 5 . and muscle tone.) The patent discloses that the 4-AP “formulations and compositions of the present invention exhibit a desired release profile that may be described in terms of the average maximum plasma concentration of the drug or active agent at steady state (CavSS ).” (Id. at 8:5–8.) Independent claim 2 requires that the twice-daily dosage of 4-AP is “10 milligrams.) Independent claim 1 requires that the twice daily dosage of 4-AP is “less than 15 milligrams.440. at 3:1–3. muscle strength. at 29:58–62. at 3:66–4:15. Each of the two independent claims describes: A method of improving lower extremity function in a human multiple sclerosis patient in need thereof comprising orally administering to said patient a sustained release composition … of 4-aminopyridine twice daily for a time period of at least two weeks. The ’703 Claims The ’703 Patent has 52 claims. (Id.) 2.
6 . • “said sustained release composition is a tablet” (claims 10–13). 39–41). • “the lower extremity function is lower extremity muscle tone” (claim 5). • “twice daily is about every 12 hours” (claims 8–9. • “the lower extremity function is lower extremity muscle strength” (claim 4). • “said sustained release composition provides a mean Tmax in a range of about 2 to about 6 hours after administration of the sustained release composition to the patient” (claims 16–17.Patent No. • “initiating treatment of said patient with 4-aminopyridine by orally administering said sustained release composition twice daily to said patient” (claims 6–7.440. 35–36). 33). 37–38). 8. 34). • “said sustained release composition provides a release profile to obtain a CavSS of about 15 ng/ml to about 35 ng/ml” (claims 14–15. • “said sustained release composition provides a mean Tmax in a range of about 2 to about 5.2 hours after administration of the sustained release composition to the patient” (claims 18–19.703 Dependent claims 3–52 each ultimately depend directly or indirectly from claims 1 or 2. and contain the following additional limitations: • “the improving lower extremity function in the patient is increasing walking speed of the patient” or simply “the lower extremity function is walking” (claims 3. 32–52).
1002-55–56. 3.Patent No. -56–57.. 48–49).” See. • “said 4-aminopyridine is dispersed in a rate of release controlling polymer” (claims 22–23. 42–43). (Ex.440. which were generally directed to “administering to a patient with multiple sclerosis…twice daily…less than 15 milligrams of 4-aminopyridine” for “increasing walking speed” or “improving lower extremity muscle strength” or “improving lower extremity muscle tone. and 12. • “said patient has relapsing remitting multiple sclerosis” (claims 26–27. 50–51). upon administration to the patient. • “said sustained release composition comprises a matrix. Prosecution History of the ’703 Patent The ’969 application included original claims 1–16. in which said 4- aminopyridine is uniformly dispersed.g. e.) 1 All hyphenated references to Exhibit pin-cites are to the Exhibit’s Bates-labeled page number. 44–45). 1) Original claims 17–20 were generally directed to “methods of selecting individuals based on responsiveness to treatment. a release profile of the 4-aminopyridine extending over at least 6 hours” (claims 20–21.703 • “said sustained release composition is capable of providing. • “said time period comprises twelve weeks” (claims 30–31. 7. • “said time period is more than two weeks” (claims 28–29. 46–47). 8. as-filed claims 1. 52). 7 . that is suitable for controlling the release rate of the 4-aminopyridine” (claims 24–25.” (Id.
but included the limitation that the 4-AP composition be administered for “at least two weeks. with regards to the treatment period instantly claimed of at least two weeks … treatment regimen is dependent on … the disease condition. 1002-120. and it would have been obvious to use a release matrix and to optimize treatment time (such as for at least two weeks): Finally. but did not explicitly address “a method of treating the symptoms of multiple sclerosis.) Schwid addressed this limitation because it disclose treating MS patients with 4-AP to improve “muscle speed and lower extremity muscle tone and strength. (Id..) The new claims included limitations directed to particular pharmacokinetic parameters and rate-of-release compositions. SR 4-AP pharmacokinetic parameters would have been obvious to a person of ordinary skill in the art (“POSA”). but cancelled claims 1–20 and replaced them with new claims 21–54.Patent No.440. less than 15 mg). (Id. weight. 1009). the patients age.e. 1002-119.” (Id. 8.) The Examiner also found that based on the prior art. -80–85. co-existing conditions and other 8 . (Ex.” (Ex. 1008) in view of Schwid (Ex.) The new claims were similar to original claims 1–16. (Id.703 The Examiner issued a restriction requirement for the applicant to elect Group I (claims 1–16) or Group II (17–20) for further prosecution. -73. 1002-119–20.) The Examiner’s first substantive rejection was for obviousness over Masterson (Ex.” (Ex. -81–82.) Applicant elected Group I. -80.) The rejection stated that Masterson taught a method of treating MS patients with low-dose 4-AP (i.
-137. and this guidance was to use dosage amounts of 4-AP that were much higher than the less than 15 mg BID [twice daily] of sustained release (‘SR’) 4-AP that are recited in the instant claims.) The applicant did not directly address these arguments. (Id. 8. Sabella alleging commercial success of its product.) A Notice of Allowance followed. the applicant submitted a declaration from Ms.) 9 .’ to make it clear that the 4-aminopyridine dosage amount is a stable amount over said time period. adding: “‘wherein the amount of said 4-aminopyridine administered to said patient in each said administering step is the same over said time period. -122–24. long-felt but unmet need. -161–63.) The applicant also submitted a declaration from Dr.” (Id. commercial success) exhibited by the claimed invention” (Id.703 [individually optimized] factors … and it would have been obvious to a person of ordinary skill in the art to optimize the treatment time. as well as failure by others. -139). and submitted a declaration from Dr.440.) In view of the amendments.” (Id. -164–65. Medori alleging long-felt but unsolved needs.) The applicant alleged “secondary considerations of nonobviousness (surprising results. (Id.) Finally. 1047-959. but instead amended independent claim 21.Patent No. (Id. Blight—one of the listed inventors—setting forth allegedly surprising results. (Ex. -160. (Id. applicant stated “the [prior] art did provide some guidance regarding what dosage of 4aminopyridine (“4-AP[”]) should be used. -138.
Cir. Cir. Cir. 2004 (Ex. 1571–72 (Fed.) Nevertheless.C.703 B. a POSA must immediately discern that the Provisional “necessarily discloses” the ’703 Patent’s claim limitations from the four corners of the Provisional at the time is was filed—it is not enough that a POSA could speculate as to modifications to the Provisional’s disclosure that the inventor might have envisioned but failed to disclose—and it is not even enough if such limitations are obvious from the Provisional’s disclosure. 2005. 1007. 1294-96 (Fed. L.3d 1565.3d 556. 298 F. it must contain an equivalent description of the claimed subject matter based on an examination of the Provisional’s words. Vermeer Mfg. 8. New Railhead Mfg. figures. Osteonics Corp. and diagrams. 107 F. Effective Priority Date of the ’703 Patent Claims The ’703 Patent claims the benefit of the ’894 Provisional application (“the Provisional”). at least claims 1–30 and 32–52 are not entitled to the benefit of the Provisional’s filing date.L.3d 1290. See also Lockwood v. The priority date for those claims is the ’559 application’s filing date: April 8. Id. Though the Provisional need not use the exact words of later-filed claims. 1994).440. 10 . 1997). 558–59 (Fed. Waldemar Link v.. v. structures.C. American Airlines.S. The ’703 Patent’s challenged claims can only receive the benefit of the Provisional’s filing date if its disclosure satisfies the requirements of 35 U. § 112 ¶1. at 1296. 2002). filed April 9... To satisfy written description. 32 F.Patent No. Co.
Patent No.” (Ex. First. 1007-50.) However. (Ex. the disclosure of a 12-week “treatment period” to improve lower extremity function in MS patients does not adequately disclose to a POSA that the challenged claims’ two-week limitations were necessarily present from the Provisional’s disclosure. and the claimed time period of administration must be “at least two weeks” or “more than two weeks” (together.440. 20 mg) to improve lower extremity function in MS patients—and that is the only disclosure in the Provisional where less than 15 mg 4-AP is administered twice daily to MS patients. (Ex. parallelgroup study…designed in accordance with the Figure entitled Example 11 Study Design. 1007-56. 8. the “two-week limitations”).” Example 11 of the Provisional describes administering 4AP during a 12-week “treatment period” at 3 different doses (10 mg.) The Provisional nowhere discloses a method of improving lower extremity function by administering 10 mg 4-AP. “2-week upward titration (10/15 mg bid or placebo)”. Example 11 discloses a “double-blind.) The Study Design discloses the following time periods: “2-week placebo run-in”. the Provisional fails to provide adequate written description for the challenged claims. 107 F. for “at least two weeks” or “more than two weeks. 11 . 1001 at 29:55–32:43. all challenged claims (except claims 30–31 and 46–47) require that 10 mg (or less than 15 mg) 4-AP be administered twice daily. or less than 15 mg 4-AP. 15 mg. placebo-controlled. For a host of reasons. 20 week.703 Lockwood.3d at 1572.
clear. In fact.) Example 11 discloses data collected at Visit 4 (end of upward titration period) and not again until Visit 7. 298 F. ¶ 43. “1-week downward titration”. “does not disclose any data for the first two weeks of the 12-week treatment period.” (Id. a POSA would understand that Visit 7 occurred no earlier than week 4 of the 12-week treatment period. and exact disclosure of the challenged claims’ two-week limitations—and “a POSA would not immediately discern that the Provisional necessarily disclosed the two-week limitations based on reviewing the Provisional. 8. Nor does Example 11’s two-week upward-titration period prior to the stable 12-week “treatment” period support the claimed two-week limitations in the challenged claims.) A POSA would have inferred from such non-disclosure that “the applicant either collected no data after the first two weeks of the treatment period. (Ex.3d at 1294–96. ¶¶ 43. However. 36.) New Railhead.Patent No. and does not disclose improvement of lower extremity function after the first two weeks of this treatment period. based on the placement of Visit 7 in the 12-week treatment period figure. the Provisional is silent as to precise method of 12 .703 “12-week stable treatment period”.) As a result. ¶ 42. 1023 ¶ 41.440. or the applicant collected data but did not disclose it because such data did not show lower extremity function improvement. emphasis added. The Provisional does not disclose when Visit 7 occurred. 1007-56. concise.” (Id. this disclosure is not a full.” (Id.” (Ex. and “2-week post treatment follow-up.) Example 11. therefore.
upon reviewing the Provisional.) However. Ex. 1001 at 20:3–19.703 performing “upward titration (10/15 mg bid or placebo)” for two weeks. Nothing in Example 11 suggests that different treatment groups took different dosages during the upward titration period. to ensure patients do not have an adverse reaction. (Ex. 8.) As noted. a POSA would have understood this disclosure to mean that the “2-week upward titration” period involved administering SR 4-AP BID at a dose of 10 mg for some portion of the 2-week period. (Ex. And the applicant essentially acknowledges the Provisional’s failure to disclose the upward titration method of Example 11 because it added at least 15 lines of text to the ’703 Patent to explain the dosing parameters of the upward-titration period. “a POSA would have understood from experience that the ‘2-week upward titration’ period refers to a standard phrase in the industry that describes the time period during which a dose is introduced and gradually increased to ensure the patient does not have an adverse reaction to the medication. 13 . following by an upward dose of 15 mg for the remaining portion of the 2-week period. 1007-56.” (Id. ¶ 44. 1007-56.) Specifically: The figure entitled “Example 11 Study Design” ambiguously alludes to “2-week upward titration (10/15 mg bid or placebo)” without further explanation.Patent No. 1023 ¶¶ 46–47.) At best. that explanation is different from how a person of ordinary skill in the art at the time the Provisional was filed would have understood the Example 11 Study Design.440. (Ex.
(Ex.703 (Ex. from the perspective of a POSA such claims “do not disclose to a POSA that the two-week limitations were necessarily present—because such limitations. 1007-52. are not disclosed by the original claims based on a POSA’s evaluation of the disclosure as a whole. because those claims require administration of 10 mg 4-AP for at least two weeks or more than two weeks—not merely for some portion of the two-week upward titration period. because those claims are entirely open-ended with respect to duration of dosing. (Id. 1023 ¶ 47. Likewise.) Lockwood. or their equivalents.) Likewise.” (Id. original claims 1–2 of the Provisional do not satisfy § 112 ¶ 1 for the challenged claims. the “upward titration period of Example 11 does not disclose to a POSA that the two-week limitations of claim 1 and its dependent claims were necessarily present from the Provisional’s disclosure. 8.3d at 1571–72.) Those claims also require administering the same dose of 4-AP for at least two weeks or more than two weeks—“not merely for a portion of the two-week upward titration period as suggested by Example 11’s disclosure.440. “Example 11’s upward titration period does not adequately disclose to a POSA that the two-week limitations in ’703 Patent claim 2 (and its dependent claims) were necessarily present from the disclosure.” (Id. 107 F.” 14 .) As a result.) Therefore. because those claims require administration of less than 15 mg 4-AP—not the 15 mg disclosed in Example 11’s upward titration period.Patent No.
1.0 to 3...703 (Ex.3d 1035.A. 1023 ¶ 37. e. In re Lukach.’” (Id. 2010) (en banc). Ralston Purina Co.P.2d 1570. 1575–76 (Fed.” See Section V. 134951 (Fed.. claim 1 and its dependent claims require a dosing of “less than 15 milligrams of 4-aminopyridine twice daily….C.D.6”).Patent No.” (Ex. Second. Cir. Eiselstein v.) Example 11 of the Provisional “describes a 12-week dosing of 10 mg 4-AP BID.3d 1336. The Provisional does not provide support for “less than 15 milligrams” because it does not adequately describe the full scope of the range “less than 15 milligrams. Cir. 1971) (patentee not entitled to an earlier application’s filing date for a claimed Mw/Mn ratio ranging “from 2.0” based on a “single example” in the priority application disclosing a “Mw/Mn ratio of 2. 442 F. a POSA considering this single data point would not immediately discern that the Provisional necessarily disclosed the full scope of the claimed range of “less than 15 milligrams” 4-AP BID.. 1995) 15 .. 598 F. Cir. 52 F. 969 (C.g.2d 967.440. 1985) (parent application disclosing 25%–27% water does not support broader claims “in the range of 20%–30%”). 8. infra. v. other than this 10 mg dosing.” (Ex. Eli Lilly & Co.) A POSA would have understood this phrase to encompass the range of “between 0 and 15 milligrams (exclusive of 0 and 15). Far-Mar-Co.) See Ariad Pharms. 1001 at 29:55–32:43.) Consequently. Inc. the Provisional does not describe any other 4-AP doses in the range ‘less than 15 milligrams. (Id. 772 F. 1040 (Fed. However.) See. 1023 ¶ 48. v. Frank.
g. the only CavSS ranges disclosed in the Provisional are in Table 7. e. (Ex.A. Cir.C. which only discloses CavSS ranges of 15. 1007-45.P. Third.P. v. In re Fisher. Genentech. 1108 (C. 8.1 ng/ml to 26. 1001 at 8:21–27) is absent from the Provisional.3d 1247. 57 C. 1099.2d at 969.6 ng/ml–35 ng/ml—claims 14–15 and 35–36 of the ’703 Patent cannot claim priority to the Provisional.5 ng/ml. Ralston Purina. Chiron Corp.Patent No.A.) Because all claimed ranges for claims 14–15 and 35–36 claim up to 35 ng/ml—while the Provisional does not disclose at least the upper range of 26. See.2d at 1575–76. 772 F.703 (disclosed range of 45% to 55% does not provide written description for claimed range of 50% to 60%). 363 F. thus a POSA 16 . The written support for the claimed CavSS ranges found in the ’703 Patent (Ex. 2004) (claims broader than the specification lack written description where disclosure lacks a specific and useful teaching commensurate with claim scope).. 1970) (explaining that “a single embodiment” is less likely to support a claimed range broader than the embodiment when claims are directed to physiological activity rather than the more predictable mechanical or electrical arts). Inc. In re Lukach. 1259 (Fed. claims 14–15 and 35–36 are unsupported by the Provisional because they require a CavSS range of 15 ng/ml to 35 ng/ml in MS patients receiving 10 mg (or less than 15 mg) 4-AP BID.C. Cf. 442 F.. By contrast.440.
¶ 17. at least claims 1–30 and 32–52 are entitled to a priority date that is no earlier than April 8..440. 1007. 1023. U. C.3d 1370. 1378 (Fed. 2004—the earliest possible priority date for the ’703 Patent—“would have an M. ¶ 49.Patent No.) 2 The Provisional purports to incorporate by reference certain documents that cannot provide the missing disclosure because they do not identify where the incorporated material is found.D.) See Zenon Envtl.” but also take advantage of “specialized skills of others on the team. (Ex. 8. 1023 ¶ 16.S.703 would not have immediately discerned that the Provisional necessarily disclosed the full scope of the claimed CavSS ranges. passim. with access to a person having an advanced degree (M.S.” (Id. in neuroscience or a related field with an understanding of pharmacokinetics and at least some experience in providing drug therapy to MS patients.) “A POSA may work as part of a multi-disciplinary team and draw upon not only his or her own skills. Cir. Inc. specifically oral sustained release formulations. 2007). 506 F. Level of Ordinary Skill in the Art A POSA as of April 9. or at least 5 years of experience in formulating oral sustained release pharmaceutical drug products. 17 . (Ex. or Ph.D. Filter Corp..) 2 For all of the foregoing reasons.” (Ex. v. or Ph.) in pharmaceutics or pharmaceutical formulation.D. 2005.
1023 ¶ 52. 8. Tech.440.F.) 18 . The broadest reasonable construction of claim language is not one that permits any reading.703 D. Unless otherwise noted.” 37 C. 1. of Sci. § 42. Ex. Claim Construction of Challenged Claims A claim subject to IPR receives the “broadest reasonable construction in light of the specification of the patent in which it appears. “release profile” The term “a release profile” should be construed to mean “a concentration of a drug in a patient’s plasma over time.3d 1359. for purposes of this IPR only. Acad.” In re Am. Cir. see In re Cuozzo Speed Techs.R. that the claim terms of the ’703 Patent are presumed to take on the ordinary and customary meaning that they would have to a POSA.3d 1271 (Fed. 778 F. 2004) (quotation omitted).. exclusive of 0 and 15 milligrams..” (See Ex.) 2. LLC. Cir.100(b).” (Ex. Petitioner accepts. 1023 ¶ 54.Patent No. “less than 15 milligrams” The term “less than 15 milligrams” should be construed to mean “between 0 and 15 milligrams. 367 F. Ctr. 1001 at 7:11–15. 1364 (Fed. but instead is one that must be made “in light of the specification as it would be interpreted by one of ordinary skill in the art. 2015).
703 3. 1001 at 3:19–21. 1023 ¶ 56.) E. 1001 at 13:30–34. Statutory Grounds of Challenge Petitioner requests IPR of the ’703 Patent claims 1–52 in view of the following references. §§ 102(a) and (b) or 103.” (See Ex. Claims for Which Review is Requested Petitioner requests IPR under 35 U. § 311 of claims 1–52 of the ’703 Patent. 2.Patent No. Statement of Precise Relief Requested for Each Claim Challenged 1.C. “initiating treatment” The phrase “initiating treatment” means “beginning administration of a therapeutic agent or drug. The S-1 was not cited by the applicant or otherwise introduced to the Examiner during the ’703 Patent prosecution. “improving walking” Improving walking (claim 32) means “to quantifiably make better a patient’s ability to walk.S. and cancellation of these 52 claims as unpatentable. “matrix” The term “matrix” should be construed to mean “a composition which provides for a sustained release of a drug into the plasma of a patient.” (Ex. and the Examiner did not rely on any of the prior art in the following chart as the basis of any 19 . 9:16–19.” (Ex.) 5. 1023 ¶ 60.C. each of which is prior art to the ’703 Patent under 35 U.) 4.440. 1023 ¶ 58. Ex. Ex.S. 8.
1003. 10–11. e.g. (See Exs.S. 34–41. 52 are obvious Exhibit Number(s) 1003 under 35 U. 1002.Patent No.S. 1046-47.. because those teachings were known in the art. § 103 in light of the S-1 in view of Hayes 3 Claims 22–25. (Ex. (Id.703 rejection in any Office Action.440.C.) Claims 1–52 are unpatentable under 35 U. (See. 1020. passim. 1005 under 35 U. Ex. 44–46. Overview of the State of the Art and Prior Art References 1. 4-AP History and State of the Art at the Time of the ’703 Patent The ’703 Patent does not claim the 4-AP compound.) Instead.C.C. 26–33.) The ’703 Patent does not even claim that the oral administration of 10 mg 4-AP (or less than 15 mg) BID to MS patients or the use of sustained release 4-AP are novel. 1005.C.) Nor does it claim to have pioneered the use of 4-AP to treat MS patients. 1001.S. 2004—the earliest possible priority date for the ’703 20 . Ex. 12–21. Ex. § 103 in light of the S-1 in view of Juarez F. 47–49 are obvious 1003.S. § 103: Ground Proposed Rejections for the ’703 Patent 1 Claims 1–7. the ’703 Patent claims methods of administering 4-AP BID to MS patients for a time period to attain therapeutic objectives such as improving walking. passim. 50–51 are obvious under 35 1003. By at least April 9. 8. 42–43. 1006 U. § 103 in light of the S-1 2 Claims 8–9.
) By the 1990s. 1011. coordination.” (Id.) In 1990.703 Patent—a POSA would have known to apply the claimed methods to achieve those objectives. For over 30 years. researchers have shown the effectiveness of 4-AP treatment in MS patients—“an inflammatory demyelinating disease featuring selective destruction of the central nervous system (CNS) myelin. 1008. researchers conducted double-blind studies evaluating the effectiveness of oral 4-AP administration in MS patients. increase walking speed. administered 21 .) By 1987. 1023 ¶ 26. Davis et al. Ex. Ex. 1012.” (Ex. ¶ 27. The pharmacological properties of 4-AP have been studied for decades. (Ex.) And by 1991. 8. were to improve walking. it was even known in the art that sustained-release oral compositions of 4AP were effective in treating MS. a POSA would have known that MS is a chronic disease that causes problems with walking and lower extremity muscle function on an ongoing basis.” (Ex. 1023 ¶ 18. (See generally. researchers had measured neurological changes from 7–35 mg of 4-AP in 1–5 mg doses administered every 10–60 minutes.) By April 2004. with “motor function (power. (See. Ex. gait)” in 5 out of 12 patients improving “within minutes of drug injection at doses as low as 2 mg. and increase lower extremity muscle strength and tone. 1010-2.. e. passim.440. and especially as the disease progresses over time. among the therapeutic objectives of a POSA “seeking to treat MS patients with 4-AP prior to April 2004. 1013-1.Patent No.) As a result.g.
1015-1.g. in doses as low as 10 mg. 1023 ¶ 28.Patent No. because all four disease states require continuous treatment to maintain the benefits of the drug over time. including gait. by April 2004. the National Multiple Sclerosis Society (“NMSS”) had introduced four disease categories for MS: relapsing-remitting. at Table 1. (See id. 10 mg) 4-AP to improve lower extremity function in MS patients. 8. (Ex.) Thus. 6. relapsing-progressive. 1011-2–3. By 1996. with an efficacy analysis performed only in patients who completed “at least two weeks” of treatment.) Polman also found that “4-Aminopyridine was more effective than 3.4-diaminopyridine..) A typical MS treatment regimen would almost certainly extend for at least two weeks or even months. 1014-1. Ex.703 10–25 mg 4-AP (total doses per individual) to MS patients and observed marked improvements in motor functions. Healthcare Grp.) For example. especially for ambulation” in patients with MS. 1012-3. affecting 85% of patients. 1022-2.) Relapsing-remitting MS is the most common form of MS. (Ex. (Ex.) van Diemen further teaches a statistically significant estimated effect of 4-AP on the mean EDSS score after 2. a POSA would have known to use less than 15 mg (e. (Ex. 1023 ¶¶ 21–22. (Ex. 22 .) It is a basic precept in medicine that “physicians always seek to prescribe the lowest effective dose of any medication” to minimize side effects.440. and 12 weeks of treatment. and secondary-progressive. (Ex. primary-progressive. van Diemen taught administering 4-AP to treat MS disability for at least two weeks.
while minimizing adverse effects.440.3d 1370. 1023 ¶ 29.] exercising reasonable diligence.703 LP v.C. Inc. Pharm.S. 2005 (for claims without provisional priority). Inc.Patent No. v. 642 F. 1371–72 (Fed. 1004-9.) Even assuming arguendo that the priority date is April 9. (Ex. 698 F. 2004. §§ 102(a) and (b) because it was printed and made publicly available at least as early as September 30. 1380 (Fed. Ex. § 102(a). 8.) A reference is a “printed publication” if it was “available to the extent that persons interested and ordinarily skilled in the subject matter or art[.. can locate it. and to sustain treatment for a period of time of at least two weeks to maintain the benefits from treatment. 10 mg BID) would be effective in achieving the treatment objectives for an MS patient. Therefore.3d 1374. 1003.. Co. see generally. Cir.g. the S-1 would still qualify as prior art against all claims under 35 U. 1001-1–10. 2011). If the S-1 was accessible to interested persons skilled in the art “it is unnecessary to show that anyone actually inspected the reference. 1003) The S-1 constitutes prior art under 35 U.. Mut. (Ex. a POSA would be motivated to combine the elements of the prior art showing that an oral sustained-release tablet of 4-AP at a low dose (e.S.) 2. Premier Election Solutions. 2012) (quotation omitted).C. Cir.” In re 23 . 2003— more than one year before the earliest effective filing date of April 8. The S-1 (Ex.” Voter Verified. (See Ex. The touchstone is access. The S-1 was not art of record during the ’703 Patent prosecution.
”).. Ex. a POSA would have been motivated to consult information—particularly public filings such as the S-1—relating to Acorda’s research.703 Lister. 848 F.) Based on such information.) This had received attention in prominent publications in the field as well as general news sources from 2002 until the date of the S-1 filing. 1019-1 (“[t]he Company’s lead product.2d 1560. 583 F. “and would have been motivated to keep apprised of Acorda’s research and studies conducted with 4-AP in 2003. 1988) (holding if publication is accessible.Patent No. Fampridine-SR.440. As early as 2000. (See id. Ex. 8.”). Cir. 2009).” (Ex. is in Phase 3 clinical trials for chronic SCI and Phase 2 for MS.3d 1307. “there is no requirement to show that particular members of the public actually received the information. 1569 (Fed. Advanced Micro-Devices. A POSA interested in researching and treating MS would have known that Acorda is active in the field of SR 4-AP research to treat patients with MS. Cir. 1017-1. See also Constant v. A POSA would therefore monitor and seek information about such studies by looking for and accessing statements and publications by researchers and companies 24 . a POSA would have known that Acorda was investigating fampridine [4-AP] “for the potential treatment of spinal cord injuries and multiple sclerosis. 1018-1 (“[f]ampridine-SR is also in Phase 2 clinical trials to evaluate safety and efficacy in the treatment of symptoms associated with multiple sclerosis (MS).”). 1314 (Fed. Inc.
on 26 September 2003” and “filed it on 29 September 2003. which provided instructions to the public for obtaining a printed copy of the S-1 publication via mail. ¶ 11. Acorda has admitted that the S-1 is prior art to a European counterpart of the ’703 Patent with the same priority date. companies in the United States making an initial public offer of stock must file certain forms with the U.) The September 30.2. the S-1 was available to a POSA interested in reviewing information regarding Acorda Therapeutics.” (Id. “[t]he SEC received the Acorda Therapeutics filing.S. including Acorda’s research and disclosures. ¶¶ 62–63. ¶¶ 14–15. 2003 SEC Registration Statement.) Thus.703 conducting such studies.) The S-1 HTML properties establish that. including the S-1 form.” (Ex. by at least September 30.” (Ex.” which endeavors to make the filings publicly available within “a matter of minutes. ¶ 12. n.) Lest there be any doubt. Securities and Exchange Commission (SEC). these public filings have been available online in the SEC’s EDGAR (Electronic Data Gathering.” (Id. (Ex.” (Id. and that 25 . and Retrieval) system. further establishes its public availability. 848 F.) See Constant. 8.2d at 1569 (“Evidence of routine business practice can be sufficient to prove that a reference was made accessible before a critical date. 1023. 1016 ¶ 11.Patent No. 1004-9. Analysis. which contains basic business and financial information about the issuer.) “Since 1996. 2003.”) “Included in these disclosures is the S-1 form. (Id.440.) “By law.
) 4 The S-1 is document C27 in the EPO appeal. 1985) (collecting authority).39. telling you if similar patents have been claimed in other countries. See. 6.. (Ex. 6.S.g.703 admission is binding here.g. 1025). LEXIS 3 The EPO’s “Espacenet” search tool provides access to “patent family information. 1026. 5. Eagle Mfg.g. 26 . requirements for prior art printed publications.3 Specifically. Cir. 1026 ¶ 5. 1028.. 1732548 (B9) (“EP ’548”) (Ex.) The Federal Circuit has held that a patentee’s admissions of a reference’s prior art status is “clear and convincing evidence” that the reference is prior art. on September 16. 2014. Acorda repeatedly admitted that the S-1 was prior art to EP ’548 (See e.) Espacenet’s bibliographic data for the ’703 Patent states it was “also published as” Acorda’s opposed “EP1732548 (B9)” patent (Ex. Dist. 2003 WL 25539702.. The fact that the admissions occurred during EPO proceedings does not negate Acorda’s admissions. Tyler Refrig. ¶¶ 4.440.Patent No. Sentry Prot.61.27. v.S. Annex A. 2003 U. Co. the EPO standards for writings as prior art are comparable to the U. e. 1027-2. 777 F. Prods. No.2d 687.” (Ex. e. id. (Ex. and countered an opponent’s argument that the S-1 (the “C27” reference) anticipates EP ’548’s claims.) 4 In its EPO brief.19. 1:01-cv-2240. 690 (Fed... Kysor Indus. 5 See. Corp.6. 1021-1 (“everything made available to the public by means of a written… description …before the date of filing of the European patent application.”). v. Acorda responded to an appeal opposing its European Patent No. 8. (See Ex.) 5 For purposes of Acorda’s admissions.
) The S-1 described using sustained-release fampridine in an MS Phase II clinical trial: The current late Phase II clinical trial. 2003) (collecting authority and finding “[s]everal other cases have held that statements made by a patentee during foreign patent proceedings can constitute admissions”). v.” (Ex. after extensive consultation with a panel of expert MS neurologists and with the FDA. -37. 1134–35 (W. The primary endpoint of the study is an improvement in average walking speed using the Timed 25 Foot Walk.Patent No.D. Gentex Corp. The reference teaches the effectiveness of the 10–25 mg BID dosing range.S. The clinical trial is also designed to compare three doses of 10. and to assess their relative safety and efficacy over a treatment period of 12 weeks. (Id.) 27 . to provide pivotal data for support of an NDA for the use of fampridine-SR in MS. emphasis added. Thus. 30. 1003-37. 15 and 20 mg.440. MS-F202.. possibly being offset by increased side effects.703 27435. Mich. 918 F. 8. proceedings under FRE 801(d)(2)). 1126. Ohio Sept. twice per day. The S-1 describes clinical trials conducted using a sustained-release (“SR”) composition of 4-AP. Supp.D. stating that “clinical trials indicated that there was evidence of increasing dose-response through the range of 10 to 25 mg twice a day. 1996) (finding public use admissions from foreign patent proceedings admissible in U. was designed. but that evidence of increasing efficacy at doses higher than 25 mg twice a day was limited. the S-1 is a prior art printed publication to the challenged claims. Donnelly Corp. at *32–33 (N.
) Rather. MS-F201. passim.C.C. Clinical Neuropharmacology—more than one year before the earliest effective filing date of April 8. Hayes was not the basis of any Examiner rejection during the ’703 Patent prosecution.S. (Id. and 11 subjects were given placebo over the same period.440. “a total of 25 subjects received fampridine-SR in doses increasing from 10 mg to 40 mg twice per day over eight weeks of treatment. § 102(a). 8. at doses from 10 to 25 mg twice a day. 3. Hayes (Ex. which was completed in 2001. 1005. 1046-47. as explained in more detail below. 1016 ¶¶ 16–21) in the peer-reviewed journal. 1002. the applicant cited Hayes as 28 . Hayes would still be prior art against all claims under 35 U. for claims not entitled to provisional priority.703 The S-1 also discussed a previously conducted Phase II study. The MS-F201 Phase II trial “demonstrated that doses up to 25 mg twice a day were well tolerated. (Exs. 1005) Hayes constitutes prior art under 35 U.” (Id. priority date. 2004.) Even assuming arguendo an April 9.Patent No.” Id. 2005. (Ex.) The S-1 disclosures teach nearly all claim limitations. and were associated with statistically significant improvements in walking speed and leg muscle strength” and that “[m]ost of the improvement in strength and walking speed was apparent within the first three weeks of the Fampridine-SR treatment. §§ 102(a) or (b) to all claims because it was published and accessible by September 2003 (Ex.S.) In that study.
incomplete SCI. (Id.) The doses in each study were 10 mg. 15 mg. 8.) 29 . and 25 mg. -3. 20 mg. a tmax of 10 mg SR 4-AP is 2.1 ng/mL to 26. and Table 3 provides pharmacokinetic data.) It presents the results of two studies “conducted to determine the pharmacokinetics and safety profile of an oral. (Ex.703 prior art evidence supporting its claimed pharmacokinetic ranges. 1005-1. (Id. (Id.7 ± 1.Patent No.) The data for 10 mg BID showed a CavSS (average plasma concentration at steady state) of 20. (Id.) Hayes notes that “[c]linical trials have confirmed that administration of fampridine [4-AP] results in symptomatic improvements in patients with SCI and multiple sclerosis.7) ng/mL—a range of 15. 157.) Dose administrations occurred every 12 hours.7 hours (accounting for error). -5.5 ng/mL (accounting for error). 10–25 mg)  administered as a single dose…and  twice daily for 1 week…in patients with chronic.) Hayes reported that “[s]teady state was achieved by day 5…after twice-daily administration” and recorded pharmacokinetic data in relation to the plasma concentration of the drug.440.7–3. 1002-151– 52. 7. -2. 1005-1. 7. -4.0 hours—a range of 1. -5.) Figure 1 provides release profile information for the drug.” (Ex.8 (± 5. (Id.” (Ex. and a release profile of 24 hours. sustained-release (SR) formulation of fampridine (fampridine-SR.
because it was published in the Int’l J. 1006) Juarez constitutes prior art under 35 U.) Juarez teaches the preparation of an oral tablet comprising 4-AP and a rate of release controlling polymer. 26–33. passim. and 52 are obvious in light of the S-1 in view of the knowledge of a POSA.) VI. (Ex.) Juarez was not the basis of any Examiner rejection during the ’703 prosecution. 8. in 2001.” while claim 2 requires the dosage to be “10 30 .Patent No. 1046-47.703 4. DETAILED EXPLANATION OF THE CHALLENGE Ground 1: Claims 1–7. 10–11.440. (Ex.) Claim 1 further requires that the twice daily dosage of 4AP is “less than 15 milligrams. (Ex. (Exs.C. Juarez (Ex. 1006-2–3. 44–46. 2004. (Ex. 1006-1. 1006-1–3. of Pharm.) Juarez further discloses that the purpose of this HPMC matrix is to “prolong delivery with zero-order kinetics to maintain a constant in vivo plasma drug concentration. and with this to maintain a constant pharmacological effect.) Juarez also discloses a sustained release 4-AP composition formulated as a matrix with the polymer hydroxypropyl methylcellulose (“HPMC”). 1002. § 102(b) regardless of priority date.” (Id. -2. A. 1001 at 29:55–67. Independent claims 1 and 2 require: A method of improving lower extremity function in a human multiple sclerosis patient in need thereof comprising orally administering to said patient a sustained release composition … of 4-aminopyridine twice daily for a time period of at least two weeks. which is more than one year before April 9.S.
” (Ex.) The combination of the S-1 with common knowledge available to a POSA teaches each element of the challenged claims. oral tablet formulation of fampridine. which includes fampridine”).Patent No.” (Ex. 1003-34 (“We have a worldwide exclusive license from Elan to its patent for the sustained release formulation of aminopyridines.) 1. that Fampridine-SR is another name for sustained release 4-aminopyridine. 67–68. 1023 ¶¶ 62–120.” (Ex. 66. and a POSA would have understood. 8.) Thus. A POSA would have been motivated to combine the S-1 with common knowledge in an effort to arrive at low-dose methods for improving lower-extremity functions associated with MS. (Ex.) The S-1 also discloses the details of multiple clinical trials in which Fampridine-SR was administered to patients suffering from MS. The S-1 teaches every limitation of claims 1 and 2. Independent claims 1 and 2 are obvious in light of the S-1 disclosure and the knowledge of a POSA. 1001 at 29:58–62.703 milligrams. 66.440.) 31 . 1023 ¶¶ 63. (Ex. 1003-34 (emphasis added). or SR 4-AP. The S-1 describes research into “Fampridine-SR.) Claim 1 further requires that “the amount of said 4-aminopyridine administered to said patient in each said administering step is the same over said time period. 1023 ¶ 39. all with the intended outcome of improving lower-extremity function. suitable for twice daily dosing. Ex. (Ex. the S-1 confirms. while minimizing adverse side effects. [which] is a sustained release. 1001 at 29:58.
) In sum. wherein patients exhibited improvements in walking strength and speed within the first 3 weeks. the S-1 disclosed the results of a completed clinical trial. timed walking. MS-F201.” (Id. “A POSA considering the teachings disclosed in the S-1 as clinical trial MS-F201 would have understood that low-dose SR 4-AP could be orally administered to MS patients for a short period of time (e.) Significantly..g. 32 . -37 (emphasis added).” (Ex. MS-F201…was designed to determine the optimal dose level of Fampridine-SR and to evaluate possible ways in which to measure the effect of the drug on symptoms of the disease. several weeks) to achieve an improvement in lower extremity strength and walking speed. at doses from 10 to 25 mg twice a day. 1003-37 (emphasis added). and self-reported fatigue.” and “demonstrated that doses up to 25 mg twice a day…were associated with statistically significant improvements in walking speed and leg muscle strength.703 The S-1 discloses that the “Phase 2 clinical trial of Fampridine-SR in Multiple Sclerosis. in which MS patients received 4-AP twice a day orally for 8 weeks.” (Ex. “subjects received Fampridine-SR in doses increasing from 10 mg to 40 mg twice per day over eight weeks of treatment.” (Id. (emphasis added). 8.) To do so. The 4-AP dosing during the first 3 weeks of treatment was 10–25 mg twice per day.440. “[m]ost of the improvement in strength and walking speed was apparent within the first three weeks of the Fampridine-SR treatment. including motor strength.Patent No.
MS-F202. Following the MS-F201 trial. as here. and 20 mg. this trial. 315 F.”). which was “designed to compare three doses of 10. the [obviousness] conclusion is even more compelling than in cases of mere overlap.3d 1325. LP. “common knowledge available at the time would have motivated a POSA to seek similar teachings in which lower doses of 4-AP could be administered to achieve efficacious results. -37.” (Id. 2003) (“[W]hen. Inc. twice per day..) See Tyco Healthcare Grp. and to assess their relative safety and efficacy over a treatment period of 12 weeks.) According to the S-1. 1329–30 (Fed.” (Ex. 1003-37 (emphasis added). 692 33 .Patent No.) See In re Peterson. In re Applied Materials. Ex. 1023 ¶ 77.” (Id.440. 642 F. -37 (emphasis added).’ the ’703 Patent’s claimed point of novelty over the prior art—its 10 mg (or less than 15 mg) dose—would have been obvious to a POSA. [that] was designed…to provide pivotal data for support of an NDA for the use of Fampridine-SR in MS.3d at 1371–72 (“physicians always seek to prescribe the lowest effective dose of any medication”).703 1023 ¶ 113. the S-1 discloses a second “Phase 2 clinical trial. Cir.) “In light of this disclosure that a stable 10 mg dose was chosen for MS-F202 following the conclusion of the MS-F201 trial ‘designed to determine the optimal dose level of Fampridine-SR. ¶ 115. The primary endpoint of the study is an improvement in average walking speed using the Timed 25 Foot Walk.” (Id. the claimed ranges are completely encompassed by the prior art. 15. The S-1 provides exactly that teaching. 8.) Further.
456 (CCPA 1955)). Such is the case here because it is a basic precept in the field of medicine that “a POSA would have been motivated to try to use the lowest effective dose to minimize side effects. 2012) (“‘[W]here the general conditions of a claim are disclosed in the prior art. 8.” (Ex.440. Moreover.” particularly in the case of “patients sensitive to the side effects of” the medication).) See Tyco Healthcare Grp. 2012) (affirming invalidity over a 34 . 1382–83 (Fed. 642 F. 677 F. Cir.” (Ex.Patent No.2d 454. characterized by weakness and walking impairment. 1295 (Fed. 220 F. 1023 ¶ 29. 1023 ¶ 89. and particularly with respect to improving lower extremity muscle strength and walking speed.) “Based on these statements of intent to rely on this clinical data for NDA submission and drug label indications. it is not inventive to discover the optimum or workable ranges by routine experimentation.” (Ex. LP.’”) (quoting In re Aller.703 F. a POSA would reasonably expect all doses (10. 100337 (emphasis added). the S-1 further discloses that the data from the MS-F202 trial was intended “to support an indication for the treatment of lower extremity motor dysfunction.3d 1289.3d at 1371–72 (affirming summary judgment of invalidity on the basis that it would have been obvious to administer a medication at the lowest disclosed efficacious range since “physicians always seek to prescribe the lowest effective dose of any medication.) See In re Montgomery. 15. Cir. and 20 mg) of this trial to be successful in treating lower extremity motor dysfunction.3d 1375.
3) comprising orally administering to said patient.” (Ex. 7) for a time period of at least two weeks (i. 1023 ¶ 68.03’s statement that. 1003-45 (“Human clinical trials…: Phase 2: The drug is administered to a limited subject population to identify possible adverse effects and safety risks. to determine the efficacy of the product for specific targeted diseases and to determine dosage tolerance and optimal dosage. that these Phase 2 clinical trials for MS were conducted in ‘human multiple sclerosis patient[s] in need’ of treatment.703 published clinical protocol “designed to obtain data for submission to regulatory agencies” and so in “an advanced stage of testing designed to secure regulatory approval” in light of Manual of Patent Examining Procedure § 2107. 8..Patent No. 6 “A POSA would have understood. 12 weeks).) 35 . Ex. [Patent & Trademark] Office personnel should presume that the applicant has established that the subject matter of that trial is reasonably predictive of having the asserted therapeutic utility”). “if an applicant has initiated human clinical trials for a therapeutic product or process. 6) twice daily. the S-1 explicitly discloses every element common to claims 1 and 2: “1) improving lower extremity function.” See In re Applied Materials. As the bold typeface above indicates.440. 4) 10 mg (and thus less than 15 mg). and the S-1 confirms.e. 2) in a human 6 multiple sclerosis patient in need thereof. 5) of a sustained release composition of 4-aminopyridine (Fampridine-SR).”).
703 Inc. ¶ 72.) Thus. The S-1 teaches improving lower extremity function. including walking. twice a day…over a treatment period of 12 weeks’ means that 10 mg of Fampridine-SR was administered twice per day to a first patient group for 12 weeks.” (Id. The dependent claims fail to add any non-obvious limitations. 8. “[a] POSA would have understood that the MS-F202 comparison in the S-1 of ‘three doses of 10. a. and 20 mg.) With respect to the final element of claim 1. Each element of the dependent claims is disclosed in the S-1. 2012) (“A prima facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art.” 36 . 692 F. 1023 ¶ 66. 1295 (Fed. 44–46. 26–33.440. “[c]laims 1 and 2 of the ’703 Patent would have been obvious to a POSA in light of the S-1.e. muscle strength. or would have been obvious to a POSA in light of the common knowledge in the field.. ¶ 71 (emphasis added. 10–11.3d 1289. as well as increasing the patient’s walking speed (claims 3–5. Claim 3 depends from claim 1 and additionally requires that “the improving lower extremity function in the patient is increasing walking speed of the patient. hence receiving the same amount (i.Patent No.) 2. (Ex.” (Id.”) (quotation omitted). and muscle tone. 10 mg) of 4-AP at each administration step as claim 1 requires. for at least the foregoing reasons. Cir. Dependent claims 3–7. 15. 32). and 52 are obvious in light of the S-1 and a POSA’s knowledge.
) In one clinical trial. 8. including motor strength. [and] timed walking” satisfies the additional limitations of claims 3 and 32.703 (Ex. 33. and additionally requires that “the lower extremity function is walking. 37.) In particular.440.3d at 1382–83. [they] found clear differences in the pattern of response between Fampridine-SR and placebo- 37 . called the Multiple Sclerosis Functional Composite Score. 1003-37 (emphasis added). -37. when the researchers “examined the measurements from individual subjects. the S-1 teaches that “[t]he primary endpoint of the study is an improvement in average walking speed using the Timed 25 Foot Walk (“T25-FW”). (Ex. and looked at the improvement in walking speed between the baseline period and the average over the first four treatment weeks.” (Id.) The S-1 disclosure of Fampridine-SR clinical trials “to support an indication for the treatment of lower extremity motor dysfunction. 677 F.Patent No.) Claim 32 also depends from claim 1. (Id. and involves timing the subject completing a 25 foot walk.) See In re Montgomery. 1001 at 31:15–16.” (Ex. 35. 1003-30. The S-1 is replete with the researchers’ observations that the administration of the sustained-release formulation of fampridine resulted in “improvement in walking speed. 1001 at 30:1–3.” (Ex.” measuring “an improvement in average walking speed” and “the effect of the drug on symptoms of the disease.) The T25-FW “is part of a standardized set of neurological tests. characterized by weakness and walking impairment.
is indicative of not just walking speed.) Therefore.” and measuring “the effect of the drug on symptoms of the disease. 8.) Claim 4 depends from claim 1 and additionally requires that “the lower extremity function is lower extremity muscle strength. a POSA would have concluded—based on a reasonable expectation—that the administration of 10 mg BID of sustained release 4-AP” in the reference resulted in the claim 3 improved walking speed and claim 32 improved walking. characterized by weakness. ¶ 94.) “Applying this knowledge to the S-1. (Ex. (Id.” (Ex. but also other aspects of walking. these claims would have been obvious to a POSA. including motor strength.) Claim 5 depends from claim 1 and additionally requires that “the lower extremity function is lower extremity muscle tone. (Id.Patent No.703 treated subjects.” (Id.) In light of this S-1 disclosure regarding improving lower extremity weakness and motor strength.) The researchers additionally found that “the Fampridine-SR treated group showed a marked tendency for improvement in speed. it would have been obvious to a POSA that such improvements would naturally also 38 . the S-1 discloses Fampridine-SR clinical trials “to support an indication for the treatment of lower extremity motor dysfunction.” (Id. 1001 at 30:6–7.” (Ex.440.) As noted above. used as a primary measure of improvement in the studies disclosed in the S-1.” (Ex. 1003-37 (emphasis added). 1001 at 30:4–5.) A patient’s score on the T25-FW. 1023 ¶ 93.
See Perfect Web Techs., Inc. v. InfoUSA, Inc., 587 F.3d 1324, 1329 (Fed. Cir.
sense of the person of ordinary skill.”); In re Montgomery, 677 F.3d at 1382–83.
composition twice daily to said patient” (claims 6–7, 33).
relapsing remitting multiple sclerosis (claims 26–27, 52).
A. as well as the limitation “said time period comprises twelve weeks.) Claim 45 requires that the “lower extremity function is walking.” recited in claims 30–31 and 46.Patent No. Therefore. 44–46) Claim 28 depends from claim 1. 1023 ¶¶ 103–114. Inc.A. these claims would have been obvious to a POSA in light of the S-1 disclosure. 692 F. claim 46 depends from claim 32—described above in Section VI. claims 29 and 45 depend from claim 2. and claim 44 depends from claim 32—as described in Section VI. 1003-37. (Ex.” (Ex.) See In re Applied Materials.a.” (Ex. Each of claims 28–29 and 44–45 requires that “said time period is more than two weeks. Claim 30 depends from claim 1.3d at 1295. 8. 1001 at 31:11–14.” which the S-1 teaches as described in Section VI. 1001 at 31:7–10.A. Each of claims 30– 31 and 46 requires the additional limitation that “said time period comprises twelve weeks.a.2. 32:23–24..2. (Ex. The S-1 teaches the administration of sustained release 4-AP for “more than two weeks” and “twelve weeks” (claims 28–31.) The S-1 disclosure of a “treatment period of 12 weeks” meets the openended limitation of “said time period is more than two weeks” recited in claims 28–29 and 44–45.440. 32:18–22.2.) 42 . claim 31 depends from claim 2.703 e.a.
34–41.) A POSA would have been motivated to combine the S-1 with common knowledge and publications like Hayes—which focuses on the same 10 mg BID doses of SR 4-AP oral tablets disclosed in the S-1—“to further understand and apply the methods disclosed in the S-1 to treat patients suffering from MS and its associated conditions.) In particular. (Ex. 1002151–52. 8. 12–21. 34–41. and 47–49 are obvious in light of the S-1 in view of Hayes and the knowledge of a POSA.703 B. Each of claims 8–9. and 32) are obvious for at least the reasons described with respect to Ground 1. (Ex.) 43 . 12–21. and 47–49 would have been obvious to a POSA over the S-1 in further view of Hayes and common knowledge available to a POSA.” (Id. and 47–49 fail to add any additional non-obvious elements. The claims upon which those claims depend (claims 1–2.” (Id. “a POSA considering the effectiveness of the clinical trials disclosed in the S-1 implementing oral low-dose SR 4-AP twice daily would have been motivated to look to the teachings of Hayes—disclosing the use of the same oral low-dose SR 4AP—in an effort to achieve effective blood plasma pharmacokinetics. Ground 2: Claims 8–9. 34–41. 1023 ¶¶ 121–71. 12–21. ¶ 125.Patent No. 157.440. Dependent claims 8–9.) The particular relevance of the Hayes teachings to the pending claims was explicitly acknowledged by the applicant during prosecution of the ’703 Patent.
1003-36. 15. and 25 mg) twice daily for 6 consecutive days …[and] were asked to take their medication at 12-hour intervals. at approximately 8:00 AM and 8:00 PM.) “The spacing of doses at 12 hour intervals is even more important and likely to occur in a clinical trial setting such as that disclosed in the S-1. and claim 34 depends from claim 32—described above in Section VI. (Ex.) Additionally. Ex. twice per day’ described in the S-1 is about every 12 hours. 15. 31:22–24.A. 1044 ¶ 51. 1001 at 30:16–19.Patent No.” (Ex. The S-1 and Hayes combination teaches “twice daily is about every 12 hours” (claims 8–9.) “A POSA would have known that the most preferable administration of the dosings ‘10. 1044 ¶ 51.) Indeed. claim 9 depends from claim 2.440. 1023 ¶ 145. and 20 mg [4-AP]. because researchers can standardize their administration of a drug by using the 12-hour mark” as the designated dosing time. Each of claims 8–9 and 34 requires that “twice daily is about every 12 hours. 1005-2–3 44 . Claim 8 depends from claim 1. 8.2. Hayes discloses a study in which patients “received doses of orally administered fampridine-SR tablets at each dose level (10. with respect to Ground 1. Ex.703 1. the S-1 discloses that the administration of Fampridine SR to spinal cord injury patients “every 12 hours produced peak concentrations of Fampridine-SR. 1003-37.” as claims 8–9 and 34 require.” (Ex. 34).” (Ex. 1023 ¶ 145. Ex. 20. (Ex.a.
stating that “Fampridine-SR. stating that “a sustained-release tablet formulation of fampridine (fampridine-SR) has been developed. The S-1 and Hayes combination teaches that sustained release 4AP “provides a release profile to obtain a CavSS of about 15 ng/ml to about 35 ng/ml” (claims 14–15. 1005-2.a.Patent No. Claim 12 depends from claim 8—described above in Section VI.B. 1023 ¶ 144. Ex. 1003-29 (emphasis added). 8. and claim 35 depends from claim 32—described above in Section VI. 1044 ¶ 50..” (Ex. with respect to Ground 1.B. contained in a sustained release tablet form.2. 1001 at 30:24–27.) Thus. Ex.c. (Ex. Claim 14 depends from claim 1.) “Thus. these claims would have been obvious to a POSA in light of the S-1 and Hayes.440.1. is an oral. Each of claims 14–15 and 35–36 requires that “said sustained release composition provides a release profile to obtain a CavSS of about 15 ng/ml to 45 . 1023 ¶ 148.) 3. Each of claims 12–13 requires that “said sustained release composition is a tablet.) 2. 1044 ¶ 54.) Hayes also discloses this limitation.703 (emphasis added).” (Ex.2. The S-1 and Hayes combination teaches “wherein said sustained release composition is a tablet” (claims 12–13). claims 15 and 36 depend from claim 2.) As explained above in Section VI.” (Ex.” (Ex. the S-1 discloses the “said sustained release composition is a tablet” limitations of claims 12–13.. 35–36).A. claims 8–9 and 34 would have been obvious over the S-1 in view of Hayes. small molecule drug.1. and claim 13 depends from claim 9—also described above in Section VI.A.
and 32. Inc. (Ex. applicant’s basis for patentability relied squarely on the known “pharmacokinetics of SR 4-AP. 8. 1002-151.. 1002-151.) Specifically. 31:25–31..) Claim 36 further requires the additional limitation that the “lower extremity function is walking. 2012) (affirming obviousness because “an obvious formulation cannot become nonobvious simply by administering it to a patient and claiming the resulting serum concentrations. Cir. with respect to Ground 1. v. the applicant conceded as much during the prosecution of the ’703 Patent. See also Santarus.” (Ex.”) (citation omitted).Patent No. The S-1 teaches or suggests each and every element of claims 1.” (Ex. 1001 at 30:28–33. Hayes discloses the pharmacokinetic ranges recited in dependent claims 14–15 and 35–36.703 about 35 ng/ml. Additionally. In fact. Par Pharm.2. 2. During examination. 191 teaches that in 46 .) The applicant further admitted that “[Hayes] at Table 3 on p.” which is taught by the S-1 for reasons discussed in Section VI. the applicant cited “[t]he pharmacokinetics of SR 4-AP reported by [Hayes]” as being reliable data points for demonstrating the in vivo pharmacokinetics recited in the claims of the ’703 Patent. Inc. 1354 (Fed.440. At the least.a. claims 14–15 and 35–36 are obvious over the combination of the S-1 and Hayes.A.3d 1344. 694 F.
3 53.2 39.’” (Ex.8 (+5. Ex. Pleasure and Polli agree.) Drs. 1044 ¶ 42.4±9.) 47 . (Ex. because these disabilities were and are not expected to affect metabolism of half-life of 4-AP.0±7.703 patients with spinal cord injury 7 [the[ CavSS…(in ng/ml) w[as] as follows.3±14. 1002-151–52.Patent No. the applicant admitted that one of ordinary skill “‘would expect the same pharmacokinetics in MS patients as in patients with spinal cord injury.7 31. In particular. 8.” “A POSA also would have known that the 10 mg BID sustained release 4AP disclosed in the S-1 would have the same pharmacokinetics as both Hayes and 7 During prosecution.7) in Hayes for 10 mg BID administration of 4-AP falls squarely within the claimed range of “CavSS of about 15 ng/ml to about 35 ng/ml. 1023 ¶ 136. 15 mg BID. the reported Cavss of 20. the applicant essentially admitted that the pharmacokinetic limitations recited in the claims of the ’703 Patent are obvious in view of the prior art.440.8±5.5 (Ex. which is largely renally cleared.) By acknowledging the reliability of the pharmacokinetic data points reported in Hayes. 1002-151. for 10 mg BID. 20 mg BID and 25 mg BID SR 4-AP”: CavSS 10 mg BID 15 mg BID 20 mg BID 25 mg BID 20.
Prior to that point. 1023 ¶ 129.” (Ex. as they provide guidance regarding the clinical effects of 10.” 8 (Ex. resulting in stable treatment efficacy of 4-AP. Ex. 1023 ¶¶ 137–38.) 48 . 1044 ¶ 43. respectively. and 20 mg BID doses.) “Steady state refers to the pharmacokinetic situation where the drug plasma profile is the same. and thus would have had the same Tmax. Ex.Patent No. 1023 ¶ 124. Ex.” (Ex. due to overall intake of a drug being equal to drug elimination.440. and Hayes discloses that ‘[s]teady state was achieved by day 5 (4 days of fampridine-SR dosing) after twice-daily administration of fampridine-SR. 1044 ¶ 44. any observed efficacy could correspondingly change. 1023 ¶ 137.) Similarly. 1023 ¶ 139. 1005-4. Ex. 8. “[a] POSA also would have understood that the S-1 and the Hayes study each used similar formulations and dosing. because there are overall increasing or decreasing levels of drug in the system. 1044 ¶ 45.703 the claimed invention. 1044 ¶ 35. 15.” (Ex. Ex.) “A POSA looking to optimize a stable dose regimen of sustained release 4-AP would have been motivated to look to both the S-1 and Hayes. 1044 8 Although “the S-1 teaches administration of 10 mg BID SR 4-AP for twelve weeks and Hayes teaches administration of 10 mg BID SR 4-AP for 6 ½ days. a POSA would have understood that the pharmacokinetics for the two administrations would have been the same because the CavSS was measured at steady state. Ex. as well as the plasma concentrations resulting from those doses.’” (Ex.
4.2.5 when accounting for error—“rendering obvious the pharmacokinetic limitations of claims 14–15 and 35–36 when combining the teachings of Hayes with the 10 mg BID dosing regimen of sustained release 4-AP described in the S1.S. (Id. Teleflex Inc.) A POSA would find further motivation to combine the references to assess the safety of sustained release 4-AP. a POSA would have known that “the CavSS of 10 mg sustained release 4-AP at steady state was 20. 420 (2007) (holding that “any need or problem known in the field of endeavor at the time of invention and addressed by the patent can provide a reason for combining the elements in the manner claimed”).. Ex. as demonstrated by Table 3 of Hayes. 15.2 or 6 hours after SR 4-AP administration (claims 16–19. and claim 37 depends from claim 32—described above in Section VI. Inc.” (Ex. and 20 mg. The S-1 and Hayes combination teaches a mean Tmax in a range of about 2 to about 5.1–26. with 49 . 1003-37 (“The clinical trial is also designed to compare three doses of 10. and to assess their relative safety and efficacy”). single-center studies designed to examine the pharmacokinetics and safety profile of fampridine-SR”. 37–41). 692 F. Thus.7”—a range of 15.3d at 1295.A..440. claims 17 and 38 depend from claim 2.) See In re Applied Materials..a. twice per day. Ex. Claim 16 depends from claim 1.) See KSR Int’l Co.Patent No.703 ¶ 55. 398. 1005-2 (“This paper describes 2 open-label. 1023 ¶ 154. 8. v.). 1044 ¶ 60. 550 U.8±5. Ex.
” (Ex. Inc. the S-1 teaches or suggests each and every element of that claims from which claims 16–19 and 37–41 depend.B. for 10 mg BID sustained 50 . the applicant admitted that Hayes teaches the “tmax of SR 4-AP in fasting patients given 15 or 20 mg BID is about 3h.1. Each of claims 16–17 and 37–38 requires that “said sustained release composition provides a mean Tmax in a range of about 2 to about 6 hours after administration of the sustained release composition to the patient.3d at 1354. See also Santarus. with respect to Ground 1—and claim 40 depends from claim 34—described above in Section VI. Each of claims 18–19 and 39–41 requires that “said sustained release composition provides a mean Tmax in a range of about 2 to about 5. 694 F. 31:41–32:9.) Claim 18 depends from claim 1. 1001 at 30:34–41.a.A.440. 31:32–40. claim 39 depends from claim 32—described above in Section VI.” which is as the S-1 teaches as discussed in Ground 1. claims 19 and 41 depend from claim 2. Additionally. 8.703 respect to Ground 1.a.A.2.. 1002-151.) Claims 38 and 41 further require that the “lower extremity function is walking. 1001 at 30:42–49.” (Ex.2. Section VI.2 hours after administration of the sustained release composition to the patient. Hayes discloses the steady state tmax pharmacokinetic ranges for sustained release 4-AP. During prosecution.) And in Table 3.” (Ex.Patent No. For reasons similar to those stated above with respect to the CavSS pharmacokinetic parameter.
” (Ex. “which overlaps substantially with the claimed tmax ranges. (Ex.” (Ex. (Ex. upon administration to the patient. with respect to Ground 1.7 hours falls squarely within the claimed ranges of “about 2 to about 5.A. 1023 ¶¶ 138.7 ± 1.2. 32:28–36. Each of claims 20–21 and 48–49 requires that “said sustained release composition is capable of providing. Moreover.7–3.440. 1044 ¶ 70. the combination of the S-1 and Hayes teaches each and every limitation of claims 16–19 and 37–41. a release profile of the 4-aminopyridine extending over at least 6 hours. there is nothing non-obvious about the full scope of the claimed tmax range. claims 16–19 and 37–41 are obvious over the S-1 and Hayes.0 hours. 48–49). 164. claims 21 and 49 depend from claim 2. 8. 1023 ¶ 164.) For at least this additional reason.7 hours.0 hours. Claim 20 depends from claim 1.7 ± 1.” providing for a range—accounting for error—of 1.” Thus.) 5.a. Ex.2 hours” and “about 2 to about 6 hours. 1005-7. 1001 at 30:50–57. (Id. the S-1 teaches or suggests each and every element of 51 .703 release 4-AP. Ex. and claim 48 depends from claim 32—described above in Section VI.) For reasons similar to those stated above with respect to the CavSS pharmacokinetic parameter.) “A POSA considering Hayes would have known that the tmax of 10 mg sustained release 4-AP is 2.) A tmax of 2. 1044 ¶ 70. The S-1 and Hayes combination teaches a release profile extending over at least 6 hours (claims 20–21.Patent No. Hayes teaches that the tmax is 2.
) extending over 24 hours: (Ex. 48–49. Ex..) See In re Applied Materials. Inc.3d at 1354. 52 . a POSA would have known that “the release profile of the 10 mg sustained release 4-AP described in the S-1 and Hayes extends over 24 hours.Patent No. Hayes discloses in Figure 1 B. Inc.440. that a 10 mg BID dose of SR 4-AP has a release profile (as defined in Section V. according to Figure 1 of Hayes. Additionally.2. copied below.D. 1023 ¶ 169.703 claims 20–21. Hayes discloses the steady state pharmacokinetic ranges recited in claims 20–21 and 48–49.3d at 1295. 1005-5. 694 F.” (Ex. Specifically..) Thus. rendering obvious the additional pharmacokinetic limitations of claims 20–21 and 48–49 when combining the teachings of Hayes with the 10 mg BID dosing regimen of sustained release 4-AP in the S-1. 692 F. 8. 1044 ¶ 75. See Santarus.
The claims upon which those claims depend (claims 1–2 and 32) are 53 . 1001 at 32:25–27.) As explained above in Section A.3d at1382–83. (Ex.2.B. 42–43 and 50–51 fail to add any non-obvious limitations. 677 F. 1023 ¶ 171.) C... the S-1 disclosure of SR 4-AP clinical trials “to support an indication for the treatment of lower extremity motor dysfunction. 42–43. claim 47 would have been obvious to a POSA in light of the S-1 and Hayes.2.” and that “the lower extremity function is walking.703 6. The S-1 and Hayes combination teaches administration of sustained release 4-AP for “more than two weeks” and “twelve weeks” (claim 47).Patent No.. Dependent claims 22–25. and 50–51 are obvious in light of the S-1 in view of Juarez and the knowledge of a POSA.) See In re Applied Materials. including motor strength. the S-1 disclosure of a “treatment period of 12 weeks” meets the open-ended limitation “said time period is more than two weeks” limitation recited in claim 47. 1003-37. (Ex. Claim 47 depends from claim 40—described above in Section VI. characterized by weakness and walking impairment.3d at 1295. Therefore.440.a. Ground 3: Claims 22–25.e.) See In re Montgomery. (Ex.” (Ex. 1003-37 (emphasis added). 692 F.4—and additionally requires administration of SR 4-AP for “twelve weeks. As explained above in Section A. [and] timed walking” meets the additional limitation of claim 47. 8. Inc.” measuring “an improvement in average walking speed” and “the effect of the drug on symptoms of the disease.
2. 1001 at 30:58–61.) 1. 1023 ¶¶ 172–92. in which said 4-aminopyridine is uniformly dispersed.) Claim 24 depends from claim 1. that is suitable for controlling the release rate of the 4aminopyridine. Claims 22–25. 1001 at 30:62–31:2.) Claims 43 and 51 also recite 54 .703 obvious for at least the reasons set forth above with respect to Ground 1.A. Each of claims 22–23 and 50–51 requires that “said 4aminopyridine is dispersed in a rate of release controlling polymer. with respect to Ground 1.a. and claim 42 depends from claim 32—described above in Section VI. Claim 22 depends from claim 1. 8.440. such as a matrix in which the 4-AP is uniformly dispersed (claims 22–25. with respect to Ground 1. claims 25 and 43 depend from claim 2. 42–43 and 50–51 are obvious over the S-1 in view of Juarez. and 50–51).a.” (Ex. 32:10–18.A.” (Ex. “A POSA would have been motivated to combine the S-1 with common knowledge and publications like Juarez—which focuses on optimizing the same SR 4-AP oral tablets disclosed in the S-1”— in an effort to further understand and apply the methods disclosed in the S-1 “to treat patients suffering from MS and its associated conditions.Patent No. Each of claims 24–25 and 42–43 requires that “said sustained release composition comprises a matrix. and claim 50 depends from claim 32—described above in Section VI.2. 1044 ¶ 76. 32:37–41. The S-1 and Juarez combination teaches “controlling the release rate” of the 4-AP by dispersing it in a rate of release controlling polymer. Ex.” (Ex. claims 23 and 51 depend from claim 2. 42–43.
1023 ¶ 182. Ex. for such a matrix to function properly. Specifically. “the drug whose release rate was being controlled should be uniformly dispersed in this matrix. 1044 ¶ 77. would have been motivated to look to Juarez. as disclosed in S-1. 1006-1–3. 1023 ¶ 173.A.) A POSA also would have known that. would be the use of a hydrophilic polymer-formed matrix to control rate of release” as in claims 22–23 and 50–51.” (Ex.440. 1044 ¶ 86. (Ex.” an obvious limitation for the reasons discussed in Section VI.) Juarez indicates that “[t]ablets of the model drug 4-aminopyridine with hydroxypropyl methylcellulose [HPMC] were prepared with different proportions of polymer 55 . (Ex. 550 U.a.) Juarez discloses this claimed matrix. Ex. “A POSA reading the S-1 would have known that one of the methods available to control the rate of release of a drug.. 1044 ¶ 87. 1023 ¶ 183.2. Juarez teaches preparation of an oral tablet comprising 4aminopyridine and a rate of release controlling polymer. 420. Ex.Patent No.) A POSA working with a sustained release form of 4-AP.) See KSR Int’l Co. 1006-1–2.” (Ex. 398. as in claims 24–25 and 42–43. (Ex. 8. because Juarez teaches how to use a polymer-formed matrix to provide a sustained-release composition of 4-AP that could maintain desirable “in vivo plasma concentrations and thus a constant pharmacological effect.” such as would be necessary for the sustained release 4-AP disclosed in the S-1.703 “wherein the lower extremity function is walking.S.
(Id. 1044 ¶ 94. 184–91. these claims would have been obvious to a POSA applying Juarez to the S-1 regime. 1044 ¶ 94.” and to “prolong delivery with zero-order kinetics to maintain a constant in vivo plasma drug concentration.) A POSA would have understood that these mixing instructions would result in “the 4-AP being uniformly dispersed in the matrix. 8.) Therefore.” (Ex.) A POSA would have understood that Juarez teaches that 4-aminopyridine could be readily and easily formulated into a useful rate of release controlling polymer. Ex. 1044 ¶ 95.) 56 . 1023 ¶ 191. (Ex. -1. kneaded for 5 min and sifted using a sieve number 12. such that the matrix ‘is suitable for controlling the release rate of the 4-aminopyridine’ as in claims 24–25 and 42–43. -1–2. (Ex.) Therefore. 1023 ¶ 192. and with this to maintain a constant pharmacological effect.) Juarez also teaches forming the matrix: Ten grams of each different formula were prepared by gently mixing in a mortar the corresponding proportions of 4-aminopyridine and HPMC for 20 min. Ex. 1023 ¶¶ 183.440.” (Id. these claims would have been obvious to a POSA.) Juarez discloses that the purpose of this HPMC matrix is “for controlling the release of soluble drugs from solid dosage forms.” as in claims 22–23 and 50–51.703 content. (Ex. more commonly known as a sustained release composition. Each mixture was moistened with 2 ml of distilled water.Patent No. The resulting granulations were dried at 40oC for 3 h in beds with a thickness up to 5 mm. Ex. 1023 ¶ 192. 1044 ¶ 95. (Ex. using universally known compounds such as HPMC. Ex. 1006-3.
1002-172.440. The Blight Declaration data is “consistent with the expected dose-benefit correlation.e. 1023 ¶ 194.703 VII.” (Ex. the results described are neither unexpected nor surprising in view of the disclosures in the prior art that render the treatment methods obvious. ANY SECONDARY CONSIDERATIONS ARE INSUFFICIENT TO OVERCOME THE OBVIOUSNESS OF CLAIMS 1–52 During prosecution of the ’703 Patent. (Ex..) First. the higher the dose the greater the therapeutic benefit. 8. However.Patent No.) However. 15 mg BID.) The declarants argued that this result was surprising because of an “understanding in the field…that there was a dosebenefit correlation for 4-AP’s clinical effects. the declarants’ assertion that the results were unexpected is incorrect.” (Id. ¶ 195. Even though the increase was not statistically significant. -173. i. The crux of the secondary considerations discussed in the declarations was “that there were no notable differences among the 10 mg BID. these declarations fail to overcome the particularly strong evidence of obviousness presented above. albeit in small increments (1–2 percentage points). it showed an upward trend.” (Id.) For example. and where the 57 . and 20 mg BID treatment groups with respect to improving walking” and this “comparable efficacy of the 10 mg BID dosage of SR 4-AP as compared to the 15 mg and 20 mg BID dosages…is surprising and unexpected. the applicant submitted declarations stating that the claimed inventions were nonobvious in light of secondary considerations. improvement in walking did increase with the dosage.
440.” (Ex. Cir.) The Federal Circuit’s opinion in Galderma Labs.” Id. even if the level of success may have turned out to be somewhat greater than would have been expected.” Hoffmann-La Roche Inc.. LP v. Apotex Inc. Second. v. Here. 2014). 2013). is particularly instructive.Patent No. Cir.3d 731. the Medori declaration touts Ampyra’s approval as “an MS treatment effective to treat all four forms (subtypes) of MS…Ampyra® was the first FDA-approved drug indicated for improving walking in patients with MS. none of the claims of the ’703 Patent require that a covered drug be an MS treatment effective to treat all four forms (subtypes) of MS. The court found unexpected results insufficient for nonobviousness. 737 F. 1002-161–62. 748 F. applicant’s argument regarding the lack of significant improvement from one dose to another is a difference in degree. (Id. because the unexpected result—the lack of a percent increase in the prevalence of side effects—constituted “only a difference in degree from the prior art results” rather than a “difference in kind. 739 (Fed. Tolmar Inc. the only subtype required by only two of the patent’s 52 claims is the most common 58 . 1334 (Fed.) However.703 dosage difference was slight to begin with—a mere 5 to 10 mg compared with studies in which up to 50–60 mg of 4-AP had been administered—such small increases would be expected. 8. By contrast. Any “evidence of superior efficacy does nothing to undercut the showing that there was a reasonable expectation of success with the  dose.3d 1326. and it remains the only drug approved for this purpose.
703 subtype—relapsing remitting multiple sclerosis. 780 F. (Ex. (See id. Where a strong prima facie obviousness showing exists. passim. none of the declarations establish a nexus between the alleged secondary considerations and the particular limitations of the challenged patent claims. Ex. 1046.) However.) The Medori declaration points to other MS drugs.3d 1376. 1385 (Fed. v.) The S-1 and Hayes disclose the claimed dosing of 10 mg BID. none of the declarations attribute a treatment period of at least two weeks to the success of 4AP. Ex. Ingersoll Cutting Tool Co.Patent No. 2015) (“secondary consideration actually results from something other than what is both claimed and novel in the claim. (See Ex. Although the claims also require a treatment period of at least two weeks (which the S-1 also discloses).) Nor was there evidence that any long-felt need allegedly solved by Ampyra was due to treatment for at least 2 weeks. 8. Inc. they do not control obviousness.. 1047.440. the Federal Circuit repeatedly finds even relevant secondary considerations 59 .”) Third. passim. Cir. 1002-169–345. although secondary considerations must be taken into account. so there is no nexus to the merits of the claimed invention. there is no showing that an “at least two weeks” regimen of 10 mg (or less than 15 mg) sustained release 4-AP or the pharmacokinetic parameters recited in the claims were—or could have been—the particular elements that rendered Ampyra successful where other MS drugs failed. 1046-34. Fourth. (See id.” which failed to enter Phase III clinical trials. like “Nerispirdine. Kennametal.
. 726 F.3d 1369. Spires/ Sarah E.. Parvathi Kota (Reg. Texas 75201 P: 214-978-6600/F: 214-978-6601 Lead Counsel for Petitioner Dr. 713 F. Inc.Patent No.3d 1286. Cir. Cir.501) SKIERMONT PUCKETT LLP 2200 Ross Ave. September 2. Texas 75201 P: 214-978-6600/F: 214-978-6621 Back-Up Counsel for Petitioner 60 . 2013) (rejecting secondary considerations. 1376 (Fed.122) Paul J. Sandoz Inc. Respectfully submitted. Ste. 8.703 supported by substantial evidence may not dislodge the primary conclusion of obviousness. 1293 (Fed. 2015 /Sarah E. 65. CONCLUSION Petitioner respectfully requests IPR of claims 1–52 of the ’703 Patent.440. 2013) (secondary considerations “d[id] not overcome the express teachings of multiple references”). No. Watson Pharms. Inc. e. No. 4800W Dallas. See. VIII. v. Skiermont (pro hac vice requested) SKIERMONT PUCKETT LLP 2200 Ross Ave. Allergan Inc.. v. Spires (Reg. including evidence of unexpected results from the claimed drug combinations). 4800W Dallas. 61. Bayer Healthcare Pharms. Ste.g.
2015. Inc. NY 10502 Date: September 2. 8. overnight delivery.703. a copy of this Petition for Inter Partes Review of U. 2015 /Sarah E. upon the following: AcordaJD Jones Day 222 East 41st Street New York. NY 10017 Anthony Michael Acorda Therapeutics.S.Patent No. 8. Spires/ . including all exhibits. 420 Saw Mill River Road Ardsley.703 CERTIFICATE OF SERVICE I hereby certify that on September 2.440. was served via FedEx. Patent No.440.

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