Paper 57, Filed: June 20, 2024
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`TWI PHARMACEUTICALS INC.,
`Petitioner,
`v.
`MERCK SERONO SA,
`Patent Owner.
`
`IPR2023-00050 (Patent 8,377,903 B2)
`
`Before ULRIKE W. JENKS, ZHENYU YANG and TINA HULSE,
`Administrative Patent Judges.
`
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`TWI PHARMACEUTICALS INC.,
`Petitioner,
`v.
`MERCK SERONO SA,
`Patent Owner.
`
`IPR2023-00050 (Patent 8,377,903 B2)
`
`Before ULRIKE W. JENKS, ZHENYU YANG and TINA HULSE,
`Administrative Patent Judges.
`
`PETITIONER’S REPLY TO PATENT OWNER’S RESPONSE
`
`
`
`
`
`TABLE OF CONTENTS
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`Page
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`TABLE OF CONTENTS ........................................................................................... i
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`TABLE OF AUTHORITIES .................................................................................... iii
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`I.
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`The Challenged Claims Are Anticipated By The Bodor Art. ............................ 1
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`A. The Bodor Art Is “By Another.” ................................................................. 1
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`B. Bodor Discloses Weight-Based Dosing. ..................................................... 6
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`1. Differing Patient Weights Is The Only Reason For Differing Total
`Doses. .................................................................................................. 7
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`2. Fixed, Flat Dosing .............................................................................. 8
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`3. Patent Owner Incorporation by Reference ......................................... 9
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`C. A PHOSITA Would Read Bodor To Disclose A Maintenance Period. ..... 11
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`1. Bodor’s Expressly Teaches That The Period Of No Treatment
`Ends After 10 Months. ...................................................................... 11
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`2. Alternatively, Resumption Of Treatment Is The Only Reasonable
`Inference A PHOSITA Would Draw From Bodot’s Disclosure. ........ 12
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`II. The Challenged Claims Are Obvious Over Bodor In View Of The General
`Knowledge of a PHOSITA. ............................................................................. 15
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`A. Any Element Bodot May Be Deemed Not To Disclose Within Its Four
`Corners Would Have Been Obvious To A PHOSITA Based On Their
`General Knowledge. ................................................................................. 15
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`B. A PHOSITA would have had a motivation and reasonable expectation
`of success to repeat Bodor’s regimen. ...................................................... 15
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`III. The Challenged Claims Are Obvious Over Bodor In View Of Rice 2000. ..... 19
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`A. Bodor and Rice 2000 teach all limitations. .............................................. 20
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`B. Motivation to Combine and Expectation of Success ............................... 20
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`IV. No Secondary Considerations Overcome The Strong Showing Of
`Obviousness. .................................................................................................... 21
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`V. Conclusion ....................................................................................................... 23
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`CERTIFICATION OF WORD COUNT .................................................................... 1
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`CERTIFICATE OF SERVICE ................................................................................... 2
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`– ii –
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`TABLE OF AUTHORITIES
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`CASES
`Adapt Pharma Operations Ltd. v. Teva Pharms. USA, Inc.,
`25 F.4th 1354 (Fed. Cir. 2022) ............................................................................. 22
`Advanced Display Sys., Inc. v. Kent State Univ.,
`212 F.3d 1272 (Fed. Cir. 2000) ............................................................................ 11
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) .............................................................................. 23
`Cohesive Techs., Inc. v. Waters Corp.,
`543 F.3d 1351 (Fed. Cir. 2008) ............................................................................ 22
`Dayco Prods., Inc. v. Total Containment, Inc.,
`329 F.3d 1358 (Fed. Cir. 2003) ............................................................................ 11
`Duncan Parking Techs., Inc. v. IPS Grp., Inc.,
`914 F.3d 1347 (Fed. Cir. 2019) ..........................................................................2, 6
`Hockerson-Halberstadt, Inc. v. Avia Grp. Int’l, Inc.,
`222 F.3d 951 (Fed. Cir. 2000) ................................................................................ 4
`ModernaTx, Inc. v. Arbutus Biopharma Corp.,
`18 F.4th 1352 (Fed. Cir. 2021) ............................................................................... 8
`Riverwood Int'l Corp. v. R.A. Jones & Co.,
`324 F.3d 1346 (Fed. Cir. 2003) .............................................................................. 4
`Spectra-Physics, Inc. v. Coherent, Inc.,
`827 F.2d 1524 (Fed. Cir. 1987) .............................................................................. 7
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) ............................................................................ 22
`STATUTES
`35 U.S.C. § 102 ......................................................................................................1, 2
`REGULATIONS
`37 C.F.R. § 1.57 ................................................................................................... 3, 11
`– iii –
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`Petitioner TWi Pharmaceuticals Inc. (“Petitioner”) respectfully submits this
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`Reply to Paper 27, Patent Owner’s Response (“PO’s Resp.”), and in further support
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`of Paper 1, its Petition (“Petition”).
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`I.
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`The Challenged Claims Are Anticipated By The Bodor Art.
`Bodor discloses all elements of the challenged claims. (See Ex. 1047,
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`Greenberg Rebuttal Decl. ¶ 15.)
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`A. The Bodor Art Is “By Another.”
`Patent Owner’s assertion that the named inventors of the challenged patent
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`also conceived the relevant disclosure in Bodor is legally insufficient, inconsistent
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`with its position during prosecution and not born out by the evidence.
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`First, Patent Owner’s argument that Bodor is not prior art under 35 U.S.C.
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`§ 102(b) (PO’s Resp. 9 n.3) fails because the challenged claims are due a priority
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`date no earlier than December 18, 2009. As explained in the Petition, the ’903 Patent
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`is a continuation of, and claims priority to, the ’947 Patent. (Petition at 8.) The
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`challenged claims are continuations of claims added by amendment during
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`prosecution of the application for the ’947 Patent, dated December 18, 2009, (Ex.
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`1003, 405–423; Ex. 1004, 10, 25, 51-55) and recite a regimen in which the
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`maintenance period dose can be equal to the induction period dose. (Petition 10–
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`11.) Every previous filing (including provisional Ser. No. 60/638,669 (Ex. 1003,
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`301–332 at 309), EP 04106909 (Ex. 1003, 268–299 at 276), PCT/WP2005/056954
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`– 1 –
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`(Ex. 1003, 333–364 at 340–41), Ser. No. 11/722,018 (Id.), and all earlier
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`amendments) all required that the total dose in the maintenance period be less than,
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`not equal to the total dose in the induction period. These claims in the December
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`2009 amendment added new matter without written description support, and the
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`challenged claims are not entitled to the asserted priority dates any earlier than
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`December 18, 2009. For the challenged claims, the Bodor PCT published October
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`14, 2004, is therefore § 102(b) prior art published more than a year before February
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`19, 2013, of Ser. No. 12/766,173 (Ex. 1004), the December 2009 amendment, the
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`June 18, 2007, filing date of Ser. No. 11/722.018, and the December 20, 2005 filing
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`date of PCT/EP2005/056964.
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`Petitioner met its initial burden to show that the Bodor PCT (Ex. 1007) is prior
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`art under § 102(a) and Bodor ’328 (Ex. 1029) is prior art under § 102(e), because
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`Bodor names a completely different, not the same, inventive entity. Duncan Parking
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`Techs., Inc. v. IPS Grp., Inc., 914 F.3d 1347, 1357 (Fed. Cir. 2019) (“The statute’s
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`reference to ‘by another’ means that an application issued to the same inventive
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`entity cannot qualify as § 102(e) prior art.”). Petitioner’s new, litigation induced
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`argument that the named inventors conceived the cited disclosure is inconsistent with
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`the contemporaneous position taken during prosecution. The challenged patent cites
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`and purports to incorporate by reference the Bodor PCT (Ex. 1002 col. 6, ℓ. 23, col.
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`11, ℓ. 61, col. 14, ℓℓ. 32, 49), but essential material to provide written description
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`– 2 –
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`support for claim language can be incorporated by reference only from a U.S.
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`application, not from an international application. 37 C.F.R. § 1.57(d). When the
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`Examiner rejected claims over Bodor (Ex. 1004, 103–106), applicants relied on the
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`Examiner’s statement that Bodor did not “teach that the total dose of cladribine
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`reached at the end of the maintenance phase is lower than the total dose reached at
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`the end of the induction phase” (Ex. 1004, 106, 125), but the challenged claims here
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`are challenged precisely because they omit that “lower than” limitation.
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`At no point during prosecution did applicants argue that the named inventors
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`of the challenged claims conceived the disclosure in Bodor. This omission is not
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`plausibly an oversight because the challenged patent’s named lead inventor was
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`Chief Intellectual Property Counsel for Serono. (Ex. 1045, Munafo Dep. 30:2–32:3)
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`. (Ex. 1043, Dandiker Dep 109:22–116:14,
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`120:17–121:12; Ex. 1044, Bodor Dep. 31:21–41:11.) The public is entitled to rely
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`on the patentees’ conduct during prosecution admitting and acquiescing that Bodor
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`was prior art, and Patent Owner should now be estopped to deny that it is. See
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`Riverwood Int’l Corp. v. R.A. Jones & Co., 324 F.3d 1346, 1354 (Fed. Cir. 2003)
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`(“Valid prior art may be created by the admissions of the parties.”); Hockerson-
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`– 3 –
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`Halberstadt, Inc. v. Avia Grp. Int’l, Inc., 222 F.3d 951, 957 (Fed. Cir. 2000) (“The
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`prosecution history constitutes a public record of the patentee’s representations
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`concerning the scope and meaning of the claims, and competitors are entitled to rely
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`on those representations ....”).
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`Patent Owner’s evidence also fails to establish that the named inventors
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`conceived the specific disclosure in Bodor. Dr. Munafo (the only named inventor to
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`testify) attributed the regimen not to any one named inventor but to undifferentiated
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`members of “my team at Serono,” which was a much larger group than the named
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`inventors. (Ex. 1045, Munafo Dep. 19, 21.) He could not remember who had what
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`roles on his team or who contributed exactly what ideas. (Ex. 1045, Munafo Dep.
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`23, 25.) Neither Dr. Dandiker nor Dr. Bodor remembered any source for that
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`information, whether from one of the named inventors, someone else at Serono, or
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`elsewhere. (Ex. 1043, Dandiker Dep 45:1–46:6; Ex. 1044, Bodor Dep. 42:5–46:6.)
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`Finally, the named inventors of Bodor are at least co-inventors of the oral
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`dosing regimen disclosed because the significant contribution to the art of that
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`regimen is the oral formulation, not the routine schedule which is substantially
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`similar to prior art cladribine injection schedules and thus does no more than “merely
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`explain . . . well-known concepts and/or the current state of the art.” Duncan Parking
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`Techs., 914 F.3d at 1357–58. For example, Rice 2000 taught a substantially similar
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`schedule of administering a set dose (0.07 mg/kg) for 5 consecutive days in a cycle
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`of about a month or 28 days, for two consecutive cycles (or four consecutive cycles
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`for another arm of the study), followed by a cladribine-free period. (Ex. 1008, Rice
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`2000; Ex. 1002 col. 2, ℓℓ. 31–42; Ex. 1045, Munafo Dep. 32:16–44:20; Ex. 1042,
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`Lublin Dep. 77:21–78:11.) The challenged patent describes their contribution as
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`providing for oral administration on such a schedule, and every claim, including the
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`challenged claims, recites “oral administration.” (Ex. 1002 col. 3, ℓℓ. 22–30, col. 16,
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`– 5 –
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`ℓ. 52–col. 18, ℓ. 56.) It references Bodor in disclosing a formulation for use in the
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`invention (Ex. 1002 col. 11, ℓ. 61–67) and in its Example (Ex. 1002 col. 14, ℓℓ. 6–
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`49). Oral administration, as opposed to the routine schedule, clearly makes Bodor
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`inventors at least co-inventors.
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`B.
`Bodor Discloses Weight-Based Dosing.
`Patent Owner’s argument that Bodor does not disclose weight-based dosing
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`(PO’s Resp. 20) cannot be reconciled with the record. (See Ex. 1047, Greenberg
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`Decl. ¶¶ 23–30.) Dr. Lublin agrees that articles Bodor incorporated by reference (Ex.
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`1016, Romine 1999; Ex. 1031, Selby 1998; Ex. 1008, Rice 2000; Ex. 1026,
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`Tortorella 2001) as disclosing “various dosing amounts and dosing regimens
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`reported in the literature for use in the treatment of multiple sclerosis” (see Ex. 1029
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`col. 12, ℓ. 65–col. 13, ℓ. 8) do disclose weight-based dosing (Ex. 1042, Lublin Dep.
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`76:20–81:1)—so that means Bodor does, too. PO argues that Bodor does not disclose
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`the weight of any specific patients (PO’s Resp. 20; Ex. 2019, Lublin Decl. ¶¶ 106–
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`108), but those same articles also do not recite the weight of patients treated.
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`Moreover, the typical weight range of patients for dosing medicine was already well-
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`known to those of skill in the art as reflected by standard reference works. The
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`Goodman 2001 treatise cited by Bodor (Ex. 1029 col. 6, ℓℓ. 45–53) confirms the 70
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`kg average weight and the weight ranges that Petitioner’s expert Dr. Greenberg used
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`in his calculations. (Ex. 1039, 3–4, Goodman 2001 at 20–21; Ex. 1047, Greenberg
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`– 6 –
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`Rebuttal Decl. ¶¶ 19, 34.) Bodor did not need to repeat the disclosure of such basic
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`information as ordinary patient weights for dosing when that was already well
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`known to a PHOSITA—indeed it is preferable to omit such unnecessary background.
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`Spectra-Physics, Inc. v. Coherent, Inc., 827 F.2d 1524, 1534 (Fed. Cir. 1987) (“A
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`patent need not teach, and preferably omits, what is well known in the art.”).
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`Contrary to the argument of Patent Owner and Dr. Lublin that “nothing in Bodor”
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`would lead a PHOSITA to account for a patient’s weight (PO’s Resp. 21; Ex. 2019,
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`Lublin Decl. ¶¶ 110–111), Bodor is replete with such disclosure.
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`1.
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`Differing Patient Weights Is The Only Reason For Bodor’s
`Differing Total Doses.
`It is undisputed that Bodor’s dosing regimen produced multiple different total
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`dose amounts. (Ex. 1042, Lublin Dep. 71:21–73:1; see Ex. 2019, Lublin Decl.
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`¶¶ 107–108.) The only reasonable explanation for these different dosages is to match
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`patient weight (Ex. 1047, Greenberg Rebuttal Decl. ¶ 34.), as was done in the dosing
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`regimens incorporated by reference from Romine 1999 (Ex. 2016), Selby 1998 (Ex.
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`2031), Rice 2000 (Ex. 1008), and Tortorella 2001 (Ex. 1026). PO argues that in
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`previous FDA-approved drugs dosing was flat regardless of weight (PO’s Resp. 23-
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`24; Ex. 2019, Lublin Decl. ¶¶ 112–115), but those therapies did not disclose a range
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`of total doses to administer (and the prior art is not limited to FDA approved
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`therapies).
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`Patent owner also argues that “Petitioner arrives at the claimed about 1.7–3.5
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`– 7 –
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`mg/kg doses through mere hindsight.” (PO’s Resp. 24) First, an anticipatory
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`reference need not disclose the entire range—it is sufficient to disclose a point within
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`that range. ModernaTx, Inc. v. Arbutus Biopharma Corp., 18 F.4th 1352, 1364 (Fed.
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`Cir. 2021) (“When a patent claims a range, as in this case, that range is anticipated
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`by a prior art reference if the reference discloses a point within the range.”).
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`Moreover, the cumulative total doses cladribine for MS of 1.7 mg/kg is merely an
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`approximation of the same known cumulative dose of 0.7 mg/kg incorporated by
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`reference in Bodor from Rice 2000 (Ex. 1008; Ex. 1042, Lublin Dep. 77:21–78:8;
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`Ex. 1045, Munafo Dep. 35:9–44:20) adjusted for the known bioavailability of about
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`40% for oral dosing, which Bodor also discloses for its 10 mg tablet in Table VIII.
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`(Ex. 1029 col. 21, ℓℓ. 20–33; Ex. 1002 col. 15, ℓℓ. 47–61.)
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`2.
`“Fixed, Flat Dosing” Does Not Distinguish Bodor.
`PO argues that the other dosing regimens incorporated by reference and fully
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`part of the disclosure in Bodor “cannot change Bodor’s express teaching to use flat,
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`fixed dosing.” (PO’s Resp. 23.) Patent Owner’s witness Dr. Lublin says that it is flat,
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`fixed dosing because “a POSA would have understood that all patients, regardless
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`of weight, receive the same 10 mg daily dosage of cladribine for that number of days
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`and thus the dosage remains flat and fixed.” (Ex. 2019, Lublin Decl. ¶ 107.) Dr.
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`Lublin’s explanation does not make sense. First 10 mg is not the total dose or
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`cumulative dose received. It is the strength of the pill given as a daily dose. That
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`– 8 –
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`strength is multiplied by the total number of pills in each cycle and the total number
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`of cycles to determine the dose. (See, e.g., Ex. 1002 col. 4, ℓℓ. 19–37.) Dr. Lublin
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`admits that the dose described in Bodor varies from 100 mg to 140 mg. (Ex. 1042,
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`Lublin Dep. 71:21–73:1; see Ex. 2019, Lublin Decl. ¶ 107–108.)
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`Moreover, the challenged patent also indicates that its invention would include
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`a regimen “wherein Cladribine is to be orally administered at a daily dose of about
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`10 mg.” (Ex. 1002, col. 11, ℓℓ. 63–64.) Similarly, for Mavenclad® (which is
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`allegedly a commercial embodiment of the challenged patents) the prescribing
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`instruction is “Administer the cycle dosage as 1 or 2 tablets once daily over 4 or 5
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`consecutive days.” (Ex. 1011, 6.) For both, the patient received the same flat, fixed
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`daily dose each day, but the total cumulative dose is based on the patient’s weight.
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`Administering a fixed strength tablet daily, as disclosed in Bodor, for a varying
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`number of days and cycles to achieve a varying total dose, is thus clearly consistent
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`with what the Patent Owner calls weight-based dosing—and, as noted above, none
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`of the evidence identifies any reason other than the patient’s weight for giving an
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`MS patient different total doses of cladribine.
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`3.
`Patent Owner Disregards Incorporation by Reference
`Patent Owner disregards what it characterizes as “disclosures purportedly
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`incorporated by reference” (PO’s Resp. 23) and did not instruct Dr. Lublin about the
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`law for incorporation by reference. On cross-examination he indicated he limited his
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`– 9 –
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`analysis to “what Bodor is – is disclosing” and not the “things that he referenced.”
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`(Ex. 1042, Lublin Dep. 57:20–58:5.) He explained that his understanding of those
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`materials was, “I think they’re things he references. I think disclosed is something
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`that he’s doing that he’s bringing out that’s new.” (Id. 58:6–11.)
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`The law is to the contrary. Bodor plainly stated that those references “are
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`incorporated by reference herein in their entireties and relied upon.” (Ex. 1029 col.
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`13, ℓℓ. 7–8; Ex. 1047, Greenberg Rebuttal Decl. ¶¶ 5, 10, 13, 24–28, 39.) The dosing
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`regimens disclosed are not “essential matter” under 37 C.F.R. § 1.57(d) because
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`Bodor does not recite them in its claims, so they can be incorporated by reference
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`from a nonpatent publication, 37 C.F.R. § 1.57(e), and are part of the patent
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`specification for purposes of anticipation. “Material not explicitly contained in the
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`single, prior art document may still be considered for purposes of anticipation if that
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`material is incorporated by reference into the document.” Advanced Display Sys.,
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`Inc. v. Kent State Univ., 212 F.3d 1272, 1282 (Fed. Cir. 2000). Patent Owner’s
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`argument that Bodor is limited to “recognizing certain weight-based cladribine
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`dosages in prior art” ignores this incorporation by reference, and that Bodor
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`expressly disclosed these “various dosage amounts and dosing regimens … reported
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`in the literature for use in the treatment of multiple sclerosis” (Ex. 1029 col. 12, ℓℓ.
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`65–67) as fully as though it were expressly set forth in the specification verbatim.
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`Patent Owner’s citation to Dayco Prods., Inc. v. Total Containment, Inc., 329
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`– 10 –
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`F.3d 1358, 1369 (Fed. Cir. 2003) does not change this analysis. Dayco concerned
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`inherency, not incorporation by reference. Here, these materials that Bodor
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`incorporated by reference to explain dosing regimens for cladribine for MS all taught
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`weight-based dosing. A PHOSITA would then necessarily read Bodor’s own
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`disclosure of a range of total cumulative doses as differing doses to be administered
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`based on the patients’ weights, especially because no other reason is given for the
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`varying the total doses. That is not merely what could have been inferred—it is the
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`only reasonable inference a PHOSITA could draw and is necessarily present in the
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`disclosure of Bodor.
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`C. A PHOSITA Would Read Bodor To Disclose A Maintenance
`Period.
`1.
`Bodor Expressly Teaches That The Period Of No Treatment
`Ends After 10 Months—So Treatment Resumes.
`Patent Owner argues that there “is no express or inherent teaching in Bodor
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`regarding a second year of cladribine treatment after its 10-month cladribine-free
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`period.” (PO’s Resp. at 25.) But the only way to limit a cladribine-free period to ten
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`months of no treatment is to resume treatment with cladribine. (See Ex. 1047,
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`Greenberg Rebuttal Decl. ¶¶ 35–38) Otherwise, it is not a cladribine-free period of
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`ten months but instead of some other length.
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`Patent Owner misconstrues Dr. Greenberg’s testimony that “Bodor is silent on
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`exactly what parameters would apply to the dosing regimen of the maintenance
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`phase.” (PO’s Resp. 25; Ex. 1005 ¶ 117.) Dr. Greenberg did not testify that Bodor
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`was silent as to retreatment—instead Bodor expressly calls for retreatment by setting
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`a defined end to the cladribine-free period. What it is silent about is describing any
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`other, different dosing regimen to use when treatment resumes. The absence of any
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`other guidance would tell a PHOSITA to end the cladribine-free period by
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`administering again the same cladribine dosing regimen that is taught. This is not a
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`strained interpretation, but instead the same reasonable understanding of Bodor that
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`the Examiner applied during prosecution. (Ex. 1004, 103–106, 139–142.)
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`2.
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`Alternatively, Resumption Of Treatment Is The Only
`Reasonable Inference A PHOSITA Would Draw From
`Bodor’s Disclosure.
`Petitioner maintains its assertion that the express disclosure that the
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`cladribine-free period of no treatment comes to an end at 10 months is necessarily
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`an express disclosure that the same cladribine treatment resumes. However, even if
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`one were to deem that not an express disclosure it is the only reasonable inference a
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`PHOSITA would draw from reading the disclosure of Bodor. Patent Owner’s
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`arguments concerning safety and retreatment in the prior art do not counter
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`inference.
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`Patent Owner argues that a PHOSITA would not have inferred a retreatment
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`period because of “concerns arising from cladribine’s lymphocytotoxic activity.”
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`(PO’s Resp. at 5–6; Ex. 2019, Lublin Decl. ¶¶ 84–85.) But that lymphocytotoxicity
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`– 12 –
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`was part of the reason cladribine could treat diseases like leukemia and MS. (Ex.
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`1047, Greenberg Rebuttal Decl. ¶ 21.) “The potent and
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`long-lasting
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`lymphocytotoxic activity of cladribine has also suggested its potential for
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`influencing favorably the autoimmune process underlying the evolution of MS.”
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`(Ex. 1026, 1, Tortorella 2001 at 1751.) MS is an autoimmune disorder, and a
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`PHOSITA would understand that treatments for autoimmune disorders including MS
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`carry risks and require careful monitoring.
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`Moreover, Patent Owner’s other arguments show that a PHOSITA would have
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`accounted for such safety concerns, not been deterred by them. (Ex. 1047, Greenberg
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`Rebuttal Decl. ¶¶ 14, 19–22.) Patent Owner argues, “[a] POSA would have
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`reasonably understood that Bodor’s disclosure of a 10-month cladribine-free period
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`after a two-month dosing period relates to safety considerations” because “a
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`cladribine-free period allows a physician to evaluate a patient’s condition, including
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`patient safety markers such as lymphocyte levels.” (PO’s Resp. 27.) Thus, Patent
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`Owner’s argument confirms that Bodor already accounts for such safety concerns
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`by providing a cladribine-free period in which safety testing can be done. Nothing
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`in Bodor discourages any such safety monitoring, and the presence or absence of
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`any such safety monitoring is not an element of the challenged claims that Bodor
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`anticipates. That in no way detracts from Bodor’s anticipation of the challenged
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`claims. (Ex. 1047, Greenberg Rebuttal Decl. ¶ 21.)
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`– 13 –
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`
`
`
`
`Patent Owner’s argument that “any re-treatment would have taken into
`
`consideration safety concerns such as hematologic criteria; there was no automatic
`
`re-treating after a set period of time” (PO’s Resp. 34) is a red herring. Taking into
`
`consideration safety concerns does not prevent Bodor from anticipating. It also
`
`would not discourage a PHOSITA from applying retreatment, but instead confirms
`
`that a PHOSITA would have known how to apply retreatment.
`
`Patent Owner further argues that “Bodor’s disclosure of multiple dosing
`
`regimens and using other MS treatment agents in combination” (PO’s Resp. 35)
`
`would prevent a PHOSITA from inferring retreatment with cladribine, but that is not
`
`what the patent says. The “ten months of not treatment” is in the same paragraph, in
`
`the same sentence, describing treatment with the cladribine. (Ex. 1029 col. 13, ℓℓ.
`
`19–25.) Only later does Bodor suggest “administering cladribine according to the
`
`invention with another active ingredient” and that “administration of cladribine in
`
`accord with this invention may be accompanied by administration of one or more
`
`additional active ingredients for treating the cladribine-responsive condition” (Ex.
`
`1029 col. 12, ℓℓ. 31–44 (emphasis added).) The cladribine-free period of ten months
`
`of no treatment clearly refers to the administration of cladribine in the same sentence,
`
`not to some other therapy, and even when other therapies are mentioned they are in
`
`combination administered “with” cladribine and cladribine is “accompanied by”
`
`them. They are not alternatives to cladribine, and the disclosed cladribine treatment
`
`– 14 –
`
`
`
`
`
`therapy cannot resume after ten months without including cladribine.
`
`II. The Challenged Claims Are Obvious Over Bodor In View Of The
`General Knowledge of a PHOSITA.
`A. Any Element Deemed Not Disclosed In Bodor Would Have Been
`Obvious To A PHOSITA Based On Their General Knowledge.
`For the reasons explained above, Petitioner maintains that Bodor discloses
`
`weight-based dosing and retreatment after the cladribine-free period of ten months
`
`with no treatment, either expressly or by reasonable and necessary inference of a
`
`PHOSITA reading the disclosure. To the extent either of those claim elements Patent
`
`Owner disputes are deemed not to have an anticipatory disclosure in Bodor, they
`
`would have been obvious to a PHOSITA, for the same reasons explained
`
`hereinabove.
`
`B. A PHOSITA Would Have Had a Motivation and Reasonable
`Expectation of Success to Repeat Bodor’s Regimen.
`Patent Owner argues that the Petition “fails to establish that a POSA would
`
`have been motivated to modify Bodor’s method to include a second treatment period
`
`after its 10 months of no treatment, or have a reasonable expectation of success in
`
`doing so” and “has identified no motivation for a POSA to implement the claimed
`
`dosing regimen based on Bodor or any of the cited secondary references.” (PO’s
`
`Resp. 39.) Among other things, the challenged patents themselves contradict that
`
`argument by explaining that “it would be desirable to have a method for treating
`
`multiple sclerosis comprising the oral administration of Cladribine that would permit
`
`– 15 –
`
`
`
`
`
`the same or improved effect on MS lesions while decreasing the occurrence and/or
`
`severity adverse events,” confirming the motivation for a PHOSITA. (Ex. 1002 col.
`
`3, ℓℓ. 22–26.)
`
`First, Patent Owner again argues that “it was not standard practice to re-treat
`
`at regular intervals for a drug-based immunotherapy.” (PO’s Resp. 39.) Second,
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`Patent Owner argues that “a POSA would have understood it was important to
`
`monitor patients during cladribine treatment and only further administer cladribine
`
`if it was at least safe to do so.” (PO’s Resp. 41.) These two arguments are
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`substantially the same as the arguments addressed above, and fail for the same
`
`reasons.
`
`Third, Patent Owner argues that “Rice provides a POSA with no motivation
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`to repeat Bodor’s regimen to ‘manage symptoms.’” (PO’s Resp. 41.) The Rice study
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`did not show a statistically significant clinical impact for progressive MS patients,
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`but it explained that the lack of clinical benefit was an anomaly due to unanticipated
`
`recruitment patterns. (Ex. 1047, Greenberg Rebuttal Decl. ¶¶ 16–18.) It also noted
`
`that the study design did not anticipate enrolling patients with more severe disability,
`
`who would not show disease progression because they already had advanced cases.
`
`(Id.) But it then went on to note, “…the MRI changes in this study were robust.” In
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`another publication in 2002, Dr. Lublin wrote, “[t]his poorly designed study did not
`
`demonstrate any clinical benefit after 1 year but did show a marked reduction in
`
`– 16 –
`
`
`
`
`
`gadolinium-enhancing lesions in the cladribine-treated group,” validating the
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`conclusion of Rice 2000 that taught PHOSITAs to separate out the clinical outcome
`
`data cited in the Rice study, from the robust MRI data. (Ex. 1047, Greenberg Rebuttal
`
`Decl. ¶¶ 16–18.)
`
`Patent Owner argues that after Rice 2000 “skilled artisans remained skeptical
`
`of cladribine’s utility for treating MS.” (PO’s Resp. 42.) But the studies it cites
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`merely show that Rice 2000 failed to achieve statistical significance on its primary
`
`outcome. The papers all called for further research, instead of concluding that
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`cladribine lacked utility. (See Greenberg Rebuttal Decl. ¶¶ 19–22.)
`
`Patent Owner also argues that “Dr. Rice himself later questioned whether the
`
`observed MRI effects ‘would have had a subsequent clinical impact.’” (PO’s Resp.
`
`43.) That characterization does not fairly summarize the Filippi 2000 article.
`
`Concerning Rice 2000, it noted that “cladribine dramatically reduced the number of
`
`enhancing lesions and had a moderate, but statistically significant, effect on the
`
`accumulation of T 2 lesion burden.” (Ex. 2016, 3.) It also explained, “[t]his
`
`clinical/MRI discrepancy is not surprising, considering the clinical characteristics
`
`and the relative small size of the patients cohort studied, the relative short duration
`
`of the follow up period [5] and the much greater sensitivity of MRI-derived measures
`
`compared to clinical measures in detecting MS-related changes [7].” (Id. (emphasis
`
`added)) It encouraged further study, noting that due to these shortcomings the study
`
`– 17 –
`
`
`
`
`
`had “left unanswered” further questions. (Id.) And its speculation about what might
`
`prove to be clinically unimportant related to “severe tissue destruction in lesions of
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`progressive MS patients.” (Id.) It certainly did not indicate that cladribine should not
`
`be pursued.
`
`Fourth, Patent Owner argues that “Romine would not have motivated a POSA
`
`to repeat Bodor’s regimen.” (PO’s Resp. 43.) Romine 1999 shows that a PHOSITA
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`would already have known of retreatment with another course of cladribine when
`
`treating MS, and it specifically teaches, “[t]he lengthy but impermanent duration of
`
`effect of cladribine means that retreatment will be necessary if cladribine is to
`
`become a practical long-term therapy for MS.” (Ex. 1016, 5, Romine 1999 at 43
`
`(emphasis added).) That’s not merely a motivation—it is an express teaching and
`
`suggestion to retreat.
`
`Fifth, Patent Owner argues that “neither of Rice, Romine, nor the
`
`mitoxantrone label would have led a PHOSITA to reasonably expect success in
`
`repeating Bodor’s method.” (PO’s Resp. 44.) Patent Owner argues again that Rice
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`2000 and Romine 1999 both provided for safety monitoring during retreatment (PO’s
`
`Resp. 44-45), but that is not inconsistent with obviousness. Instead, it confirms that
`
`Romine 1999 and Rice 2000 taught how to engage in retreatment, as would have
`
`been known by a person of skill in the art. Patent Owner argues that “Bodor provides
`
`no efficacy results for its dosing regimen.” (PO’s Resp. 44.) But Bodor does show
`
`– 18 –
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`
`
`
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`the bioequivalence of its oral dosing to the subcutaneous of earlier studies, which
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`had shown promising result with cladribine. Such bioequivalence of the oral dosing
`
`is sufficient for a reasonable ex
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