UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`TWI PHARMACEUTICALS INC.,
`Petitioner,
`v.
`MERCK SERONO SA,
`Patent Owner.
`
`IPR2023-00049 (Patent 7,713,947 B2)
`IPR2023-00050 (Patent 8,377,903 B2)1
`
`Before ULRIKE W. JENKS, ZHENYU YANG and TINA HULSE,
`Administrative Patent Judges.
`
`REBUTTAL DECLARATION OF BENJAMIN M. GREENBERG, M.D.
`
`1 The identical paper is filed in each proceeding identified in the caption.
`
`EXHIBIT 1047
`Petitioner TWi
`IPR2023-00049, -00050
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`TWI PHARMACEUTICALS INC.,
`Petitioner,
`v.
`MERCK SERONO SA,
`Patent Owner.
`
`IPR2023-00049 (Patent 7,713,947 B2)
`IPR2023-00050 (Patent 8,377,903 B2)1
`
`Before ULRIKE W. JENKS, ZHENYU YANG and TINA HULSE,
`Administrative Patent Judges.
`
`REBUTTAL DECLARATION OF BENJAMIN M. GREENBERG, M.D.
`
`1 The identical paper is filed in each proceeding identified in the caption.
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`EXHIBIT 1047
`Petitioner TWi
`IPR2023-00049, -00050
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`I.
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`II.
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`III.
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`IV.
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`TABLE OF CONTENTS
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`Page
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`Summary of My Opinions ............................................................................... 1
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`Bodor Discloses Cladribine as a Treatment for Multiple Sclerosis ................ 2
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`POSAs Would Preferentially Apply The Bodor Disclosure to Relapsing
`Remitting Multiple Sclerosis and active Secondary Progressive Multiple
`Sclerosis Patients ............................................................................................. 3
`
`POSAs were familiar with a wide variety of therapeutic approaches to
`multiple sclerosis ............................................................................................. 4
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`V.
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`POSAs and Dr. Lublin interpreted the Rice Study as a Positive Study .......... 7
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`VI. POSAs would not be skeptical of cladribine .................................................. 9
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`VII. Bodor Teaches Weight-Based Dosing ........................................................... 12
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`VIII. A POSA Would Default to Weight-Based Dosing ........................................ 16
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`IX. A POSA Would Use 70kg Weights When Applying the Bodor
`Disclosure ...................................................................................................... 17
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`X.
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`Bodor Discloses a Maintenance Period as Claimed. ..................................... 18
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`XI. Conclusion .................................................................................................... 20
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`EXHIBIT 1047
`Petitioner TWi
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`1.
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`I have had the opportunity to review the opinion submitted by Dr. Fred
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`Lublin and now submit a rebuttal to his opinions.
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`I.
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`Summary of My Opinions
`2.
`It remains my opinion that at least claims 36, 38–39, and 41–48 of the
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`’947 patent are invalid because they are either anticipated by or obvious over Bodor
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`WO ’101 (Ex. 1007) and/or its US counterpart, Bodor ’328 (Ex. 1029) (collectively
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`“Bodor”). It is further my opinion that each of these claims are invalid as obvious
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`over Bodor in view of Rice 2000 (Ex. 1008).
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`3.
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`It is my opinion that at least claims 17, 19–20, and 22–29 of the ’903
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`patent are invalid because they are either anticipated by or obvious over Bodor. It is
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`further my opinion that these claims are invalid as obvious over Bodor in view of
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`Rice 2000.
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`4.
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`Dr. Lublin did not disagree with my testimony concerning the standard
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`for obviousness. Specifically, I have been told that a reference may be modified or
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`combined with other references or with the person of ordinary skill in the art’s own
`
`knowledge if the person would have found the modification or combination obvious.
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`5.
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`Additionally, Dr. Lublin acknowledged that Bodor incorporates by
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`reference multiple publications including the Selby article (Ex. 1031), the Tortorella
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`article (Ex. 1026), the Rice article (Ex. 1008) and the Romine article (Ex. 1016) (e.g.
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`Lublin deposition, page 78, lines 12-13.) It is my understanding that Bodor thus
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`EXHIBIT 1047
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`discloses everything written in the patent and all incorporated references. Thus,
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`when addressing the issue of anticipation and obviousness I considered all of the
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`disclosures included in the Bodor patent.
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`6.
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`Additionally, I understand that prior art must disclose the invention, but
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`does not have to provide proof of safety and efficacy required by drug approval
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`authorities. For example, a disclosure of a treatment for a given indication is enough
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`to render a later patent application anticipated or obvious without reporting phase 3
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`clinical trial confirmatory evidence.
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`7.
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`Finally, I understand that a disclosure in prior art does not have to
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`disclose the entire range of a patent’s claims. For example, relative to dosing, if
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`Bodor discloses a dose within the range of doses recited in the ’947 and ’903 patent,
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`then the ’947 and ’903 patent that claim element would be disclosed by Bodor for
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`purposes of anticipation and obviousness.
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`II. Bodor Discloses Cladribine as a Treatment for Multiple Sclerosis
`8.
`Bodor discloses the use of “10mg of cladribine . . . in the [disclosed]
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`solid dosage form” for the “treatment of multiple sclerosis.” (Bodor WO ’101, Ex.
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`1007 at 25; Bodor ’328 col. 13, ℓℓ. 19–25, Ex. 1029 at 10.)
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`III. POSAs Would Preferentially Apply The Bodor Disclosure to Relapsing
`Remitting Multiple Sclerosis and Active Secondary Progressive Multiple
`Sclerosis Patients
`9.
`The most common form of multiple sclerosis was relapsing remitting
`
`multiple sclerosis. Dr. Lublin agrees with this (Ex. 2019 ¶ 47). It has been and
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`remains quite common for clinicians, scientists and POSAs to use the term “Multiple
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`Sclerosis” in place of specifying “Relapsing Remitting Multiple Sclerosis” because
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`that phenotype is the overwhelming dominant form. This includes papers authored
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`by Dr. Lublin, who utilizes the term “Multiple Sclerosis” as a synonym or shorthand
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`when referring to relapsing remitting multiple sclerosis (Ex. 2025, Tullman 2002 at
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`273, 275; Exhibit 2013, Lublin 2005 at III/4).
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`10. Bodor incorporates by reference Romine 1999 (Ex. 1016). (Ex. 1029
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`col. 12, ℓℓ. 67–col. 13 ℓ. 2.) This study reported positive clinical and radiographic
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`results from an 18-month placebo-controlled trial of cladribine in relapsing remitting
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`multiple sclerosis.
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`11. The applicability of Bodor to relapsing remitting multiple sclerosis and
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`active secondary multiple sclerosis patient populations is important in light of MRI
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`data from Rice 2000 (Ex. 1008). While Dr. Lublin reports having “skepticism of
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`cladribine’s utility for treating MS…” (Exhibit 2019 ¶ 199), this is not a full
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`portrayal of his published statements, the conclusions of the study authors, or the
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`views a POSA would have. Importantly, while Dr. Lublin asserts that Rice 2000 (Ex.
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`EXHIBIT 1047
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`1008) included patients with progressive MS and the study failed to reveal a robust
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`impact on clinical outcomes, he is a coauthor of that study, which clearly states:
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`“[s]tudies with cladribine….showed evidence for a good response in terms of
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`gadolinium-enhancing lesions….”(Exhibit 2019 ¶ 90).
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`12. POSAs recognized reduction of gadolinium enhancing lesions to be
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`consistent with a positive effect on relapsing remitting MS patients. Combining
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`Bodor and Rice 2000 would lead a POSA to recognize the value of cladribine dosing
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`in relapsing remitting and active secondary progressive MS patients. Dr. Lublin
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`repeatedly suggests that a dissociation between clinical and MRI data would lead to
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`skepticism amongst POSAs, but when asked during his deposition if he had ever
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`retracted or corrected his authored statements in the Rice article, referencing positive
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`impacts on MRI measures, Dr. Lublin indicated that he had not. (Ex. 1042, Lublin
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`Dep. 21:18–22:9, 67:8–68:20). So, regardless of Dr. Lublin’s view of the Rice study,
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`today, a POSA reading his article in 2000 would have a positive interpretation of
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`cladribine’s ability to suppress acute inflammation and hence, treat relapsing
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`remitting multiple sclerosis.
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`IV. POSAs Were Familiar With a Wide Variety of Therapeutic Approaches
`to Multiple Sclerosis
`13. Dr. Lublin provides an overview of disease modifying therapies in his
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`testimony (Ex. 2019 ¶¶ 51–60) that focuses on the FDA approved interferons,
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`glatiramer acetate and natalizumab. He reviews dosing regimens and mechanisms of
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`EXHIBIT 1047
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`action for these medications suggesting that the use of these medications would teach
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`a POSA away from the Bodor disclosed weight based dosing regimen of Cladribine
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`that involved an initial and maintenance dosing period. But, this supposition fails to
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`acknowledge three critical pieces of information well known to a POSAs at the time.
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`First, the dosing regimen for each disease modifying therapy was unique to the
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`mechanism of action of the drug. Indeed, natalizumab did not require weekly dosing
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`like some interferons, because of the unique mechanism of action, pharmacokinetics
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`and immunologic impact. No two drugs are exactly alike, so a POSA would know
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`to consider the unique aspects of each therapeutic in order to decide how it should
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`be applied to multiple sclerosis. The experience with disease modifying therapies
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`like interferon, glatiramer acetate and natalizumab would not dissuade a POSA from
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`using a different dosing strategy with a different therapeutic agent. Second, this fact
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`is proven in the use of mitoxantrone which utilized a wholly different dosing strategy
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`than interferon, glatiramer acetate and natalizumab. Thus, a POSA, recognizing this
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`FDA approved therapy had its own dosing strategy that had intermittent dosing and
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`a maximum dose that could be used over time, a highly similar concept to cladribine,
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`would recognize the disclosure in Bodor as being a valid approach to therapy. Third,
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`prior art specific to use of cladribine in multiple sclerosis utilized weight based
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`dosing and initial treatment periods followed by subsequent dosing (in a pattern
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`unique from interferons, glatiramer acetate and natalizumab.) This point is critical.
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`EXHIBIT 1047
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`A POSA did not need to read the Bodor variable dosing regimen of 100 – 140 mg
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`and create connections between cladribine and any other multiple sclerosis therapy.
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`Prior art incorporated into Bodor specifically utilized weight based dosing for dose
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`selection when using cladribine for multiple sclerosis. Dr. Lublin does not articulate
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`any other parameter that a POSA would use when reading the dose range of Bodor
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`and indeed, prior art only utilized weight based dosing for dose selection of
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`cladribine.
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`14. Dr. Lublin acknowledged that there was no one “standard” dosing
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`regimen for immunosuppressants. (Ex. 2019 ¶ 66.) POSAs would incorporate
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`knowledge of the disease, knowledge of a drug’s mechanism of action, knowledge
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`of a drug’s safety and prior art to determine a dosing strategy. A POSA would
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`recognize from Bodor, Bodor in light of Rice and Bodor in light of Rice, and
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`Romine, that a dose would be selected based on weight, provided to a patient and
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`then repeated after a ten-month drug free period. Dr. Lublin goes on to agree with
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`this when noting, “a POSA would have understood that (1) there was no single
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`‘proper administration’ for mitoxantrone, let alone immunosuppressants generally
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`and (2) even mitoxantrone’s FDA-recommended ‘intermittent equal dosing’ was but
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`one approach to achieving immunosuppressant effects.” (Ex. 2019, Lublin Decl.
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`¶ 68.) This is a critical admission that recognizes a POSA would utilize experience
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`from drugs like mitoxantrone and cyclophosphamide to interpret Bodor’s disclosure.
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`EXHIBIT 1047
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`15. The Patent Owner spends significant time focused on my 2008
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`publication relative to cyclophosphamide treatment for MS. They note that this
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`publication refers to a “single treatment period” of cyclophosphamide 50 mg/kg
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`daily for four days and thus, argues against retreatment as disclosed in Bodor. This
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`mischaracterizes the publication and reveals a fundamental discounting of a POSA’s
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`perspective and knowledge. POSAs through knowledge, prior art disclosures and
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`experience recognize that the various medications used to treat MS have a broad
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`array of mechanisms and potency. Cyclophosphamide at 50 mg/kg/day for four days
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`was known to be the dose used prior to bone marrow transplants, far different than
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`the dose of cladribine disclosed by Bodor (e.g. about 1.7 mg/kg followed by a
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`maintenance period). A publication by me and colleagues that discussed a dosing
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`strategy for cyclophosphamide does not change the ability of POSAs to recognize
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`and use the cladribine dosing strategy disclosed by Bodor.
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`V.
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`POSAs and Dr. Lublin Interpreted the Rice Study as a Positive Study
`16. Dr. Lublin’s declaration that the “clinical-MRI paradox has been
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`observed with cladribine, as MRI findings from certain cladribine studies for MS
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`have been found to have insufficient correlation with clinical benefit” (Ex. 2019,
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`Lublin Decl. ¶ 73) and his suggestion that Rice 2000 (Ex. 1008) was a negative study
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`and one that POSAs would not rely upon when considering Cladribine as a treatment
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`for MS, is not what he published in 2000 and is an overly narrow characterization of
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`EXHIBIT 1047
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`the study. Rice 2000, coauthored by Dr. Lublin, did not show a statistically
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`significant clinical impact relative to progressive disease, but Rice 2000 (Ex. 1008)
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`would teach POSAs that lack of clinical benefit was an anomaly due to unanticipated
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`recruitment patterns: “The lack of overall treatment difference in this study is likely
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`due to the majority of patients having relatively high EDSS scores at baseline
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`(median score for all three treatment groups 6.0) and the placebo group having only
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`a modest increase from baseline in mean EDSS score.” (Ex. 1008, 8, Rice 2000 at
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`1152.) Additionally, Dr. Lublin and coauthors noted, “The statistical sizing and
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`duration of the double-blind phase of this study were based on assumptions that
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`placebo-treated patients with progressive MS would show a greater degree of disease
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`progression over the course of 12 months and did not anticipate enrollment of mainly
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`patients with more severe disability.” (Ex. 1008, 8–9, Rice 2000 at 1152–1153.) Dr.
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`Lublin and coauthors went on to note, “…the MRI changes in this study were
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`robust.” (Ex. 1008, 9, Rice 2000 at 1553.)
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`17.
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`In light of Bodor, Romine 1999 and Rice 2000 (which includes Dr.
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`Lublin as a coauthor), POSAs would separate out the potential impact on relapsing
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`remitting disease from primary progressive disease and would be motivated to use
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`cladribine in the most common form of MS (relapsing remitting MS and active
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`secondary progressive MS).
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`EXHIBIT 1047
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`18.
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`Indeed, additional published articles by Dr. Lublin, contemporaneous
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`to Rice 2000 and Bodor reveal his conclusion that cladribine would be useful in MS.
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`Notably, Tullman 2002 (Ex. 2025) stated “[s]everal small, randomized, double-
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`blind, placebo-controlled studies suggested that cladribine may have a favorable
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`effect on clinical and MRI outcomes in patients with RRMS and progressive MS.”
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`(Ex. 2025, Tullman 2002 at 279.) This publication, co-authored by Dr. Lublin, is
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`important for three reasons. First, it is coauthored by Dr. Aaron Miller, who Dr.
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`Lublin cites as being skeptical about cladribine. Second, within the paper, Dr. Lublin
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`and coauthors reference the Sipe and Romine studies to justify their conclusions.
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`Third, Dr. Lublin and coauthors cite the Rice study and indicate that “[t]his poorly
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`designed study did not demonstrate any clinical benefit after 1 year but did show a
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`marked reduction in gadolinium-enhancing lesions in the cladribine-treated group”
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`(Ex. 2019 ¶ 157) validating the conclusion of Rice 2000 (Ex. 1008) which he also
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`co-authored, which taught POSAs to separate out the clinical outcome data cited in
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`the Rice study, from the robust MRI data. Within his declaration and during his
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`deposition Dr. Lublin focused on Rice being a “negative” study, but this was not his
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`conclusion when writing about in 2000 and it would not be the conclusion POSAs
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`would have reached.
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`VI. POSAs Would Not be Skeptical of Cladribine
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`EXHIBIT 1047
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`19. Dr. Lublin’s declaration stated, “[t]he results of MS clinical studies on
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`cladribine through 2004, as a whole, left skilled artisans in the field, including
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`myself, skeptical about the utility of cladribine for treating MS due to both (1) the
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`reported lack of cladribine clinical efficacy and (2) safety concerns for long-term
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`side effects of cladribine’s lymphocytotoxic activity.” (Ex. 2019 ¶ 79.) Dr. Lublin is
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`incorrect in his characterization of statements and literature relative to both of these
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`points. First, the “reported lack of …clinical efficacy” is not accurate based on the
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`results of Romine and recognition of design flaws in Rice. Indeed, many prior trials
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`of disease modifying therapies that went on to FDA approval and commercial
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`success had an impact on reducing relapse rates, but not reducing disability. Thus, a
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`POSA would clearly recognize that the prior art for cladribine identified a clinical
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`benefit to multiple sclerosis patients. Second, POSAs recognition of safety concerns
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`would not cause skepticism relative to the use of cladribine for multiple sclerosis.
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`Prior art had disclosed acceptable risk profiles and POSAs were familiar with the
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`use of mitoxantrone under an FDA approved label that warned of far greater risks
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`than those reported with cladribine. Thus, a prior FDA approved therapy was
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`understood to be substantially riskier than the oral therapy regimen disclosed by
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`Bodor.
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`20. Dr. Lublin suggests that practitioners would be wary of cladribine due
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`to the need for monitoring, but there is no reason why monitoring would dissuade a
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`EXHIBIT 1047
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`POSA from using this agent. Indeed, monitoring was commonplace among FDA
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`approved therapies such as mitoxantrone, and was even disclosed in Bodor (e.g.
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`“…with continuous clinical evaluations by a skilled practitioner…” in the definition
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`of “treating.” Ex. 1029 col. 14, ℓℓ. 43–47.)
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`21. Dr. Lublin and Patent Owner repeatedly suggest that the risk of
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`cladribine, specifically, “lymphocytotoxicity” would limit a POSA’s enthusiasm for
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`using cladribine to treat MS, but this is not accurate. The mechanism of action of the
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`drug was to induce death of lymphocytes, this was not an untoward effect, but the
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`actual root of efficacy. What Romine 1999 (Ex. 1016), Sipe 1998 (Ex. 2004), Rice
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`2000 (Ex. 1008), and Bodor disclose is a way to use cladribine in a way that balances
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`efficacy with safety.
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`22. Additionally, other publications such as Dr. Lublin’s own Lublin 2002
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`(Ex. 1046) do not express skepticism about cladribine. To the contrary, his review of
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`the study of cladribine noted, “Pilot studies suggested a benefit in RR and
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`progressive patients.” and while he recognized the lack of a clinical benefit in the
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`Rice trial, he went on to note cladribine’s “…did show a marked reduction in
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`gadolinium enhancing MRI lesions….” (Ex. 1046, 16, Lublin 2002 at 135.) In his
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`review he did not express any concerns about safety data relative to cladribine but
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`did note safety and toxicity data for cyclosporine and bone marrow transplantation.
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`Thus, a POSA reading Dr. Lublin’s article in 2002 would not come away with a sense
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`of skepticism, but rather would include this in a list of therapeutics that may be
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`beneficial for multiple sclerosis.
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`VII. Bodor Teaches Weight-Based Dosing
`23. Bodor states that cladribine has been used as a modality for treating a
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`variety of conditions including multiple sclerosis. (Ex. 1029 col. 1, ℓℓ. 50–55, col.
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`12, ℓℓ. 43–52.) It then describes “therapeutically effective” doses described in the
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`literature for multiple disease states, including from about 0.04 to about 1.0
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`mg/kg/day for multiple sclerosis (Ex. 1029 col. 12, ℓℓ. 53–64), thus specifying the
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`dosage in relation to the patient’s weight.
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`24. Bodor next identifies “various dosage amounts and dosing regimens …
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`reported in the literature for use in the treatment of multiple sclerosis,” expressly and
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`expressly incorporates by reference those articles as part of its own disclosure. (Ex.
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`1029 col. 12, ℓ. 65–col. 13, ℓ. 8.)
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`25. By incorporating Romine 1999 (Ex. 1016), Bodor disclosed a weight-
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`based regimen in which each patient “received a course of five consecutive daily
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`subcutaneous injections of cladribine, 0.07 mg/kg/day” that was “given monthly for
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`6 months for a total cumulative dose of 2.1 mg/kg of cladribine.” (Ex. 1016 at 2,
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`Romine 1999 at 36; Ex. 2019, Lublin Decl. ¶ 78.) It also discloses that “retreatment
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`will be necessary if cladribine is to become a practical long-term therapy for MS.”
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`(Ex. 1016, 5, Romine 1999 at 43; Ex. 2019, Greenberg Decl. ¶ 63.) During the study
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`“no significant toxicity was observed” and the dose “appears to be safe and
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`effective.” (Ex. 1016, 5, Romine 1999 at 42.) It concluded that “cladribine shows
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`promise as a relatively safe and at least temporarily effective treatment in reducing
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`the frequency and severity of MS exacerbations and in suppressing new contrast-
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`enhancing MRI lesions.” (Ex. 1016, 6, Romine 199 at 44.)
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`26. By incorporating Selby 1998 (Ex. 1031), Bodor disclosed a weight-
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`based regimen in which cladribine “was administered at a dose of 0.07 mg/kg/day
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`by subcutaneous injection for 5 days per cycle, or 0.35 mg/kg/cycle, repeated every
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`4 weeks for 6 cycles in total” for a total treatment dose of 2.1 mg/kg. (Ex. 1031, 1,
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`2, 3, Selby 1998 at 295, 296, 297.) This safety and tolerability study determined that
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`cladribine “is remarkably well tolerated … with no significant toxicity despite
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`achieving profound and long lasting immunosuppression,” finding cladribine “safe
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`and easy to use.” (Ex. 1031, 4, Selby 1998 at 298.)
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`27. By incorporating Rice 2000 (Ex. 1008), Bodor disclosed a weight-
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`based regimen in which patients “received six courses of cladribine 0.07 mg/kg/day
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`SC for 5 consecutive days (total dose, 2.1 mg/kg), followed by two courses of
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`placebo or two courses of cladribine 0.07 mg/kg/day SC for 5 consecutive days (total
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`dose, 0.7 mg/kg).” (Ex. 1008, 1, 2, 9, Rice 2000 at 1145, 1146, 1153.) It determined
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`that cladribine “doses of 0.7 mg/kg and 2.1 mg/kg were well tolerated.” (Ex. 1008
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`at 1, 7, 9, Rice 2000 at 1145, 1151, 1153.)
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`EXHIBIT 1047
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`28. By incorporating Tortorella 2001 (Ex. 1026), Bodor disclosed weight-
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`based dosing regimens from other studies, indicating that in both Filippi 2000 (Ex.
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`2016) and Rice 2000 (Ex. 1008) “cladribine was administered sc at 0.07 mg/kg for
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`5 consecutive days for 2 to 6 monthly courses, ie, at a total dose of 0.7 to 2.1 mg/kg.”
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`(Ex. 1026, 2, Tortorella 2001 at 1752.) It also indicated that, in another study, “[o]ral
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`cladribine
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`treatment was well-tolerated and relatively safe.” (Id.)
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` Oral
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`administration of cladribine was known, and it was known to have a bioavailability
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`of 37–51%, such that “a double dose of orally administered cladribine can substitute
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`for a sc injection.” (Ex. 1009, 3, Liliemark 1997 at 122; Ex. 1026, 2, Tortorella 2001
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`at 1752.) Tortorella 2001 also indicates that oral cladribine had been used in a
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`preliminary study by Greib in 1995 in which the “dose was of 10 mg once a day for
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`5 consecutive days in six monthly courses, followed by one or two additional courses
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`at 3 or 6 month intervals.” (Ex. 1026, 2, Tortorella 2001 at 1752.) “Oral cladribine
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`treatment was well-tolerated and relatively safe.” (Id.)
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`29. Dr. Lublin suggested that a POSA would “have understood that Bodor
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`expressly teaches flat, fixed dosing, which is fundamentally different from weight-
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`based dosing.” (Ex. 2019, Lublin Decl. ¶ 19.) Bodor does not teach flat fixed dosing.
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`Bodor’s invention of a cladribine formulation included a disclosure that it would be
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`used to treat multiple sclerosis and inherently allowed for variable dosing, not fixed
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`dosing. To reach this conclusion, I noted the following statements from Bodor: “As
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`– 14 –
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`
`EXHIBIT 1047
`Petitioner TWi
`IPR2023-00049, -00050
`
`
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`
`
`used herein, the recitation of a numerical range for a variable is intended to convey
`
`that the invention may be practiced with the variable equal to any of the values within
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`that range.” (Ex. 1029 col. 6, ℓℓ. 27–30.) Subsequently, Bodor states, “[r]eference is
`
`made herein to various methodologies and materials known to those of skill in the
`
`art. Standard reference works setting forth the general principles of pharmacology
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`include Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th
`
`Ed., McGraw Hill Companies Inc., New York (2001)” (Ex 1029 col. 6, ℓℓ. 47–53.)
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`Bodor references “therapeutically effective dosages” of cladribine from the
`
`literature and all were weight-based dosing (Ex. 1029 col. 12, ℓℓ. 53–64). Bodor
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`incorporates references to prior multiple sclerosis trials including those published in
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`Romine 2000 (Ex. 1016), Selby 1998 (Ex. 1031), Tortorella 2001 (Ex. 1026) and
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`Rice 2000 (Ex. 1008), all of which utilized weight-based dosing for the treatment
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`of multiple sclerosis. Finally, Bodor discloses a variable range of cladribine in the
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`oral form, “[a]t the present time, it is envisioned that, for the treatment of multiple
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`sclerosis, 10 mg of cladribine in the instant complex cladribine-cyclodextrin
`
`complex in the instant solid dosage form would be administered once per day for a
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`period of five to seven days in the first month, repeated for another five to seven
`
`days in the second month, followed by ten months of no treatment.” (Ex. 1029 col.
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`13, ℓℓ. 19–25). The range of 5 to 7 days of dosing equates to 50 to 70 mg per month.
`
`– 15 –
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`
`EXHIBIT 1047
`Petitioner TWi
`IPR2023-00049, -00050
`
`
`
`
`
`The only criteria in the prior art, disclosed in Bodor or relevant to a POSA for
`
`selecting a first dose would be weight-based dosing.
`
`30. Dr. Lublin’s argument that Bodor teaches flat fixed dosing is flawed.
`
`He states that “[a]lthough the regimen may vary in the number of days of dosing
`
`over two months, i.e., 10 days, 12 days or 14 days, a POSA would have understood
`
`that all patients regardless of weight, receive the same 10 mg daily dosage of
`
`cladribine for that number of days and thus the dosage remains flat and fixed.” (Ex.
`
`2019, Lublin Decl ¶ 48.) Referring to the 10 mg tablet as “the dosage” is incorrect.
`
`It is clear from Bodor, prior art and knowledge used by a POSA that “the dosage”
`
`refers to the total dose provided in month one and two. This amount is variable and
`
`not fixed. The only covariate Bodor, prior art or a POSA used to vary a dose in this
`
`situation is weight-based. Dr. Lublin acknowledges the range of doses disclosed by
`
`Bodor, but offers no alternative method a POSA would use for utilizing this range.
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`The only referenced material pertinent to this topic is weight-based dosing.
`
`VIII. A POSA Would Default to Weight-Based Dosing
`
`31. A POSA would default to weight-based dosing when reading to Bodor
`
`disclosure for three reasons. First, Bodor discloses variable doses (100–140mg of
`
`cladribine) in the context of prior art, all of which utilized weight-based dosing.
`
`Second, prior studies of cladribine in MS utilized weight-based dosing and no other
`
`dose selection criteria is offered by Dr. Lublin when reading Bodor. Third, POSAs
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`– 16 –
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`
`EXHIBIT 1047
`Petitioner TWi
`IPR2023-00049, -00050
`
`
`
`
`
`were very familiar with weight-based dosing in MS therapeutics. Dr. Lublin’s own
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`articles refers to weight-based (and patient size based – mg/m2) dosing for
`
`intravenous immunoglobulin, cyclophosphamide and mitoxantrone.
`
`32. Bodor explicitly states that his invention can be practiced with values
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`equal to “any of the values within that range.” (Ex. 1029 col. 6, ℓℓ. 29–30.) When
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`selecting a dose for cladribine between 100 and 140 mg, a POSA’s knowledge and
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`experience on its own and in combination with prior art would dictate weight-based
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`dosing.
`
`33. Dr. Lublin incorrectly states that when MAVENCLAD® was FDA
`
`approved none of the FDA-approved MS drugs were dosed by body weight. At the
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`time of approval, mitoxantrone had been on the market with personalized dosing
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`based on patient size. Additionally, POSAs had been utilizing intravenous
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`immunoglobulin in an off-label fashion in neuroimmunology with weight-based
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`dosing.
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`IX. A POSA Would Use 70kg Weights When Applying the Bodor Disclosure
`34. Dr. Lublin acknowledges (as the Board found on institution) that
`
`applying the Bodor disclosure to the accepted standard average weight population
`
`of 70-80.28 kg would reasonably overlap with the dosage as recited in the ’947
`
`patent. (Ex. 2019, 48, Lublin Decl. ¶ 108.) Dr. Lublin does not deny that the 70kg
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`standard weight was used throughout pharmacology as reflected in standard
`
`– 17 –
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`
`EXHIBIT 1047
`Petitioner TWi
`IPR2023-00049, -00050
`
`
`
`
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`reference works such as Goodman 2001 (Ex. 1039), cited by Bodor (Ex. 1029 col.
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`6, ℓℓ. 49–53.) Dr. Lublin just restates the argument that despite the prior art, all of
`
`which was weight-based dosing for cladribine, and Bodor’s disclosure of variable
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`dosing a POSA would not apply weight-based dosing to Bodor’s dose range of 100
`
`to 140 mg. Dr. Lublin refers to this range as fixed, flat dosing, but Bodor notes that
`
`a POSA will utilize the range based on skill and prior art, both of which would teach
`
`using weight as the deciding factor when picking from this variable dose range. Of
`
`note, Dr. Lublin does not disagree with the 70kg–80kg weight range that would be
`
`applied, thus if we agree that a weight-based criteria would be used to tailor dosing
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`within the disclosed range then it is clear the ’947 and ‘903 patents are anticipated
`
`and obvious.
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`X. Bodor Discloses a Maintenance Period as Claimed.
`35. Bodor’s disclosed treatment regimen includes two months of dosing,
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`“followed by ten months of no treatment.” (Ex. 1029 col.13, ℓ. 25.) Critically, Bodor
`
`does not disclose two months of treatment and then is silent, but instead specifies a
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`ten-month treatment free period. The primary conclusion a POSA would reach is
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`that retreatment could and would occur after this treatment free period.
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`36. Bodor in view of Rice 2000 (Ex. 1008) makes re-treatment clear.
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`Bodor’s incorporation of Rice 2000 (Ex. 1008) experience explicitly includes
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`recognition of use of cladribine in a paradigm of treatment, followed by a treatment
`
`– 18 –
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`
`EXHIBIT 1047
`Petitioner TWi
`IPR2023-00049, -00050
`
`
`
`
`
`free period leading to retreatment. In light of Rice 2000 (Ex. 1008), a POSA reading
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`Bodor’s disclosure of a specific ten-month treatment free period would understand
`
`this to be a period of time before retreatment.
`
`37. Bodor’s incorporation by reference of Romine 1999 (Ex. 1016) further
`
`makes retreatment clear, teaching that “retreatment will be necessary” (Ex. 1016, 5,
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`Romine 1999 at 43.) Of note, neither Romine 1999 (Ex. 1016) nor Rice 2000 (Ex.
`
`1008) suggest using alternative therapies after an initial course of cladribine, but
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`instead both indicate that a practitioner would retreat with cladribine. Thus, a POSA
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`reading Bodor would rightfully interpret Bodor to disclose a course of cladribine,
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`followed by a 10-month cladribine free period that would lead to repeat dosing. The
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`incorporation by reference in Bodor of Rice 2000 (Ex. 1008) and Romine 1999 (Ex.
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`1016) makes retreatment with cladribine an express disclosure of Bodor.
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`38.
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`In contending that a POSA would not redose with cladribine as
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`disclosed by Bodor, Dr. Lublin suggests safety concerns about cladribine as a
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`limiting factor for POSAs. Yet, Dr. Lublin co-authored Rice 2000 which taught the
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`opposite to POSAs. Specifically, he and coauthors noted, “[c]ladribine doses of 0.7
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`mg/kg and 2.1 mg/kg were well tolerated. The most common adverse events were
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`related to the patients’ underlying disease or to SC administration of the study drug.
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`They were mild or moderate in severity, not treatment limiting, and were judged by
`
`the investigator to be unr
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