`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________________________________________
`
`HOPEWELL PHARMA VENTURES, INC.,
`Petitioner,
`
`v.
`MERCK SERONO S.A.,
`Patent Owner.
`_________________________________________________
`Case IPR2023-00481
`Patent 8,377,903
`____________________________________________________
`
`PATENT OWNER’S RESPONSE
`
`
`
`
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`
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`IPR2023-00481
`U.S. Patent No. 8,377,903
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`
`TABLE OF CONTENTS
`
`Page
`Introduction ...................................................................................................... 1
`
`State Of The Art ............................................................................................... 3
`
`I.
`
`II.
`
`A. MS ......................................................................................................... 3
`
`1. MS Clinical Course and Treatment as of 2004 ........................... 3
`
`2.
`
`3.
`
`Outcome Measures In MS Clinical Trials .................................. 5
`
`Cladribine Investigations For MS ............................................... 5
`
`B. Alleged Prior Art ................................................................................... 6
`
`1.
`
`2.
`
`Bodor (Ex. 1022)......................................................................... 6
`
`Stelmasiak (Ex. 1013) ................................................................. 7
`
`III. The ’903 Patent Invention ............................................................................... 7
`
`IV. Person Of Ordinary Skill In The Art ............................................................... 8
`
`V.
`
`Claim Construction .......................................................................................... 9
`
`VI. The Cited Portion of Bodor is not “By Another” ............................................ 9
`
`A.
`
`The Cited Portion of Bodor is not Prior Art Under Pre-AIA 35
`U.S.C. § 102(a) or (e). ........................................................................... 9
`
`1.
`
`2.
`
`3.
`
`Petitioner bears the burden to prove Bodor is “by
`another.” .................................................................................... 10
`
`Petitioner fails to show Bodor’s regimen is “by another.” ....... 12
`
`Bodor’s regimen is not “by another.” ....................................... 12
`
`
`
`i
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`

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`VII. The Challenged Claims Would Not Have Been Obvious Over Bodor
`And Stelmasiak .............................................................................................. 18
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`IPR2023-00481
`U.S. Patent No. 8,377,903
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`
`A.
`
`Bodor And Stelmasiak Do Not Disclose Or Suggest All Claim
`Limitations ........................................................................................... 19
`
`1.
`
`2.
`
`Bodor And Stelmasiak Do Not Disclose Or Suggest The
`Claimed Weight-Based Induction Or Maintenance
`Dosing ....................................................................................... 19
`
`Neither Bodor Nor Stelmasiak Discloses Or Suggests A
`Maintenance Period As Claimed .............................................. 24
`
`a)
`
`Bodor Does Not Teach or Suggest Re-treatment ........... 24
`
`(1) Cladribine Safety .................................................. 25
`
`(2) Dosing of Approved DMAs For MS Was
`Based on Pharmacological Effects and Safety ..... 27
`
`(3) The Art Did Not Suggest A Maintenance
`Period As Claimed ............................................... 30
`
`b)
`
`Stelmasiak Does Not Teach Or Suggest A
`Maintenance Period As Claimed .................................... 33
`
`B. No Motivation To Combine Bodor With Stelmasiak To Arrive
`At The Challenged Claims Or Reasonable Expectation Of
`Success In Doing So ............................................................................ 35
`
`1.
`
`Petitioner’s Routine Optimization Arguments Fail .................. 35
`
`
`
`ii
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`

`

`2.
`
`3.
`
`4.
`
`5.
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`IPR2023-00481
`U.S. Patent No. 8,377,903
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`
`A POSA Would Not Have Been Motivated To Adopt
`Weight-Based Dosing Or Reasonably Have Expected To
`Arrive At The Claimed Weight-Based Dosing Regimen ......... 48
`
`A POSA Would Not Have Been Motivated To Combine
`Bodor With Stelmasiak To Arrive At The Claimed
`Induction Doses Or Have Had A Reasonable Expectation
`Of Success In Doing So ............................................................ 49
`
`A POSA Would Not Have Been Motivated To Re-Treat
`Patients After Bodor’s 10-Month Cladribine-Free Period
`With A Reasonable Expectation Of Success ............................ 53
`
`A POSA Would Not Have Been Motivated To Combine
`Bodor With Stelmasiak To Arrive At The Claimed 1.7
`Mg/Kg Maintenance Dose ........................................................ 55
`
`C.
`
`The Dependent Claims Would Not Have Been Obvious Over
`Bodor And Stelmasiak ........................................................................ 57
`
`VIII. Objective Indicia Support Non-Obviousness ................................................ 58
`
`A.
`
`Skepticism Of Others .......................................................................... 58
`
`B. Unexpected Results ............................................................................. 60
`
`C.
`
`Satisfaction of a Long-Felt, Unmet Need ........................................... 63
`
`D. Nexus ................................................................................................... 63
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`IX. Conclusion ..................................................................................................... 65
`
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`U.S. Patent No. 8,377,903
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`
`TABLE OF AUTHORITIES
`
`
`
`Page(s)
`
`CASES
`Apple Inc. v. Samsung Elecs. Co., 839 F.3d 1034 (Fed. Cir. 2016) (en
`banc) ............................................................................................................... 58
`Duncan Parking Techs., Inc. v. IPS Grp., Inc., 914 F.3d 1347 (Fed.
`Cir. 2019) ........................................................................................... 11, 12, 18
`Dynamic Drinkware, LLC v. National Graphics, Inc., 800 F.3d 1375
`(Fed. Cir. 2015) .............................................................................................. 11
`Fox Factory, Inc. v. SRAM, LLC, 944 F.3d 1366 (Fed. Cir. 2019) ......................... 64
`
`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule Pat.
`Litig., 676 F.3d 1063 (Fed. Cir. 2012) ........................................................... 47
`In re DeBaun, 687 F.2d 459 (C.C.P.A. 1982) ..................................................... 9, 18
`In re Enhanced Sec. Research, LLC, 739 F.3d 1347 (Fed. Cir. 2014) .................... 54
`In re Gurley, 27 F.3d 551 (Fed. Cir. 1994) .............................................................. 23
`In re Land, 368 F.2d 866 (C.C.P.A. 1966) .............................................................. 10
`In re Peterson, 315 F.3d 1325 (Fed. Cir. 2003) ...................................................... 36
`Neptune Generics, LLC v. Eli Lilly & Co., 921 F.3d 1372 (Fed. Cir.
`2019) .............................................................................................................. 60
`Quanergy Sys., Inc. v. Velodyne Lidar USA, Inc., 24 F.4th 1406 (Fed.
`Cir. 2022) ....................................................................................................... 64
`Rambus Inc. v. Rea, 731 F.3d 1248 (Fed. Cir. 2013) .............................................. 64
`Riverwood Int’l Corp. v. R.A. Jones & Co., 324 F.3d 1346 (Fed. Cir.
`2003) .............................................................................................................. 11
`Standard Oil Co. v. Am. Cyanamid Co., 774 F.2d 448 (Fed. Cir. 1985) ................ 24
`Unigene Lab’ys, Inc. v. Apotex, Inc., 655 F.3d 1352 (Fed. Cir. 2011) .................... 48
`
`
`
`iv
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`Volvo Penta of the Americas, LLC v. Brunswick Corp., 81 F.4th 1202
`(Fed. Cir. 2023) .............................................................................................. 58
`WBIP, LLC v. Kohler Co., 829 F.3d 1317 (Fed. Cir. 2016) .................................... 58
`STATUTES, RULES, AND REGULATIONS
`Pre-AIA 35 U.S.C. § 102 ..................................................................................passim
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`
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`
`
`v
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`

`

`INTRODUCTION
`By 2004, skilled artisans in the field of neurology, including Petitioner’s
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`IPR2023-00481
`U.S. Patent No. 8,377,903
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`
`I.
`
`declarant Dr. Miller, did not expect cladribine to be of clinical benefit in treating
`
`multiple sclerosis (“MS”), much less with any durability and without dangerous
`
`side effects. Ex. 2005, 45, 67; Ex. 2031, 753; Ex. 2004, 341; Ex. 2011, 3. Several
`
`studies had reported that cladribine was either not clinically effective, or had
`
`inconsistent outcome measure readouts, or raised significant safety concerns. See,
`
`e.g., Ex. 1018, 1153; Ex. 1016, 432; Ex. 1031, 43-44; Ex. 1023, 326. Nonetheless,
`
`the ’903 patent’s inventors persisted in designing a dosing regimen for cladribine
`
`that would be safe and effective, ultimately discovering the novel and unique
`
`dosing regimen claimed in the challenged claims, which is unexpectedly effective
`
`not just during treatment, but with sustained benefits for up to almost 11 years after
`
`treatment, while maintaining patient safety. See Ex. 2036, 719, 728.
`
`The centerpiece of Petitioner’s evidence is the declaration of Dr. Miller, but
`
`his opinion that the challenged claims are allegedly obvious should be given no
`
`weight because it conflicts with pre-IPR statements by Dr. Miller establishing
`
`exactly the opposite. Petitioner’s single ground of invalidity—alleged obviousness
`
`over Bodor and Stelmasiak—fails.
`
`Bodor discloses in passing a dosing regimen that was disclosed by the
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`inventors of the ʼ903 patent (on a confidential basis) to Bodor’s assignee IVAX as
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`
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`1
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`U.S. Patent No. 8,377,903
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`part of a joint research program between IVAX and Serono.1 Because Bodor’s
`
`dosing regimen was attributable to the inventors of the ʼ903 patent and not “by
`
`another,” it cannot be used as prior art against the ʼ903 patent. But even if Bodor
`
`were prior art, Bodor and Stelmasiak do not teach or suggest the claimed weight-
`
`based dosing or maintenance period.
`
`Moreover, there is nothing that would have motivated a person of ordinary
`
`skill in the art (“POSA”) to modify the teachings of Bodor or Stelmasiak to arrive
`
`at the disclosed regimens. Nor would a POSA have recognized that Bodor’s or
`
`Stelmasiak’s dosing regimen was effective: Bodor discloses no clinical results for
`
`its regimen, and Stelmasiak discloses only partial patient response.
`
`There is even less motivation to cobble together Petitioner’s cherry-picked
`
`parts of the regimens disclosed in Bodor and Stelmasiak to achieve the claimed
`
`regimen. Relying impermissibly on hindsight, Petitioner fails to show that a POSA
`
`would have been motivated to select those features, much less combine them with
`
`a reasonable expectation of success.
`
`Hindsight also infects Petitioner’s contention that the claimed regimen
`
`would have resulted from “routine optimization.” The complex and variable
`
`
`1 Serono is used herein to collectively refer to the challenged patent’s owner and its
`
`affiliates, including Ares.
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`
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`2
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`IPR2023-00481
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`nature of MS, its slowly evolving disability over years, and the gradual, long-term
`
`nature of disease-modifying agents (“DMAs”) combine to ensure that the treatment
`
`effects of any dosing schedule of a DMA can likewise only be assessed over a long
`
`time. A POSA would have understood that it would require years to evaluate how
`
`changes made to an MS drug’s dose and/or dosing schedule would impact clinical
`
`outcomes, making “optimization” of the dosing regimen anything but “routine.”
`
`For at least the foregoing reasons, Patent Owner (“PO”) respectfully requests
`
`that the Board uphold the challenged claims.
`
`II.
`
`STATE OF THE ART
`A. MS
`In MS, the body’s immune system attacks the central nervous system (CNS),
`
`causing destruction of myelin insulating nerve fibers. Ex. 2010, 1, 18, 56; Ex.
`
`1001, 1:26-30; Ex. 1007, 131. By 2004, it was thought that “auto-reactive”
`
`lymphocytes, a type of white blood cell, and “[m]any cells and molecules of the
`
`immune system … participate in demyelination.” Ex. 2010, 6, 44; Ex. 1016, 421;
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`Ex. 1007, 131; Ex. 2051, ¶¶39-40.
`
`1. MS Clinical Course and Treatment as of 2004
`The clinical subtypes of MS include relapsing remitting MS (“RRMS”) and
`
`secondary progressive MS (“SPMS”), which includes an initial, transitional stage
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`
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`3
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`that can be referred to as early SPMS. Ex. 1001, 1:48-50; Ex. 2051, ¶¶41-46; Ex.
`
`1038, 60-63.
`
`By 2004, FDA had approved six DMAs for MS: three beta interferons
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`(Betaseron®; Avonex®; Rebif®), glatiramer acetate (Copaxone®), mitoxantrone
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`(Novantrone®), and natalizumab (Tysabri®). Ex. 2014, 12; Ex. 2015, 3; Ex. 2016,
`
`17; Ex. 2017, 19; Ex. 2018, 29; Ex. 2019, 10; Ex. 2051, ¶50. All were
`
`injectables—none was approved for oral administration—and none was dosed by
`
`bodyweight.2 Ex. 2051, ¶53. These drugs are either immunosuppressants or
`
`immunomodulators. Id., ¶¶50-52. Immunosuppressants cause general immune
`
`system suppression and are characterized by relatively nonspecific down-
`
`regulation of immune function, whereas immunomodulators have more targeted
`
`effects and are usually less toxic. Id., ¶49; Ex. 2006, 273. By 2004, all FDA-
`
`approved MS drugs were dosed continuously to maintain the pharmacologic and
`
`clinical effects of the drug. See Ex. 2024, 9; Ex. 2020, 571, 573; Ex. 2025, 1879,
`
`1883; Ex. 2017, 3; Ex. 2051, ¶¶54-57. That is, they were dosed “continuously,
`
`without an intended interruption in dosing, because clinical efficacy is tightly
`
`linked to the period of dosing.” Ex. 2032, 1923. No FDA-approved MS drug was
`
`administered based on the “cyclical” nature of MS. Ex. 2051, ¶¶58-59.
`
`
`2 The recommended dosage of mitoxantrone is 12 mg/m2.
`4
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`2. Outcome Measures In MS Clinical Trials
`The mainstay for assessing MS treatment efficacy are clinical outcome
`
`variables such as relapse rate and physical disability status, while MRI outcomes
`
`can be indicative of disease activity. Ex. 2051, ¶¶60-61; Ex. 2011, III/4. The most
`
`widely used measure of physical disability is the Kurtzke Expanded Disability
`
`Status Scale (“EDSS”), which measures disability status based on neurologic
`
`examination of functional systems throughout the body. Ex. 1010, 1445-49; Ex.
`
`1016, 425-426; Ex. 2051, ¶60.
`
`When assessing MS treatment efficacy, a POSA would have understood that
`
`outcome measures should be considered collectively, not individually. Ex. 2051,
`
`¶62. For example, MS studies have shown a dissociation between MRI effects and
`
`clinical outcomes. See, e.g., Ex. 1018, 1145. A POSA would have understood that
`
`“[a]n important principle when interpreting clinical trial data is that of
`
`coherence,”3 i.e., all outcomes point to the same effect to confirm treatment
`
`efficacy. Ex. 2011, III/4; Ex. 2051, ¶62.
`
`3.
`Cladribine Investigations For MS
`The MS clinical studies on cladribine through 2004 left skilled artisans
`
`skeptical about cladribine’s utility for treating MS, including RRMS and early
`
`
`3 Hereinafter, all emphasis is added unless otherwise noted.
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`
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`5
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`SPMS, due to (1) the reported lack of cladribine clinical efficacy and (2) safety
`
`concerns arising from cladribine’s lymphocytotoxic activity. Ex. 2051, ¶¶64-71.
`
`For example, in 2000, Petitioner’s declarant Dr. Miller explained that “[i]n recently
`
`completed trials of oral myelin, cladribine, and sulfasalazine, these agents were
`
`found not to be of benefit.” Ex. 2005, 45; see also Section VIII.A, infra.
`
`A POSA also would have understood that cladribine posed significant long-
`
`term safety concerns due to its lymphocytotoxic activity. Ex. 2051, ¶¶72-73.
`
`Further, “[r]epeated treatment raises long-term toxicity issues.” Ex. 1031, 43-44.
`
`By 2004, there was at best a “hypothesis” that cladribine “acts by reducing
`
`the number of activated lymphocytes,” but the basis for cladribine’s therapeutic
`
`effect had not been established. Ex. 2051, ¶74; Ex. 1016, 432; see also Ex. 1031,
`
`42.
`
`B. Alleged Prior Art
`1.
`Bodor (Ex. 1022)
`Bodor is a PCT application, filed March 2004, teaching and claiming
`
`cladribine formulations. Ex. 1022, 5-6. Although the invention in Bodor is clearly
`
`directed to cladribine formulations, Petitioner focuses on a 6-line example regimen
`
`for treating MS, which teaches neither weight-based dosing nor a maintenance
`
`period. Id., 23:15-20; Ex. 2051, ¶75. What it does disclose, however, is the work
`
`of the ’903 patent inventors. Ex. 2053, ¶53; Ex. 2055 ¶¶23-27.
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`6
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`As described below, the ’903 patent inventors confidentially communicated
`
`their work on dosing regimens to IVAX before February 2004. Ex. 2053, ¶¶30-53;
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`Ex. 2055, ¶¶15-18; infra, Section VI. This communication from the ’903 patent
`
`inventors resulted in the 6-line disclosure in Bodor on which Petitioner relies. Ex.
`
`2053, ¶¶50-54; Ex. 2054 ¶¶26-29; Ex. 2055, ¶¶23-27. Because the relevant portion
`
`of Bodor is thus not “by another,” as required by 35 U.S.C. § 102(a) and (e), it is
`
`not prior art to the ’903 patent.
`
`2.
`Stelmasiak (Ex. 1013)
`Stelmasiak is a publication disclosing a cladribine study, without any
`
`placebo group, in 10 RRMS patients, in which 4 patients received a high (300 mg),
`
`flat oral cladribine dose, followed by 50 mg at month nine and month twelve or
`
`fifteen. Ex. 1013, 5; Ex. 2051, ¶77. While some patients “responded” to treatment
`
`as assessed by EDSS scores, others did not, and Stelmasiak advised that “[i]ts
`
`results concerning the effic[]acy of the treatment … be interpreted with great
`
`caution.” Ex. 1013, 6-7; Ex. 2051, ¶78.
`
`III. THE ’903 PATENT INVENTION
`Claims 17, 19, 20, and 22-27 of the ’903 patent (“challenged claims”) are
`
`directed to an oral dosing regimen for treating RRMS or early SPMS, comprising
`
`(i) an induction period having a total cladribine dose of about 1.7-3.5 mg/kg and
`
`lasting about 2-4 months; (ii) a cladribine-free period lasting from about 8 months
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`7
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`to about 10 months; (iii) a maintenance period having a total cladribine dose of
`
`about 1.7 mg/kg and lasting about 2-4 months; and (iv) a cladribine-free period.
`
`Ex. 1001, 18-7:51; Ex. 2051, ¶¶79-80.
`
`The claimed dosing regimen overcame the challenges and drawbacks of
`
`earlier cladribine clinical studies and provides a safe and effective method for
`
`treating MS, now approved by FDA in MAVENCLAD®. Ex. 2051, ¶81. The
`
`Cladribine Tablets Treating Multiple Sclerosis Orally (“CLARITY”) study, a
`
`placebo-controlled clinical trial implementing embodiments of the claims,
`
`demonstrated that “[t]reatment with cladribine tablets significantly reduced relapse
`
`rates, the risk of disability progression, and MRI measures of disease activity at 96
`
`weeks.” Ex. 2033, 416. CLARITY not only showed positive clinical and MRI
`
`outcomes, but also unexpectedly yielded a dosing regimen “sweet spot,” i.e., a
`
`minimal dosing period (two years) that achieved the same clinical benefits as four-
`
`year dosing with a lower incidence of lymphopenia, as demonstrated by the
`
`CLARITY EXTENSION trial. Ex. 2051, ¶¶82-83; Ex. 2035, 1594; infra, Section
`
`VIII.B.
`
`IV. PERSON OF ORDINARY SKILL IN THE ART
`A POSA would have an M.D. with at least two years of experience treating
`
`neurological conditions, with a focus on autoimmune disorders, including but not
`
`limited to multiple sclerosis, and prescribing immunotherapies to treat such
`
`
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`8
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`neurological conditions. Ex. 2051, ¶29. A POSA would also be part of a team
`
`including individuals with experience in investigation of the pharmacokinetics
`
`(PK) and pharmacodynamics (PD) of drugs, pharmaceutical drug development,
`
`and clinical trial design. Id.
`
`This definition is more accurate than Petitioner’s. Under either definition
`
`the claims are non-obvious for the reasons stated herein, and Dr. Fred Lublin
`
`qualifies as a POSA. Ex. 2051, ¶¶30-31.
`
`V. CLAIM CONSTRUCTION
`For the reasons identified in its Preliminary Response, PO agrees with the
`
`Board adopting PO’s proposed constructions for “an induction period” and “a
`
`maintenance period.” Paper 10, 13-17.
`
`VI. THE CITED PORTION OF BODOR IS NOT “BY ANOTHER”
`A. The Cited Portion of Bodor is not Prior Art Under Pre-AIA 35
`U.S.C. § 102(a) or (e).
`It is black letter law that “an [inventor’s] own work may not be used
`
`against” them unless it was published over a year before their application.4 In re
`
`DeBaun, 687 F.2d 459, 462 (C.C.P.A. 1982) (internal citation omitted). But that is
`
`
`4 Bodor was published on October 14, 2004, less than a year before the December
`
`22, 2004 filing date of the ’903 patent priority applications, U.S. 60/638,669 and
`
`EP04106909, and is not prior art under pre-AIA 35 U.S.C. § 102(b).
`
`
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`9
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`what Petitioner seeks here: Bodor includes the work of named inventors of the
`
`’903 patent, Drs. Munafo, Lopez-Bresnahan, Ythier, and De Luca, which IVAX,
`
`assignee of Bodor, obtained through a joint research agreement between IVAX and
`
`Serono. The dosing regimen in Bodor, the only Bodor disclosure Petitioner
`
`contends renders the challenged claims obvious, was solely the work of the
`
`inventors of the ’903 patent, and not the work of Bodor’s inventors, Dr. Bodor or
`
`Dr. Dandiker. Consequently, it is not prior art “by another” within the meaning of
`
`35 U.S.C. § 102(a) or (e), and Petitioner’s sole ground fails.
`
`1.
`Petitioner bears the burden to prove Bodor is “by another.”
`A disclosure is not prior art under pre-AIA Section 102(a) or (e) unless it is
`
`“by another.”5 The Federal Circuit has established a three-step framework for
`
`assessing whether a disclosure is “by another” under Section 102(a) or (e):
`
`[T]he Board must (1) determine what portions of the reference patent
`
`were relied on as prior art to anticipate the claim limitations at issue,
`
`(2) evaluate the degree to which those portions were conceived “by
`
`
`5 The relevant part of Section 102(a) requires knowledge or use “by others.” A
`
`patent disclosure that is not “by another” under Section 102(e) is likewise not
`
`evidence of knowledge or use “by others” under Section 102(a). In re Land, 368
`
`F.2d 866, 877-79 (C.C.P.A. 1966).
`
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`10
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`another,” and (3) decide whether that other person’s contribution is
`
`significant enough, when measured against the full anticipating
`
`disclosure, to render him a joint inventor of the applied portions of the
`
`reference patent.
`
`Duncan Parking Techs., Inc. v. IPS Grp., Inc., 914 F.3d 1347, 1358 (Fed. Cir.
`
`2019).
`
`Petitioner bears the burden of proving any alleged prior art, or a portion
`
`relied upon is “by another” and “that burden never shifts to the patentee.”
`
`Dynamic Drinkware, LLC v. National Graphics, Inc., 800 F.3d 1375, 1378 (Fed.
`
`Cir. 2015). Petitioner thus must prove that the cited regimen upon which Petitioner
`
`relies is attributable to Dr. Bodor or Dr. Dandiker, not the inventors of the ’903
`
`patent. Riverwood Int’l Corp. v. R.A. Jones & Co., 324 F.3d 1346, 1356 (Fed. Cir.
`
`2003). If the inventors of the challenged patent communicated their ideas to
`
`someone else, mere publication of the inventor’s ideas by the recipient in a
`
`reference publication is not “by another.” For example, in In re Mathews, two
`
`coworkers told each other about their inventions and each filed separate patent
`
`applications including descriptions of the other’s invention. 408 F.2d 1393, 1394-
`
`95 (C.C.P.A. 1969). The Court of Customs and Patent Appeals held that the
`
`disclosure of Mathews’s invention in his coworker’s application was not prior art
`
`
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`11
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`“by another” because it merely reflected Mathews’s own work communicated to
`
`his coworker, not the coworker’s independent work. Id., 1395.
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`2.
`Petitioner fails to show Bodor’s regimen is “by another.”
`Under step 1 of Duncan, Petitioner’s sole ground relies upon 6 lines of
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`Bodor to allegedly disclose the treatment regimen and dosage in the challenged
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`claims. Pet. 46-48. Petitioner cites no other portion of Bodor that it contends
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`discloses the claimed regimen or dosage limitations. Id.
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`Turning to Duncan step 2, Petitioner offers no argument that these 6 lines in
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`Bodor were “by another.” Indeed, as described in more detail below, Bodor
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`inventors did not invent any dosing regimen at all.
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`The analysis should end here, and the Board should hold that Petitioner’s
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`sole ground fails because Petitioner failed to prove the portion of Bodor it relies on
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`is prior art.
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`3.
`Bodor’s regimen is not “by another.”
`Even if Petitioner had satisfied step 2 of Duncan, the evidence demonstrates
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`that the disclosure in Bodor relied on by Petitioner was first developed by
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`inventors of the ’903 patent who communicated it to IVAX before February 2004.
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`The cited disclosure in Bodor states:
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`At the present time, it is envisioned that, for the treatment
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`of multiple sclerosis, 10 mg of cladribine in the instant
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`complex cladribine-cyclodextrin complex in the instant
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`solid dosage form would be administered once per day for
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`a period of five to seven days in the first month, repeated
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`for another period of five to seven days in the second
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`month, followed by ten months of no treatment.
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`Ex. 1022, 23:15-20.
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`Both of Bodor’s inventors—Drs. Bodor and Dandiker—declare they did not
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`invent this regimen. Ex. 2054, ¶26; Ex. 2055, ¶23. One of the Serono inventors,
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`Dr. Munafo, explains that he and his co-inventors developed this regimen first and
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`communicated it to IVAX before the effective filing date of Bodor’s relevant
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`disclosure. Ex. 2053, ¶¶17-53. Dr. Munafo’s explanation is corroborated by
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`documents showing communications from Serono to IVAX.
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`Serono and the assignee of Bodor (IVAX) entered into a joint research
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`agreement in October 2002 to develop oral cladribine for treating MS. Ex. 2048,
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`19-22; Ex. 2055, ¶14; Ex. 2054, ¶18; Ex. 2053, ¶23; Ex. 2056; Ex. 2057, 22, 137;
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`Ex. 2058. Under the agreement, IVAX would “develop an oral dosage formulation
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`of [cladribine] in tablet or capsule form suitable for use in clinical trials and
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`commercial sale.” Ex. 2048, 19. Serono agreed to “conduct clinical trials” to
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`determine “the dose, safety, and/or efficacy” of IVAX’s oral tablets or capsules,
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`“obtain necessary health authority approvals, and market the final product[.]” Id.,
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`2, 17-18.
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`Under this agreement, IVAX and Serono regularly and confidentially
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`exchanged substantial information about their work, including via emails and
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`meetings. Ex. 2054, ¶28; Ex. 2055, ¶¶15-18; Ex. 2053, ¶¶27-32; Ex. 2048. Those
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`emails and meetings included Dr. Dandiker, a named co-inventor of the Bodor
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`reference, and others at IVAX. Ex. 2053, ¶28-32; Ex. 2055, ¶15-18; Ex. 2049; Ex.
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`2050.
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`On December 17, 2003, Isabelle Emery of Serono emailed a Briefing
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`Document containing a clinical trial design invented by the Serono inventors,
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`including Drs. Munafo and Lopez-Bresnahan, disclosing the regimen in Bodor, to
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`Dr. Dandiker and IVAX. Ex. 2049; Ex. 2053, ¶¶29, 39-48; Ex. 2055, ¶¶18, 26.
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`This Briefing Document explained that Serono’s study would include three
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`treatment groups, who would receive either a high dose (2.1 mg/kg), a low dose
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`(0.7 mg/kg), or placebos. Ex. 2049, 47-48; Ex. 2053, ¶41; Ex. 2055, ¶26. Patients
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`receiving the low dose would receive daily 10 mg oral cladribine tablets for 5
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`consecutive days in each of the first 2 months. Ex. 2053, ¶¶43-46; Ex. 2055, ¶26.
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`At this rate, patients would have received the low dose over two months of dosing,
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`one-third as many months as the high dose which was three-times larger. Ex.
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`2053, ¶44; Ex. 2055, ¶26; Ex. 2049, 47-49. This is consistent with an August 2003
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`meeting in Amsterdam, where Dr. Lopez-Bresnahan explained to the IVAX team
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`that patients receiving the same low dose would receive oral cladribine for 5
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`consecutive days per month for 2 months. Ex. 2050, 4; Ex. 2053, ¶¶35-38.
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`Patients would receive another dose starting after month 12, leaving a 10-month
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`cladribine-free period after the first 2 months. Ex. 2049, 48-49; Ex. 2053, ¶¶45-46;
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`Ex. 2055, ¶26.
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`Although the Briefing Document says the “duration of treatment” was 6
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`months for all patients, that included placebos to keep the study “double blind.”
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`Ex. 2049, 47-49; Ex. 2053, ¶¶42-43. As Dr. Munafo explains, the low dose arm
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`(who received one-third the dose) had to receive 4 months of placebos to bring
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`their apparent treatment to 6 months, thus concealing which patients received
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`which doses, followed by 6 months with no “treatment.” Ex. 2053, ¶¶42-44; Ex.
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`2055, ¶26; Ex. 2050, 4; Ex. 2049, 47-49. Consequently, patients receiving the low
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`dose would be administered 5-days of cladribine for 2 months, followed by 4
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`months of placebos and another 6 months with no “treatment.” Ex. 2053, ¶¶43-44;
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`Ex. 2055, ¶26.
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`As Dr. Munafo further explains, Serono also communicated to the IVAX
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`team Serono’s alternative dosing regimen of daily oral cladribine tablets for 5 days
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`per month for 6-months followed by an 18-month cladribine-free period, which is
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`also disclosed in the Bodor PCT as an “alternative” regimen. Ex. 2053, ¶¶36-38,
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`51; Ex. 1022, 23:20-24.
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`As Dr. Munafo further explains, the Serono inventors’ “Study Design” was
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`in draft form, and they discussed with IVAX the possibility of adjusting certain
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`parameters, including dosing 10 mg oral cladribine tablets for 6 or 7 days per
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`month. Ex. 2053, ¶47. Thus, Serono communicated to IVAX the same dosing
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`regimen later disclosed in Bodor—daily 10 mg oral cladribine tablets for 5-7 days
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`per month for 2-months followed by a 10-month cladribine-free period. Ex. 2053,
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`¶53; Ex. 2049, 47-49.
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`Drs. Bodor and Dandiker corroborate that the cited regimen is attributable to
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`the Serono inventors. Drs. Munafo, Bodor, and Dandiker all confirm that IVAX
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`had a joint research agreement with Serono under which IVAX would develop an
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`oral cladribine formulation while Serono would design dosing regimens and
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`conduct clinical trials. Ex. 2053 ¶¶23-29; Ex. 2054, ¶¶18, 27; Ex. 2055, ¶¶14-18.
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`Drs. Bodor and Dandiker confirm that, consistent with the agreement, neither they
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`nor anyone else on their team at IVAX developed, researched, or invented any
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`cladribine dosing regimen for treating MS. Ex. 2054, ¶26; Ex. 2055, ¶23.6
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`Instead, Dr. Dandiker recalls receiving the August 2003 presentation and
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`December 2003 Briefing Document from Serono and believes the Serono inventors
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`disclosed the regimen disclosed in Bodor to him and others at IVAX. Ex. 2055,
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`¶¶16-18, 25-27. Dr. Bodor agrees it is “highly likely” the Serono inventors
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`communicated the dosing regimen in Bodor to IVAX in meetings and emails. Ex.
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`2054, ¶28. That Serono communicated Bodor’s regimen to IVAX is further
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`corroborated by the fact that before Serono disclosed its August 2003 presentation
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`and December 2003 Briefing Document to IVAX, Bodor’s first two provisional
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`applications, U.S. Nos. 60/458,922 (filed March 28, 2003) and 60/484,756 (filed
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`July 2, 2003), did not contain such dosing regimen; while after Serono’s
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`disclosures, Bodor’s third provisional application, U.S. No. 60/541,247 (filed
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`February 4, 2004), did contain this dosing regimen. Ex. 2044; Ex. 2045; Ex. 2046,
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`20:6-10.
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`6 Neither Dr. Bodor nor Dr. Dandiker was aware of the two IVAX provisional
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`applications cited in Bodor, both of which were later abandoned. Ex. 1022, 23:24-
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`29; Ex. 2055, ¶20; Ex. 2054, ¶22; Ex. 2047, 10-12.
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