UNITED STATES PATENT AND TRADEMARK OFFICE
`
`______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
`
`
`APOTEX INC., APOTEX CORP., ARGENTUM PHARMACEUTICALS LLC,
`ACTAVIS ELIZABETH LLC, TEVA PHARMACEUTICALS USA, INC., SUN
`PHARMACEUTICAL INDUSTRIES, LTD., SUN PHARMACEUTICAL
`INDUSTRIES, INC., and SUN PHARMA GLOBAL FZE,
`
`Petitioners,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`______________________
`
`Case IPR2017-008541
`
`U.S. Patent No. 9,187,405
`______________________
`
`
`NOVARTIS AG’S PATENT OWNER RESPONSE
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
` 1 Cases IPR2017-01550, IPR2017-01946, and IPR2017-01929 have been joined
`with this proceeding.
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`PRELIMINARY STATTEMENT .......................................................................... 1
`
`FACTS ....................................................................................................................... 6
`A. RRMS ................................................................................................................. 7
`B. Fingolimod Research as of June 2006 ............................................................. 8
`1. PK/PD Studies ................................................................................................. 9
`(i)
`Budde ............................................................................................................ 9
`(ii) Kahan 2003 ................................................................................................ 10
`(iii) Park 2003 and 2005 .................................................................................... 12
`2. RRMS Model Studies .................................................................................... 15
`(i) Webb .......................................................................................................... 16
`(ii) Kataoka ....................................................................................................... 19
`3. Phase II Clinical Trial .................................................................................... 20
`C. The Invention and Patent ............................................................................... 20
`D. The Phase III Trials ........................................................................................ 25
`E. These Proceedings ........................................................................................... 28
`
`ARGUMENT .......................................................................................................... 31
`I. The PTO Correctly Awarded the ’405 Patent
`for an Inventive Method of Treating RRMS ................................................ 31
`A. The Discovery Here Was Contrary to the
`Prior Art, Produced Unexpected Results,
`and Defied Skepticism in the Field ...................................................................... 33
`1.
`Teaching Away .......................................................................................... 33
`
`
`
`i
`
`
`
`

`

`Unexpected Results .................................................................................... 39
`2.
`Skepticism .................................................................................................. 40
`3.
`B. The Petitions Fail to State
`Even a Threshold Case ......................................................................................... 41
`1. Hindsight Bias Infects All of Dr. Giesser’s Testimony ................................. 42
`2. Dr. Giesser Lacks Pharmacological Competence ......................................... 44
`C. The Ground 1 References Flunk Virtually Every
`Major Obviousness Requirement ......................................................................... 46
`D. The Ground 2 References Similarly
`Lack the Major Obviousness Elements ................................................................ 55
`II. Ground 3 Is Beyond the Scope of an IPR
`and Based on a Flawed Assumption .............................................................. 57
`A. Ground 3 Is a 112 Argument
`Prohibited in an IPR ....................................................................................... 57
`B. The Specification Amply Supports the
`Claims’ Exclusion of Loading Doses ............................................................. 61
`
`CONCLUSION ....................................................................................................... 64
`
`
`
`
`
`ii
`
`
`
`

`

`TABLE OF AUTHORITIES
`
`Page(s)
`
`Cases
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 (Fed. Cir. 2015) .................................................................... 33, 34
`AstraZeneca AB v. Aurobindo Pharma LTD, et al.,
`232 F. Supp. 3d 636 (D. Del. 2017) .............................................................. 42, 43
`Avanir Pharm., Inc. v. Actavis S. Atl. LLC,
`36 F. Supp. 3d 475 (D. Del. 2014), aff’d sub nom. Avanir Pharm.
`Inc. v. Par Pharm. Inc., 612 F. App’x 613 (Fed. Cir. 2015) .............................. 40
`Belden, Inc. v. Berk-tek LLC,
`805 F.3d 1064 (Fed. Cir. 2015) .......................................................................... 44
`Bioactive Labs. v. BTG Int’l Inc.,
`IPR2015-01305, Paper 19 (PTAB Dec. 15, 2015) ............................................. 59
`Captioncall, L.L.C. v. Ultratec, Inc.,
`IPR2015-00636, Paper 97 (PTAB Sept. 7, 2016) ............................................... 44
`
`Coalition for Affordable Drugs (ADROCA) LLC v. Acorda
`Therapeutics, Inc.,
`IPR2015-01859, -01853, -01857, -01858, Paper 72 (PTAB Mar. 9,
`2017) ................................................................................................................... 61
`Coalition for Affordable Drugs V LLC, et. al. v. Biogen MA, Inc.,
`IPR2015-01993, Paper 63 (PTAB Mar. 21, 2017) ................................. 32, 33, 39
`Crown Operations Int’l, Ltd. v. Solutia Inc.,
`289 F.3d 1367 (Fed. Cir. 2002) .......................................................................... 47
`Cuozzo Speed Techs., LLC v. Lee,
`136 S. Ct. 2131 (2016) ........................................................................................ 58
`In re Cyclobenzaprine,
`676 F.3d 1063 (Fed. Circ. 2012) ......................................................................... 54
`Dexcowin Glob., Inc.,
`IPR2016-00436, 2016 WL 5219873 (PTAB July 7, 2016) ................................ 58
`
`
`
`iii
`
`
`
`

`

`Dr. Reddy’s Labs., Ltd. v. Galderma Labs., Inc.,
`IPR2015-01778, 2016 WL 1082772 (PTAB Feb. 16, 2016) ............................. 59
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 39
`Ex Parte Gary B. Goldman¸
`APPEAL 2013-007593, 2015 WL 5530202 (PTAB Sept. 17, 2015) ................ 62
`Genetics Inst., LLC v. Novartis Vaccines & Diagnostics, Inc.,
`655 F.3d 1291 (Fed. Cir. 2011) .......................................................................... 38
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) .......................................................................................... 31, 32
`In re Gurley,
`27 F.3d 551 (Fed. Circ. 1994) ............................................................................. 33
`Hitkansut LLC v. United States,
`130 Fed. Cl. 353 (2017) ...................................................................................... 48
`Inphi Corp. v. Netlist, Inc.,
`805 F.3d 1350 (Fed. Cir. 2015) .......................................................................... 61
`Keene Corp. v. United States,
`508 U.S. 200 (1993) ............................................................................................ 58
`Ex Parte Kotrla,
`APPEAL 2014-009348, 2016 WL 5846792 (PTAB Sept. 28, 2016) ................ 47
`Lucent Techs. Inc. v. Gateway, Inc.,
`No. 02CV2060-B(CAB), 2007 WL 1449804 (S.D. Cal. May 15,
`2007) ................................................................................................................... 46
`In re Magnum Oil Tools Int’l, Ltd.,
`829 F.3d 1364 (Fed. Cir. 2016) .......................................................................... 31
`Mayfield v. Nicholson,
`499 F.3d 1317 (Fed. Cir. 2007) .......................................................................... 59
`Medichem, S.A. v. Rolabo, S.L.,
`437 F.3d 1157 (Fed. Cir. 2006) .................................................................... 33, 37
`
`
`
`iv
`
`
`
`

`

`Medtronic, Inc. v. Lifeport Sci. LLC,
`IPR2014-00288, Paper 34 (PTAB Apr. 21, 2015) ............................................. 44
`Mintz v. Dietz & Watson, Inc.,
`679 F.3d 1372 (Fed. Cir. 2012) .................................................................... 46, 48
`Monarch Knitting Machinery Corp. v. Sulzer Morat GmbH,
`139 F.3d 877 (Fed. Cir. 1998) ............................................................................ 47
`In re NTP, Inc.,
`654 F.3d 1268 (Fed. Cir. 2011) .................................................................... 59, 60
`Ortho McNeil Pharm., Inc. v. Barr Labs., Inc.,
`No. CIV.A.03-4678SRC, 2009 WL 2182665 (D.N.J. July 22,
`2009) ................................................................................................................... 38
`Panduit Corp. v. Dennison Mfg. Co.,
`810 F.2d 1561 (Fed. Cir. 1987) .......................................................................... 50
`PAR Pharm., Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) .......................................................................... 49
`Ex Parte Parks,
`30 U.S.P.Q.2d 1234 (P.T.O. Sept. 2, 1993) ........................................................ 61
`Smart Modular Techs. Inc. v. Netlist, Inc.,
`IPR2014-01373, 2015 WL 1224514 (PTAB Mar. 13, 2015) ............................. 58
`Spoilage Cutter Co. v. World Kitchen,
`LLC, No. 08-C-1263, 2010 WL 3365863 (N.D. Ill. Aug. 19, 2010) ................. 48
`Standard Mfg. Co. v. United States,
`25 Cl. Ct. 1 (1991) .............................................................................................. 47
`In re Stepan Company,
`868 F.3d 1342 (Fed Cir. 2017) ............................................................... 32, 52, 53
`Teva Pharm. USA, Inc. v. Sandoz, Inc.,
`876 F. Supp. 2d 295 (S.D.N.Y. 2012), aff’d in part, rev’d in part,
`723 F.3d 1363 (Fed. Cir. 2013), vacated, 135 S. Ct. 831 (2015) ....................... 34
`
`
`
`v
`
`
`
`

`

`Transocean Offshore Deepwater Drilling, Inc. v. Maersk Drilling
`USA, Inc.,
`699 F.3d 1340 (Fed. Cir. 2012) .......................................................................... 41
`Union Oil Co. of Cal. v. Atlantic Richfield Co.,
`208 F.3d 989 (Fed. Cir. 2000) ............................................................................ 61
`United States v. Jones,
`846 F.3d 366 (D.C. Cir. 2017) ............................................................................ 58
`Warner Chilcott Labs. Ireland Ltd. v. Impax Labs., Inc.,
`No. 2:08-CV-06304 WJM, 2012 WL 1551709 (D.N.J. Apr. 30,
`2012), aff’d, 478 F. App’x 672 (Fed. Cir. 2012) ................................................ 43
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016) .......................................................................... 41
`Widdoss v. Sec’y of Dep’t of Health & Human Servs.,
`989 F.2d 1170 (Fed. Cir. 1993) .......................................................................... 59
`XpertUniverse, Inc. v. Cisco Sys., Inc.,
`No. CIV.A. 09-157-RGA, 2013 WL 865974 (D. Del. Mar. 7, 2013) ................ 46
`Statutes
`35 U.S.C. § 112 ............................................................................................ 57, 58, 59
`35 U.S.C. § 301 ........................................................................................................ 60
`35 U.S.C. § 311(b) ................................................................................................... 57
`35 U.S.C. § 321(b) ................................................................................................... 58
`Other Authorities
`157 Cong. Rec. S1375 (statement of Sen. Kyl) ....................................................... 60
`MPEP § 2103 ........................................................................................................... 48
`
`
`
`vi
`
`
`
`

`

`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`PRELIMINARY STATEMENT
`Novartis scientists Peter Hiestand and Christian Schnell discovered how to
`
`use fingolimod at less than half the dose the prior art taught was possible to help
`
`patients with relapsing-remitting multiple sclerosis (RRMS). The U.S. Patent and
`
`Trademark Office was right to award U.S. Pat. No. 9,187,405 for their discovery.
`
`To invalidate the ’405 Patent would erode innovators’ incentive to seek out the vital
`
`medical discoveries patients need.
`
`Fingolimod is a potent immuno-modulator discovered in the 1990s. Scientists
`
`generally thought fingolimod worked by disrupting chemical signals that trigger
`
`lymphocyte autoimmune cells to enter the blood stream. The resulting drop in
`
`circulating lymphocytes was believed to protect against organ transplant rejection
`
`and autoimmune diseases. RRMS was one such disease, in which the victim’s
`
`immune system attacks her central nervous system (CNS).
`
`But in prior studies, only high levels of lymphocyte suppression correlated
`
`with clinical benefit. A team from pharmaceutical giant Merck had found that “a
`
`threshold of about 70% depletion of peripheral lymphocytes was required to see any
`
`efficacy” in an established RRMS model. (Ex. 2014, “Webb.”) That jibed with
`
`similar results in organ transplant studies, which showed that 80% suppression was
`
`needed for clinical efficacy. Lesser suppression did not work. Other studies showed
`
`
`
`1
`
`
`
`

`

`
`that only 1.0 mg daily or higher could suppress human lymphocytes to 70% or more.
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`Lower doses could not, and thus would lack “any efficacy.”
`
`Hiestand and Schnell had a different idea. They focused on later disease
`
`stages than others in the art and used a novel biomarker—“angiogenesis,” new blood
`
`vessel growth—to measure efficacy. They found the prior art used doses more than
`
`double what was needed. Novartis filed for a patent on their discovery in June 2006,
`
`and the Office ultimately awarded claims to a 0.5 mg daily dose. Novartis’s
`
`Gilenya® brand RRMS medication now uses that dose.
`
`Petitioners are generic drug makers that complain the Office was wrong to
`
`award the ’405 Patent. They assemble two groups of references that supposedly
`
`would have made a 0.5 mg daily dose obvious to a person of skill in June 2006.
`
`Petitioners argue also that an alleged written description issue opens the door to an
`
`anticipation challenge based on a reference from June 2010, years after the filing
`
`date. None of these arguments withstand review.
`
`Obviousness Grounds 1 and 2 fail in the face of prior art teaching away
`
`from the invention, skepticism by those in the field, and the invention’s unexpected
`
`results. Prior art studies showed that only doses 1.0 mg or higher could suppress
`
`lymphocytes enough to have “any efficacy” for RRMS.
`
`
`
`2
`
`
`
`
`
`
`
`
`
`

`

`
`When those trials nonetheless showed that 0.5 mg was as effective as a dose more
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`than double in size, it was a complete surprise. These facts alone are fatal for the
`
`Petitions.
`
`Petitioners fail to establish even a prima facie case. Their submission relies
`
`entirely on the opinion of Dr. Barbara Giesser, an MS physician. But Dr. Giesser
`
`limited her review of the prior art solely to the references counsel gave her, virtually
`
`the definition of an unlawful, hindsight-driven methodology. Dr. Giesser is also not
`
`a pharmacologist and thus is incapable of providing the perspective of a complete
`
`person of skill as defined by the Board in the Institution Decision. Dr. Giesser indeed
`
`made multiple elementary errors that betray her unfamiliarity with pharmacological
`
`principles. These failings render her opinion incapable of providing the evidentiary
`
`foundation for even a prima facie showing.
`
`If Dr. Giesser’s declaration were to be considered, the manner in which she
`
`formed her opinions is a tacit admission that Petitioners’ theories are fatally
`
`inconsistent with the prior art. For instance, counsel conveniently never gave Dr.
`
`Giesser a key Merck study showing that only 70% or greater suppression provided
`
`“any efficacy”—even though that paper is one of the few listed on the Patent’s very
`
`first page. For the references she did review, Dr. Giesser could not say she read
`
`them in their entirety. It seems she just blessed the inclusion of selected quotations
`
`in her declaration rather than conduct a full review of the art. That may explain why
`
`
`
`3
`
`
`
`

`

`
`the references on which the Petition relies for both obviousness grounds are so
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`thoroughly off-point.
`
`First, in Ground 1, “Kovarik” (Ex. 1004) is a 2004 patent application claiming
`
`a “loading dose” regimen for drugs like fingolimod. A loading dose is a higher dose
`
`given before standard maintenance doses. The ’405 Patent’s claims expressly
`
`exclude loading doses, which Dr. Giesser agrees were known not to be used with
`
`MS drugs anyway. Kovarik is thus inapposite.
`
`Petitioners appear to have seized on Kovarik because the reference came up
`
`in prosecution. But Examiners flag references in prosecution using a hindsight-
`
`driven process different from what the law demands when reviewing an issued
`
`patent. Petitioners employ this same hindsight, and strain to make Kovarik relevant
`
`only by violating the requirement to read references as a whole.
`
`Regardless, even if Kovarik had been on the radar, a person of skill would
`
`have paid it no mind. Kovarik describes loading dose formulas for use with any
`
`given “standard daily dose.” Kovarik itself says nothing about what the daily doses
`
`should be—they are purely inputs used to calculate a loading dose. Insofar as
`
`Kovarik mentions daily dose ranges, they are hypothetical numbers used solely for
`
`illustrative purposes. One hypothetical range from 0.1 to 0.5 mg daily is for an
`
`unspecified autoimmune disease, but that would mean nothing to a researcher
`
`designing an actual daily dose for real RRMS patients.
`
`
`
`4
`
`
`
`

`

`The other Ground 1 reference, Thomson (Ex. 1005), reviewed fingolimod’s
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`
`
`potential application to RRMS as of early 2006. Thomson says the lowest dose that
`
`had been tested in humans for MS as of June 2006 was 1.25 mg, more than twice the
`
`0.5 mg daily dose the inventors here discovered—and well above the 1.0 mg daily
`
`the prior art taught was needed for “any efficacy.” Nothing in Thomson even
`
`suggested that a dose lower than 1.25 mg daily should be explored, much less have
`
`the same efficacy.
`
`Second, in Ground 2, “Kappos 2005” (Ex. 1007) described the Phase II MS
`
`clinical trial of two doses, 1.25 mg and 5.0 mg daily. Researchers were surprised
`
`those two doses were similarly effective. Nevertheless, that result was still in line
`
`with the prior art showing that daily doses below 1.0 mg would lack “any efficacy”—
`
`the trial’s lowest dose was 1.25 mg, 25% higher than 1.0 mg. The other two
`
`references are even less pertinent. “Budde” (Ex. 1008) was just a single-dose safety
`
`study in renal transplant patients. It would have had little relevance to finding a
`
`regular daily dose for RRMS. And the 1999 “Chiba” patent (Ex. 1006) merely
`
`described how fingolimod suppresses lymphocyte blood levels, along with a
`
`thousand-fold dose range that might induce that effect.
`
`Ground 3 is not an obviousness attack, but an anticipation theory predicated
`
`on a 112 argument. Petitioners say the specification does not support the claims’
`
`exclusion of loading doses—an alleged written description violation—which
`
`
`
`5
`
`
`
`

`

`
`supposedly renders the claims anticipated by a June 2010 reference. The America
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`Invents Act (AIA), however, restricts IPRs “only” to 102 and 103 challenges based
`
`“only” on written publications. The AIA thus bars challenges like Ground 3 based
`
`also on 112 arguments. Novartis respectfully disagrees with the Board’s decision to
`
`permit this Ground to proceed and preserves its position below.
`
`This Ground also fails for lack of proof. Petitioners and Dr. Giesser offer no
`
`analysis or reasoning to show that a person of skill would read the specification as
`
`they say; they just assume their view is right without any evidence whatsoever. But
`
`the specification expressly identifies a 0.5 mg “daily” dose as the complete dosing
`
`regimen, nowhere prescribing anything else . No one in the field would propound a
`
`dosing regimen for treating RRMS patients that was intended to include a loading
`
`dose without saying so expressly. Loading doses carry the risk of overdose. There
`
`is no basis for Petitioners’ assertions about the Patent specification.
`
`The Board should deny the Petition in its entirety.
`
`FACTS
`Novartis’s marshaled evidence includes comprehensive declarations from
`
`Drs. Lawrence Steinman (Ex. 2022), an MS physician, researcher, and member of
`
`the National Academy of Sciences (id. ¶¶ 1, 12-22); Fred Lublin (Ex. 2025), a
`
`physician and MS clinical trial expert who was involved with fingolimod’s Phase II
`
`
`
`6
`
`
`
`

`

`
`and III trials (id. ¶¶ 1-2, 9-15); and William Jusko (Ex. 2024), a pharmacologist
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`experienced with fingolimod (id. ¶¶ 1-4).
`
`A. RRMS
`
`Multiple sclerosis (MS) is a terrible disease that strikes patients in the prime
`
`of life with debilitating symptoms. RRMS is the most common form. It manifests
`
`over years with “clearly defined disease relapses with full recovery or with sequelae
`
`and residual deficit upon recovery.” (Thomson, Ex. 1005 at 159; see also Steinman
`
`Dec., Ex. 2022 ¶¶ 23-25, 29.) Patients vary widely in relapse frequency, symptoms,
`
`and recovery. Symptoms “can include tremor, paralysis, loss of bladder or bowel
`
`control, fatigue, pain, loss of cognitive function, disturbances in vision and speech,
`
`emotional changes, and nystagmus.” Understandably, “[t]hese symptoms can have
`
`a profound effect on patients’ quality of life and can also lead to significant reliance
`
`on their family, dependents, and care[e]rs.” (Thomson, Ex. 1005 at 158; see also
`
`Steinman Dec., Ex. 2022 ¶¶ 24, 30-31.) RRMS’s initial cause is unknown, but the
`
`disease progresses when immune system lymphocytes infiltrate the CNS, causing
`
`inflammation and stripping the protective myelin sheathing from nerve cells. Over
`
`time, this process degrades the CNS. RRMS drugs in June 2006 included symptom-
`
`management and disease-modifying therapies (DMTs). Symptom therapies
`
`included drugs like steroids to alleviate relapse inflammation. DMTs included drugs
`
`
`
`7
`
`
`
`

`

`
`like interferon-beta that reduced relapse frequency, or natalizumab that could slow
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`disease progression. (Steinman Dec., Ex. 2022 ¶¶ 26-28, 33-38, 69.))
`
`B.
`
`Fingolimod Research as of June 2006
`
`Scientists discovered fingolimod—also called “FTY720,” or just “FTY”—in
`
`the 1990s. (Steinman Dec., Ex. 2022 ¶¶ 4, 39; Jusko Dec., Ex. 2024 ¶ 115.)
`
`In 1998, scientists reported on a mechanism by which fingolimod suppresses
`
`the immune system, as claimed in the “Chiba” patent (Ex. 1006): “the compound
`
`FTY720 … directs lymphocytes to the peripheral lymph nodes, mesenteric lymph
`
`nodes, and Peyer’s patches.” (Id. at 1; see also Steinman Dec., Ex. 2022 ¶¶ 40-41;
`
`Jusko Dec., Ex. 2024 ¶¶ 37-44; Thomson, Ex. 1005 at 162; Dumont, Ex. 1018 at
`
`238.)
`
`Early animal data showed that higher amounts of fingolimod tended to
`
`suppress more lymphocytes and produce better therapeutic results. (See Steinman
`
`Dec., Ex. 2022 ¶¶ 42-46.) Some animal data even suggested that maximal
`
`lymphocyte suppression was not always enough to provide a therapeutic effect. (See
`
`Jusko Dec., Ex. 2024 ¶¶ 83-92 (discussing his own research in Exs. 2046 and 2055).)
`
`As Dr. Jusko shows, fingolimod was a “perplexing” molecule that is not fully
`
`understood to this day. Among its complexities are that is a pro-drug active only in
`
`a metabolized, phosphorylated state, and that the phosphorylated form interacts with
`
`tissue distributed throughout the body. (Id. ¶¶ 37-44; Steinman Dec., Ex. 2022 ¶ 46.)
`
`
`
`8
`
`
`
`

`

`
`
`1.
`
`PK/PD Studies
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`Researchers first explored fingolimod as a medicine to prevent organ
`
`transplant rejection. Three transplant studies—Budde, Kahan 2003, and the Park
`
`papers—reported human pharmacokinetic (PK) data on how the body processes the
`
`drug, and pharmacodynamic (PD) data on how the drug affects the body.
`
`Researchers believed these PK/PD data offered insight about the drug’s behavior not
`
`only in the transplant context but also for “patients with multiple sclerosis.”
`
`(Thomson, Ex. 1005 at 162; see also Steinman Dec., Ex. 2022 ¶¶ 47-49; Jusko Dec.,
`
`Ex. 2024 ¶¶ 33, 49-64, 75; Lublin Dec., Ex. 2025 32-34; Kovarik 2004a, Ex. 2045;
`
`Dr. Giesser agrees in her declaration. (Ex. 1002 ¶ 84.)
`
`
`
`
`
`(i)
`
`Budde
`
`Budde measured “safety, single-dose pharmacokinetics, and pharmaco-
`
`dynamics in stable renal transplant patients—the first human use of FTY720.” (Ex.
`
`1008 at 1073; see also Steinman Dec., Ex. 2022 ¶ 50; Jusko Dec., Ex. 2024 ¶¶ 49-
`
`53.)
`
`Investigators administered escalating single doses of 0.25, 0.5, 0.75, 1.0, 2.0,
`
`or 3.5 mg. Among other data, Budde reported peripheral blood lymphocyte counts
`
`at each dose. All doses reduced lymphocytes to some degree, a response the paper
`
`called “lymphopenia.” But the small, single-dose study was unable to show a
`
`significant link between dose and lymphocyte suppression. It could only identify
`
`
`
`9
`
`
`
`

`

`
`“[a] trend of increased lymphopenia with increasing doses … in 8 patients who
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`reenrolled during the course of the study and receiving a higher dose during their
`
`second treatment period.” (Ex. 1008 at 1080; see also Steinman Dec., Ex. 2022 ¶¶
`
`51-53.)
`
`Some of Budde’s authors wrote another paper elaborating on their results.
`
`There, the authors cautioned that “repeated administration of FTY may have
`
`different effects compared with those observed in the present single-dose study.”
`
`(Boehler 2004, Ex. 2028 at 712; see also Steinman Dec., Ex. 2022 ¶ 54.) They were
`
`right.
`
`
`
`
`
`(ii) Kahan 2003
`
`Kahan 2003 “extended the single-exposure study by using multiple doses of
`
`FTY720 administered to [65] stable renal transplant patients.” Researchers
`
`“examined the safety, pharmacodynamics, and pharmacokinetics” for escalating
`
`doses of 0.125, 0.25, 0.5, 1.0, 2.5, and 5.0 mg or placebo administered over 28 days.
`
`(Ex. 1031 at 1079; see also Steinman Dec., Ex. 2022 ¶ 55.)
`
`Kahan 2003 reported that fingolimod “doses greater than or equal to 1.0
`
`mg/day produced a significant reduction in peripheral blood lymphocyte count by
`
`up to 85%,” with no “major increase in adverse events or a change in renal function”
`
`as compared to placebo. (Id.) Doses less than 1.0 mg/day produced materially lower
`
`
`
`10
`
`
`
`

`

`
`reductions in peripheral lymphocyte blood counts. (Id. at 1081-82; see also
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`Steinman Dec., Ex. 2022 ¶ 56.)
`
`Figure 1 below shows how much each dose suppressed lymphocytes over 28
`
`days. (Id. at 1081.) As emphasized by the notations, 0.5 mg daily produced about
`
`50% lymphocyte suppression, whereas 1.0 mg daily produced about 70%
`
`suppression. (See Steinman Dec., Ex. 2022 ¶ 57; Jusko Dec., Ex. 2024 ¶ 56.)
`
`
`
`Thus, unlike Budde, Kahan 2003 was able to show that the extent of
`
`lymphocyte suppression over 28 days depended on daily dose. Higher doses yielded
`
`more suppression, and only doses 1.0 mg or higher consistently suppressed
`
`
`
`11
`
`
`
`

`

`
`lymphocytes by 70% or more. (See Steinman Dec., Ex. 2022 ¶¶ 55-57; Jusko Dec.,
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`Ex. 2024 ¶¶ 54-57.)
`
`
`
`
`
`(iii) Park 2003 and 2005
`
`Another multi-dose renal transplant study showed similar results, as reported
`
`in Park 2003 (Ex. 2048) and 2005 (Ex. 1019). Park 2005 showed also that lower
`
`doses failed to provide a consistent response among patients. (Steinman Dec., Ex.
`
`2022 ¶ 58.)
`
`The Park team studied 23 patients at doses ranging from 0.25 to 2.5 mg/day
`
`for 12 weeks. (Park 2003, Ex. 2048 at 333; Steinman Dec., Ex. 2022 ¶ 59.) Park
`
`2005 reported that fingolimod “produced a dose-dependent increase in mean percent
`
`reduction of peripheral lymphocyte counts[.]” (Ex. 1019 at 683; Steinman Dec., Ex.
`
`2022 ¶ 61.) Figure 7A illustrates that finding. (Id. at 690.) It shows by how much
`
`different doses suppressed lymphocytes on average in each of 7 or 8 patients over
`
`12 weeks:
`
`
`
`12
`
`
`
`

`

`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`
`The Figure shows 0.5 mg suppressed lymphocytes from patient baselines by
`
`almost 20% to almost 60%; 1.0 mg from 40% and 70%; and 2.5 mg from 70% and
`
`80%. Dose thus correlated not only with average suppression but also with inter-
`
`patient variation. Lower doses had greater variation than higher doses. (See
`
`Steinman Dec., Ex. 2022 ¶¶ 140-41; Jusko Dec., Ex. 2024 ¶¶ 60-61.)
`
`As Figure 7A shows also, the researchers concluded that about 0.5 mg (0.48
`
`mg +/- 0.08) was the “EC50,” the level that reduced average lymphocyte counts by
`
`half the maximum possible. That maximum was about 88% (Emax = 87.8% +/-
`
`5.3%); so 0.5 mg was calculated to suppress lymphocytes on average by about 44%.
`
`(See Steinman Dec., Ex. 2022 ¶¶ 59, 62-64; Jusko Dec., Ex. 2024 ¶¶ 60-63.)
`
`When the Park team published their work, Phase II clinical trials for transplant
`
`rejection had been completed. Those trials showed that doses of 2.5 or 5.0 mg daily
`
`were effective, but that 1.0 mg daily or lower was ineffective as compared to the
`
`
`
`13
`
`
`
`

`

`
`existing treatment option. (Budde 2006, Ex. 2030 at 21 (doses of 1.0 mg daily and
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`lower were worse than standard of care, but 2.5 mg daily doses and higher were
`
`better).) Park 2003 thus observed that, “[s]ince … effective doses of FTY720 are
`
`2.5 and 5 mg/day, the immunosuppressive effect of FTY720 may depend upon
`
`induction of high degree of lymphopenia (~80%).” (Ex. 2048 at 333.) Park 2005
`
`repeated the same observation, as did others in the art. (Park 2005, Ex. 1019 at 683;
`
`Dumont, Ex. 1018 at 241; see also Steinman Dec., Ex. 2022 ¶¶ 60-61, 65-66; Jusko
`
`Dec., Ex. 2024 ¶¶ 8, 60.)
`
`The need for a minimum amount of lymphocyte suppression to produce a
`
`clinical effect would have made medical sense to a person of skill. Insofar as normal
`
`lymphocyte counts were associated with effects like organ rejection, then reducing
`
`absolute counts below normal human ranges might alleviate those effects. Only
`
`substantial proportional suppression could consistently reduce absolute lymphocyte
`
`counts in a patient population below normal human ranges. Lesser suppression that
`
`left absolute counts within normal overall human ranges for a substantial number of
`
`patients would not be expected to have that net therapeutic effect. (Steinman Dec.,
`
`Ex. 2022 ¶ 65 (citing Merck Guide, Ex. 2054 for “normal lymphocyte count in
`
`adults”).)
`
`
`
`
`
`
`
`
`
`14
`
`
`
`

`

`
`
`2.
`
`RRMS Model Studies
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`Papers in June 2006 also reported on tests in MS-specific animal models,
`
`called “experimental autoimmune encephalomyelitis” or “EAE” systems. These are
`
`“the most widely used animal models of multiple sclerosis mimicking a number of
`
`pathologic characteristics of the disease.” (Thomson, Ex. 1005 at 162; see also
`
`Steinman Dec., Ex. 2022 ¶¶ 67-68; Jusko Dec., Ex. 2024 ¶¶ 65-67.)
`
`EAE models begin with injecting rodents with proteins from other rodents’
`
`nervous systems. That triggers the recipient’s immune system to attack those
`
`proteins, including in its own nervous system. An MS-like condition follows, and
`
`drugs can then be tested in the EAE animals. (Steinman Dec., Ex. 2022 ¶¶