`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`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
`______________________
`PATENT OWNER NOVARTIS’S CORRECTED ORAL HEARING
`DEMONSTRATIVES
`
`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.
`
`
`
`
`
`Apotex Inc., et al.
`Petitioners
`v.
`Novartis AG.
`Patent Owner
`
`Case IPR2017‐008541
`Patent US 9,187,405
`
`_______________________________________________________________
`
`Patent Owner’s Demonstrative Exhibits
`May 11, 2018
`
`1 Cases IPR2017‐01550, IPR2017‐01946, and IPR2017‐01929 have been joined
`with this proceeding.
`
`
`
`Introduction
`
` Prior animal and human studies showed 1.0 mg and higher
`needed for any efficacy in humans. 1
` Novel EAE experiments revealed new biomarker and that
`much lower doses could treat RRMS.2
` MS physicians and at least one MS treatment hospital
`doubted 0.5 mg would have efficacy. 3
` In Phase III trials, 0.5 mg surprisingly had efficacy in RRMS,
`unexpectedly reaching as much efficacy as 1.25 mg. 4
` ’405 Patent claims 0.5 mg fingolimod daily to treat aspects of
`RRMS. 5
` Hindsight by Petitioners’ less qualified experts cannot
`outweigh copious contemporaneous evidence. 6
`
`1 Paper 26 at 1‐2, 11‐12, 39; 2 Id. at 20‐25; 3 Id. at 25‐27, 40‐41;
`4 Id. at 3, 25‐27; 5 Ex. 1001, cls. 1‐6 ; 6 Paper 26 at 42‐46; Paper 63 at 12‐14.
`
`2
`
`
`
`U.S. Patent No. 9,187,405
`
` U.S. Patent No. 9,187,405
`
`The ’405 Patent
`
`The ’405 Patent
`
`3
`
`
`
`Representative Claims of the ’405 Patent
`
`Ex. 1001 at cls. 1‐2.
`
`4
`
`
`
`Inventors Discovered New Efficacy Biomarker
`
`•
`
`“…the inventors were able to show…that the inhibition of angiogenesis
`was positively correlated with clinical efficacy in EAE.” Dr. Steinman, Ex.
`2022 at ¶107.
`
`Ex. 2026 at 24; Ex. 2057 at 16; Ex. 2022 (Dr. Steinman) at ¶¶ 101‐108; Ex. 2024 (Dr. Jusko) at ¶¶ 101‐107.
`
`5
`
`
`
`Inventors’ New Focus on Relapse Stage of MS
`
`“[I]f [the inventors] had focused on the first attack like
`the authors in Webb and other EAE studies, they too
`may not have discovered that such low doses had a
`clinical effect. That shift in perspective appears to
`underpin the invention here.” (Dr. Steinman, Ex. 2022
`at ¶ 96.)
`
`“The inventors’ insight in focusing on
`later relapses in the assessment of
`whether a dose could be useful
`translates directly into how MS
`medicines are actually used.” (Dr.
`Steinman, Ex. 2022 at ¶ 103.)
`
`Ex. 2026 at 23; Ex. 2057 at 14; and Ex. 2022 (Dr. Steinman) at ¶¶101‐108; Dr. Jusko, Ex. 2024, ¶¶101‐107.
`
`6
`
`
`
`Unexpected Results in EAE Animal Model of MS
`
`Ex. 1001 at 10:33‐11:2; Paper 26 at 20.
`
`7
`
`
`
`Person of Ordinary Skill in the Art
`
`Person of Ordinary
`Skill in the Art
`
`8
`
`
`
`POSA Definition
`
`Paper 11 (Institution Decision) at 9; Paper 26 at 44; Paper 63 at 2.
`
`9
`
`
`
`Patent Owner’s Experts Eminently Qualified
`Dr. Lawrence Steinman 1
`‐ M.D. Physician / MS researcher
`‐ Professor, Stanford University,
`Chair of Interdepartmental
`Program in Immunology
`‐ Helped discovery MS medicine
`Tysabri®
`‐ Designs and studies MS
`medicines “bench to bedside”
`‐ Extensive experience
`interpreting EAE animal model
`data in the context of MS drug
`development
`
`1 Ex. 2022 (Dr. Steinman) ¶¶ 12‐21; Ex. 2023 (Steinman CV); Paper 26 at 6. 2 Ex. 2005 (Dr. Jusko) ¶¶ 7‐13; Ex. 2006 (Jusko
`CV); Ex. 2024 (2nd Jusko) ¶ 40; Paper 26 at 7. 3 Ex. 2003 (Dr. Lublin) ¶¶ 8‐17; Ex. 2004 (Lublin CV); Paper 26 at 6‐7.
`10
`
`
`
`Patent Owner’s Experts Eminently Qualified
`Dr. William Jusko 2
`‐ Ph.D., Pharmacologist
`‐ Distinguished Professor,
`State University of New York
`at Buffalo, New York
`‐ Experienced with
`immunosuppressants
`‐ Extensive experience with
`pharmacology of fingolimod,
`PK/PD
`‐ Published papers on
`pharmacology of fingolimod
`in rats and monkeys
`
`1 Ex. 2022 (Dr. Steinman) ¶¶ 12‐21; Ex. 2023 (Steinman CV); Paper 26 at 6. 2 Ex. 2005 (Dr. Jusko) ¶¶ 7‐13; Ex. 2006 (Jusko
`CV); Ex. 2024 (2nd Jusko) ¶ 40; Paper 26 at 7. 3 Ex. 2003 (Dr. Lublin) ¶¶ 8‐17; Ex. 2004 (Lublin CV); Paper 26 at 6‐7.
`11
`
`
`
`‐
`
`Patent Owner’s Experts Eminently Qualified
`Dr. Fred Lublin 3
`‐ M.D., MS Physician
`‐ Professor of Neurology and
`Director of Center for MS at
`Icahn School of Medicine, Mt.
`Sinai, New York
`First‐hand experience in
`determining doses in MS clinical
`trials
`‐ Member of Clinical Trial
`Advisory Board, DSMB, and
`Principal Investigator for
`fingolimod trials
`‐ Principal or Co‐Investigator for
`clinical trials related to many MS
`medicines
`1 Ex. 2022 (Dr. Steinman) ¶¶ 12‐21; Ex. 2023 (Steinman CV); Paper 26 at 6. 2 Ex. 2005 (Dr. Jusko) ¶¶ 7‐13; Ex. 2006 (Jusko
`CV); Ex. 2024 (2nd Jusko) ¶ 40; Paper 26 at 7. 3 Ex. 2003 (Dr. Lublin) ¶¶ 8‐17; Ex. 2004 (Lublin CV); Paper 26 at 6‐7.
`12
`
`
`
`Petitioners’ Experts Inexperienced in Key Aspects of Art
`Dr. Giesser:
`Dr. Benet:
`— M.D., MS clinician
`— Ph.D., pharmacologist
`— Professor of Clinical
`— Professor of Bioengineering and
`Neurology, UCLA
`Therapeutic Sciences, Schools of
`— Not a
`Pharmacy and Medicine, University of
`pharmacologist
`California
`— No animal research
`— No experience with fingolimod
`experience, including EAE
`— No publications involving MS or
`— No experience with
`EAE
`clinical dose design
`— No experience performing EAE
`— No experience with
`animal model studies
`fingolimod except
`— Alleged consulting on three MS
`prescribing it (did not read
`drugs 15‐20 years ago
`Gilenya® Label before this
`case)
`
`Paper 26 at 44‐46; Paper 63 at 2; Ex. 1002 (Dr. Giesser) ¶¶ 1‐4; Ex. 1047 (Dr. Benet) ¶¶ 1‐11; Ex.
`2100 (Benet Deposition) at 37:6‐17, 43:9‐46:2, 47:1‐6.
`
`13
`
`
`
`Dr. Giesser Admits to Facts That Defeat Petition
`
`• The law requires determination of scope and content
`of prior art when attempting to prove obviousness.
`• Dr. Giesser did not review the scope and content of
`the prior art.
`• Dr. Giesser limited her opinion to ”references supplied
`by counsel.”
`• No rebuttal opinion from Dr. Giesser.
`• Dr. Giesser employed impermissible hindsight.
`• Dr. Giesser’s opinion should be given no weight.
`• Accordingly, the Petition is fatally defective and
`should be denied in full.
`
`Paper 26 at 28‐30; 42‐44; Paper 63 at 1.
`
`14
`
`
`
`Dr. Giesser Did Not Review the State of the Art
`
`No literature
`searches to review
`state of the art.
`
`“References were
`supplied by
`counsel.”
`
`Ex. 2039 (Dr. Giesser Transcript) at 49:17‐50:9; Paper 26 at 28‐31.
`
`15
`
`
`
`Dr. Giesser Ignored Webb Even Though On Face of Patent
`
`Dr. Giesser
`ignored Webb
`in her
`Declaration,
`but reviewed it
`before her
`deposition,
`even though it
`was on the
`face of the
`’405 Patent.
`
`Ex. 2039 (Dr. Giesser Transcript) at 67:1‐68:15; Paper 26 at 42.
`
`16
`
`
`
`Law Supports Disregarding Dr. Giesser’s Opinion
`
`• Dr. Giesser “did not perform an analysis of the art as a
`whole.” Paper 26 at 42, quoting AstraZeneca.
`• Dr. Giesser only considered “references supplied by counsel.”
`• The AstraZeneca court found that an expert considering only
`“a selection of prior art handpicked by” counsel had “fatally
`undermine[d]” the credibility of the putative expert, giving
`his opinion no weight. Paper 26 at 43.
`In Warner Chilcott, the obviousness attack was “entirely
`hindsight driven” as it is here. Id.
`• The experts there “picked and chose from the already‐
`narrowed list of references that lawyers provided, and
`worked backwards using improper hindsight.” That analysis
`was simply “legally incorrect.” Id.
`
`•
`
`17
`
`
`
`State of the Art
`
`Review of state of the art is
`first step in analysis under
`35 U.S.C. § 103.
`
`KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007) (citing Graham v. John Deere Co. of Kansas City,
`383 U.S. 1, 17‐18 (1966)); Paper 8 at 23.
`
`18
`
`
`
`Multiple Sclerosis
`
`• “The symptoms of multiple sclerosis are diverse and
`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.” Thomson, Ex. 1005 at 158; Ex. 2022
`(Dr. Steinman) ¶¶ 24‐27; Paper 24 at 7.
`
`• Finding medicines to treat MS is challenging:
`—MS is a life‐long disease (there is no cure) and
`medicines need to be used over extended period of
`time
`—High level of inter‐patient variation makes it
`difficult to identify a positive signal in clinical trials
`Ex. 2025 (Dr. Lublin) ¶¶ 23‐31; Paper 26 at 25.
`
`19
`
`
`
`Efficacy in RRMS Means Sustained Therapy
`“RRMS is a life‐long condition. … Disability thus accumulates over time. As
`a result, MS doctors focus on sustained, consistent relapse prevention and
`slowing progression of the disease.” Dr. Steinman, Ex. 2096, ¶ 43.
`
`“Fingolimod
`held promise
`too, but only
`if it could
`provide
`consistent,
`sustained
`benefits to
`patients.” Ex.
`2096, ¶ 44.
`
`Ex. 2003 ¶ 46; Paper 8 at 32‐33; Paper 63 at 6‐7.
`
`20
`
`
`
`“Perplexities” of Fingolimod
`
`• Pro‐drug with long half‐life.
`
`•
`
`Inhibits movement of lymphocytes out of lymph nodes, but MOA for MS
`unknown.
`
`• “However, the effect of fingolimod on cell trafficking is not directly tied
`to its therapeutic effect.” Ex. 2024 (Dr. Jusko) ¶ 42.
`
`• “The mechanism by which fingolimod exerts therapeutic effects in
`multiple sclerosis is unknown, but may involve reduction of lymphocyte
`migration into the central nervous system.” Ex. 2040 (GILENYA Label) at
`12; Ex. 2024 (Dr. Jusko) ¶ 38.
`
`• “A skilled pharmacologist would be cautious in judging the clinical
`therapeutic benefit of administering fingolimod because one would not
`want to expose a patient to the risk of side‐effects without confidence
`that the dose provided sufficient benefit.” Ex. 2024 (Dr. Jusko) ¶ 40.
`
`Dr. Jusko, Ex. 2024 at ¶¶ 37‐44; Paper 26 at 8.
`
`21
`
`
`
`Early Biomarker for Effect ‐ Lymphocyte Suppression
`
`“Many scientists believed that…‘lymphocyte sequestration is
`a convenient surrogate marker of the pharmacodynamic
`effect of FTY720[.]’” Dr. Steinman, Ex. 2022 ¶ 41 (quoting
`Thompson, Ex. 1005 at 162.)
`
`BUT:
`
`“Studies showed, however, that only substantial lymphocyte
`suppression provided any clinical benefit.” Dr. Steinman, Ex.
`2022, ¶ 5.1
`
`1 See also, Ex. 2024 (Dr. Jusko) ¶¶ 53, 55‐57, 59, 62, 63, 65‐75; Ex. 2022 (Dr. Steinman) ¶¶ 55‐66, 74‐85;
`Paper 26 at 8, 10‐14, 16‐19.
`
`22
`
`
`
`State of the Art – Chiba Patent
`
`—> Increasing doses of
`fingolimod show
`increased effect on
`graft survival in
`transplant animal
`model.
`
`—> Increasing doses of
`fingolimod show increasing
`reduction of lymphocytes in
`periphery.
`
`Ex. 1006 (Chiba), Fig. 1A, Fig. 11; Ex. 2022 (Dr. Steinman) ¶¶ 41‐46; Paper 26 at 8.
`
`23
`
`
`
`Budde 2002: Single‐Dose Phase IA Safety Study
`
`Ex. 1008 (Budde) at 1073; Paper 26 at 9‐10.
`
`24
`
`
`
`Kahan 2003: Multi‐Dose Phase IB Safety Study
`
`Ex. 1031 (Kahan 2003) at 1081; Ex. 2022 (Dr. Steinman) ¶ 57; Paper 26 at 10‐12.
`
`25
`
`
`
`Kahan 2003: FTY ≥ 1.0 mg/day => 85% Lymphopenia
`
`Ex. 1031 (Kahan 2003) at 1079; Ex. 2022 (Dr. Steinman) ¶ 57; Paper 26 at 10‐12.
`
`26
`
`
`
`Park 2005: Teaches Away from Low Doses
`
`High inter‐
`patient
`variability at
`low doses.
`
`42% average lymphocyte
`suppression in 0.5 mg group,
`Ex. 1019, Table 3, p. 689
`
`Ex. 1019 (Park 2005) at 690; Ex. 2022 (Dr. Steinman) ¶ 62; Paper 26 at 12‐14.
`
`27
`
`
`
`Webb 2004: Teaches a Threshold of 70% Suppression
`
`Paper from Merck Research Laboratories
`
`Ex. 2014 (Webb) at 118; Paper 26 at 16‐19.
`
`28
`
`
`
`Kataoka 2005: (A Different Lab) Cites (Not Refutes) Webb
`
`Ex. 1029 at 446, 448.
`
`29
`
`
`
`Kappos 2005: Teaches No Dose Lower Than 1.25 mg
`
` Clinical and MRI results of study in
`RRMS of 5.0 mg, 1.25 mg, and placebo.
`
` “[C]learly significant effects favoring
`both FTY720 groups…” were reported.
`
` Mild adverse events were more
`common in 5 mg group.
`
`Ex. 1007 at II/41; Paper 26 at 20.
`
`30
`
`
`
`The Phase III Trial: Futility Analysis Only for 0.5 mg
`
`Ex. 2064 at 2; Paper 26 at 26.
`
`31
`
`
`
`Mt. Sinai IRB Skeptical of 0.5 mg Efficacy
`
`Ex. 2063 at 2; Paper 26 at 26‐27.
`
`32
`
`
`
`Consistent Evidence: No POSA Thought 0.5 mg Would Be Effective
`
`Teaching Away 1
`
`Skepticism of Experts 2
`
`Unexpected Results 3
`
`•
`
`Futility analysis for
`only 0.5 mg at Phase
`III.
`• DSMB could
`abandon 0.5 mg arm
`if no different than
`placebo.
`• Mt. Sinai IRB refuses
`to join PIII trial
`based on skepticism
`that 0.5 mg would
`have any efficacy.
`
`• MS is a variable
`disease that needs
`sustained therapy.
`• Webb — 70%
`lymphopenia needed
`to show any efficacy
`in EAE.
`• Park – 0.5 mg results
`in highly variable
`effects.
`• Kahan and Park — 0.5
`mg produces only
`42% (Park) or 50%
`(Kahan) average
`suppression.
`1 Paper 26 at 33‐34; Paper 63 at 5‐8. 2 Paper 26 at 40‐41; Paper 63 at 9‐12. 3 Paper 26 at 39‐40; Paper 63 at 9‐12.
`
`•
`
`Inventors saw
`unexpected
`biomarker and
`surprising EAE
`rodent model
`results.
`• Phase III trial
`surprisingly
`showed efficacy
`of 0.5 mg dose,
`and at similar
`level as 1.25 mg
`application date.
`
`33
`
`
`
`Ground I
`
`GROUND I:
`Kovarik + Thompson
`
`34
`
`
`
`Kovarik Patent Application ‐ Loading Dose Regimens
`
`**Record does
`not reflect that
`highlighted term
`refers to
`alternatives. The
`record reflects
`the term means
`incremental
`doses over initial
`four days.
`
`Ex. 1004 at 15; Paper 26 at 51‐52; Ex. 2022 (Dr. Steinman) ¶¶ 164‐68.
`
`35
`
`
`
`Kovarik: Loading Dose “Increased Stepwise”
`
`Ex. 1004 at 14; Paper 26 at 51‐52; Ex. 2022 (Dr. Steinman) ¶¶ 164‐68.
`
`36
`
`
`
`Kovarik Does Not Link MS with 0.5 mg Fingolimod
`
`Ex. 1004 at 14, 17; Paper 26 at 36.
`
`37
`
`
`
`Thomson Only Mentions 0.5 mg from Budde
`
`Paper 26 at 49‐50, 53; Ex. 1005 at 163.
`
`38
`
`
`
`Kovarik & Thomson Fail to Teach 0.5 mg for RRMS
`Reference Lacking: 1 Kovarik (Ex. 1004)2
`Thomson (Ex. 1005)3
`X
`X
`X
`X
`
`X
`
`X
`
`X
`
`X
`
`Not teach 0.5 mg to
`treat RRMS.
`Ref. not specific to
`any disease.
`Every dosing
`regimen requires a
`loading dose.
`No efficacy teaching
`for 0.5 mg daily for
`RRMS.
`
`No daily dosage of
`0.5 mg.
`
`1 Ex. 1001 at cls. 1‐6 (Claim 1 is representative); 2 Paper 26 at 49‐51; 3 Paper 26 at 4, 36, 49‐52.
`
`39
`
`
`
`•
`
`Ground I: Kovarik + Thompson – Evidence Fails to Support Theory
`Dr. Giesser:
`Dr. Benet:
`• Did not review state of the
`Lacks experience with
`art and therefore ignorant of
`fingolimod, and performing
`teaching away.
`EAE experiments.
`• Not a pharmacologist (e.g.,
`• Over‐reads certain Webb data
`relies on an off‐topic
`while ignoring full teaching.
`textbook with error in
`• Relies on max suppression
`equation).
`data inappropriate for chronic
`• Misreads Kovarik disclosure
`RRMS treatment.
`“an autoimmune disease.”
`• Cannot offer opinion on
`• Misconstrues “daily” to
`meaning of preamble because
`include single dose.
`he alone is not a POSA.
`• Mischaracterizes
`• Cherry‐picked scaling factors
`lymphopenia as a clinical
`with hindsight.
`end‐point in MS (it is not).
`
`Paper 26 at 37, 42‐46, 49‐50, 54‐55; Paper 63 at 2, 6‐8.
`
`40
`
`
`
`Ground I – Failure of Proof
`
`• References do not teach or make obvious the claimed
`invention.
`– Kovarik inapplicable to MS due to loading dose
`requirement – POSA would not look to loading
`dose patent to design a daily dose.
`– Kovarik teaches no specific regimen for RRMS, MS,
`or any particular autoimmune disease.
`• No motivation to combine.
`• Combination offers no reasonable expectation of
`success to a POSA in the context of the state of the
`art.
`
`Paper 26 at 46‐55.
`
`41
`
`
`
`Ground II
`
`GROUND II:
`Chiba + Budde + Kappos 2005
`
`42
`
`
`
`Chiba Discloses a 1000‐Fold Range of Potential Doses
`
`Ex. 1006 at II/41; Paper 26 at 56.
`
`43
`
`
`
`Budde 2002: Single‐Dose Phase IA Safety Study
`
`Ex. 1008 at 1073; Paper 26 at 5, 9‐10.
`
`44
`
`
`
`Kappos 2005: Teaches Dose No Lower Than 1.25 mg
`
` Clinical and MRI results of study in
`RRMS of 5.0 mg, 1.25 mg, and placebo.
`
` “[C]learly significant effects favoring
`both FTY720 groups…” were reported.
`
` Mild adverse events were more
`common in 5 mg group.
`
`Ex. 1007 at II/41; Paper 26 at 20.
`
`45
`
`
`
`Chiba, Budde, and Kappos 2005: Do Not Teach Claimed Invention
`
`Chiba (Ex. 1006)1
`Range of 0.1 mg to 10
`mg disclosed with
`general disclosure of
`autoimmune disease
`and transplant
`rejection.
`0.5 mg not disclosed
`specifically.
`
`•
`
`•
`
`Budde (Ex. 1008)2
`• Single, one‐time dose.
`Not a daily dose.
`• No RRMS patients.
`• Administration to
`stable, renal, transplant
`patients taking other
`immuno‐suppressants.
`
`Kappos (Ex. 1007)3
`• Only discloses dosage
`amounts of 1.25 mg
`and 5.0 mg with
`positive results in RRMS
`for each dose in Phase
`II trial.
`
`None of the references
`provides a motivation to
`combine.
`
`1 Paper 26 at 37‐38, 55‐56. 2 Paper 26 at 9‐10; Ex. 2022 (Dr. Steinman) ¶¶ 50‐54. 3 Paper 26 at 20, 56.
`
`46
`
`
`
`Prior Art Teaches Away
`
`• A reference teaches away “when a person of ordinary skill, upon
`reading the reference, would be discouraged from following the
`path set out in the reference, or would be led in a direction
`divergent form the path that was taken by the applicant.”
`
`Allergan, Inc. v. Sandoz Inc., 796 F.3d 1293, 1305 (Fed.
`Cir. 2015).
`
`• When evaluating teaching away, “the prior art must be
`considered as a whole for what it teaches.”
`
`Medichem S.A. v. Rolabo, 437 F.3d 1157, 1166 (Fed. Cir.
`2006)(emphasis in original).
`
`Paper 26 at 33‐34, 37.
`
`47
`
`
`
`Prior Art Teaches Away
`
`• Webb 2004 identifies 70% threshold for
`efficacy in EAE
`• Park 2005 and Kahan 2003 show 70%
`lymphopenia achieved only at doses 1.0 mg
`or higher in humans
`• References read as a whole teach away from
`0.5 mg
`
`Paper 26 at 10‐14, 16‐19, 33‐35..
`
`48
`
`
`
`Webb 2004: Data in Paper Supports Conclusion
`
`As to Fig. 5B, Dr.
`Steinman says “the
`lowest 0.03 mg/kg
`dose provided no
`statistically
`significant clinical
`benefit, as shown
`by the absence of
`an asterisk over
`the 0.03 mg/kg
`bar.” Ex. 2022, ¶
`81.
`
`Ex. 2022 (Dr. Steinman) ¶¶ 80‐83; Paper 26 at 16‐19, 45.
`
`49
`
`
`
`Webb 2004: Figure 6 Supports 70% Threshold
`
`Dr. Chun says: “The subjective nature of
`EAE clinical scoring renders distinctions
`of “about 70%” and 60% virtually moot.
`Our goal was to provide – in our
`concluding statements in the Discussion
`— conclusions that could be examined
`and reproduced by others. Those
`conclusions were not based solely on the
`averages reported in Figures 5 and 6 in
`isolation. Rather, we drew our
`conclusions using all of our data that
`included individual mice. We saw a
`striking pattern in that data that only
`mice with about 70% or greater
`suppression in lymphocytes compared
`to baseline showed sustained clinical
`efficacy produced by drug exposure.” Dr.
`Chun, Ex. 2098, ¶ 38.
`
`Paper 63 at 6.
`
`50
`
`
`
`Dr. Steinman: Webb Authors Meant What They Said
`
`Ex. 2096 (Dr. Steinman) ¶¶ 25‐40; Paper 63 at 6.
`
`51
`
`
`
`Dr. Chun and Dr. Steinman Confirm Webb Teaching
`
`• Dr. Chun, a co‐author of Webb 2004, testified
`that his paper meant what it said – about 70%
`suppression being needed for any efficacy. (Ex.
`2098, ¶¶ 2‐9,17‐35.)
`• Dr. Chun testified he and his co‐authors used
`judgment informed by multiple data points,
`not just averaged data. They considered data
`from individual mice, and qualitative
`assessments of various aspects of the EAE
`model. (Id. ¶¶ 2‐8,36‐41.)
`• Dr. Steinman testified that a person of skill
`would have believed Webb as written. (Ex.
`2096, ¶¶ 25‐40.)
`
`Paper 63 at 6.
`
`52
`
`
`
`Skepticism of Experts Consistent with Teaching Away
`
`“Doubt or disbelief by skilled artisans regarding the
`likely success of a combination or solution weighs
`against the notion that one would combine elements in
`references to achieve the claimed invention.”
`
`WBIP, LLC v. Kohler Co., 829 F.3d 1317, 1335
`(Fed. Cir. 2016).
`
`In WBIP, skepticism arose from audience reaction to a
`presentation.
`
`Paper 26 at 40‐41.
`
`53
`
`
`
`Dr. Lublin Expected No Efficacy From 0.5 mg
`
`Dr. Lublin, Ex. 2025 ¶¶ 2‐3; Paper 26 at 27.
`
`54
`
`
`
`Unexpected Results
`
`Ex. 1038 at 387; Paper 26 at 27; Ex. 2025 (Dr. Lublin) ¶¶ 59‐63.
`
`55
`
`
`
`RRMS Dosing Patent Recently Upheld Based Only on Unexpected Results
`
`CAFD, et al. v. Biogen M.A., Inc., IPR2015‐01933, Paper 63 (PTAB
`Mar. 21, 2017):
`
`• Patent on 480 mg daily dose of an RRMS drug, filed after Phase II
`clinical trial results showing efficacy of 720 mg but lack of
`statistical efficacy of 240 mg and 360 mg.
`• Board rejected obviousness challenge—Phase III trials showed
`480 mg had similar efficacy to 720, which was an unexpected
`result.
`
`•
`
`In the present case there is far more evidence of patentability:
` Prior art teaching away
` Innovative animal model use led to invention; and
` Unexpected results corroborated by multiple
`contemporaneous documents.
`Paper 26 at 32‐33, 39; Paper 63 at 11‐12.
`
`56
`
`
`
`Chavez Press Release: Phase II Results for 1.25 mg
`
`Ex. 2031 at 2; Paper 64 at 8; Ex. 2097 ¶¶ 8‐10.
`
`57
`
`
`
`Chavez Announces a Phase III Trial to “Confirm” 1.25 mg
`
`Ex. 2031 at 2; Paper 64 at 8‐9; Paper 63 at 9‐11.
`
`58
`
`
`
`Dr. Lublin Testified that Chavez Only Discloses a Test
`
`Paper 64 at 9‐10; Ex. 1042 at 239:10‐21.
`
`59
`
`
`
`Ground III
`
`GROUND III:
`35 USC § 112 & Kappos 2010
`
`60
`
`
`
`Ground III Improper Under 35 U.S.C. § 311
`
`• Decision in Bioactive Labs does not reach the present situation.
`
`• Here, Petitioners ask Board to accord Patent Owner April 2014
`filing date because negative limitation was added in Preliminary
`Amendment filed in August 2014, four months after filing date.
`
`• Petitioners give no reasoning to rationalize choosing the later
`April 2014 filing date instead of the earliest filing date in June
`2006 except for the proximity to the filing date of the
`Preliminary Amendment.
`
`• There are no C‐I‐Ps and no new subject matter was added.
`
`Paper 26 at 57‐61; Bioactive Labs. V. BTG Int’l Inc., IPR2015‐01778, 2016 WL 1082772, at *3 (P.T.A.B. Feb 16, 2016).
`
`61
`
`
`
`Application Filing Timeline
`
`June 27, 2006
`GB Priority
`application
`filed
`
`USSN 13/149,468
`filed on May 31,
`2011
`
`USSN 12/303,765
`filed June 25,
`2007
`
`Preliminary
`Amendment
`filed in ’342
`application on
`August 18, 2014
`
`USSN
`14/257,342 filed
`on April 21,
`2014, now ’405
`Patent
`
` No additional subject matter added.
` No C‐I‐P’s.
`Paper 26 at 61; Paper 2 at 57‐58; Ex. 1009; Ex. 1010; Ex. 1011; Ex. 1012.
`
`62
`
`
`
`35 U.S.C. § 112 Was Met as of June 2006
`
`• Dr. Steinman testified that the specification in June
`2006 would have told a person of ordinary skill in
`the art that the inventors possessed the entire
`invention – including a daily dose that excluded
`loading doses. Ex. 2022, ¶¶182‐189.
`
`• Dr. Jusko testified that the specification discloses a
`complete dosing regimen and thus a person of skill
`would know not to add in any other features to the
`prescribed dosing regimen. Ex. 2024, ¶¶173‐176.
`
`Paper 26 at 61‐64.
`
`63
`
`
`
`Contingent Motion to Amend
`
`Contingent
`Motion to Amend
`
`64
`
`
`
`Motion to Amend
`
`Motion to Amend
`
`Prunesed Claim 7.
`
`(Prcpcsed substitute claim in place bf eriginal claim 1.) A
`
`methcd for reducing or preventing er alleviating relapses in Relapsing-Remitting
`
`multiple sclerosis in a subject in need thereof, comprising bralljyr administering to
`
`a 13:]:1armaceuticall}.r acceptable salt ffl'l'fll, wherein the subject receives a desing
`
`said subject 2-aminb-2-[2 {4-ecty1phenv1)ethv1]prnpane—Lil-die]. in free form er in
`
`Paper 61 at 19.
`
`65
`
`
`
`Proposed Amended Claims Address All Three Grounds
`
`• Ground III:
`– Proposed amendments obviate the predicate by deleting
`the negative limitation.
`• Ground I and II:
`– The “consisting of” phrase closes the scope of the
`fingolimod dosing regimen so nothing more than 0.5 mg
`daily is encompassed. The narrower claims show it is even
`less reasonable for a POSA to believe the claim is obvious
`in view of the references.
`
`Paper 61 at 14‐18; Paper 64 at 11‐12.
`
`66
`
`
`
`Claim Construction: “Daily Dosage”
`
`• Petitioners argue “daily dosage” encompasses
`a single, one‐time dose.
`• Under broadest reasonable interpretation
`standard, this is not a reasonable position
`because it renders the term “daily”
`meaningless.
`• Drs. Steinman and Jusko testify that “daily”
`does not mean a one‐time, single dose.
`
`Ex. 2022 (Dr. Steinman) ¶¶ 179, 183; Ex. 2096 (Dr. Steinman) ¶¶ 21‐24; Ex. 2024 (Dr. Jusko) ¶ 114, 140;
`Paper 26 at 37; Paper 64 at 6‐7.
`
`67
`
`
`
`Claim Construction: “Dosing Regimen”
`
`• Dr. Steinman testifies:
`
`“As of June 2006 a person of skill would have understood
`that the general phrase ‘dosing regimen‘ is an umbrella
`term that encompasses different aspects of dosing. The
`definition of a dosing regimen is a schedule of doses of a
`therapeutic agent per unit of time, including the time
`between doses or the time when the doses are to be
`given and the amount of the therapeutic agent to be
`given at each specific time.”
`
`Ex. 2096, ¶ 18, underlining added.
`
`Paper 64 at 5‐6.
`
`68
`
`
`
`Claim Construction: “Consisting Of”
`
`• “Consisting of” narrows all of the original claims.
`• Petitioners’ “hypothetical” claim violates meaning of
`“consisting of” and meaning of “dosing regimen.”
`
`Paper 61 at 12‐13; Paper 62 at 10‐11; Paper 64 at 3‐6.
`
`69
`
`
`
`Preambles Are Limiting and Require Efficacy
`Dr. Giesser agrees all RRMS patients need all aspects claimed.
`
` Dr. Steinman agrees. Ex. 2096 ¶ 11.
` Presumption against claim redundancy and
`antecedent basis support efficacy requirement.
` No expert testimony from Petitioners to the contrary.
`
`Dr. Giesser, Ex. 1002, ¶ 44; Paper 64 at 2‐3.
`
`70
`
`
`
`The Preambles Require Efficacy
`
`• Petitioners do not dispute that the ’405 Patent preambles are
`limiting.
`• Petitioners cite In re Montgomery to argue that “method of
`treating claims impose no ‘efficacy requirement[.]’” (Paper
`49 at 7.)
`• But, the Federal Circuit in Montgomery assumed the claims
`there imposed an efficacy limitation.
`• Also, the Montgomery claims were to only one method with
`one effect; no claim redundancy problem like the claims
`here.
`• The specification here shows efficacy was at the core of the
`invention, unlike Montgomery.
`
`Paper 63 at 2‐5.
`
`71
`
`
`
`Preambles Require Efficacy
`• Claims to 0.5 mg daily for the purpose of achieving, or to actually
`achieve the specific effects recited in the claims.
`• Dr. Steinman testifies from point of view of POSA that:
`– Specification repeatedly emphasizes the invention’s therapeutic
`benefits. Ex. 2096, ¶ 13.
`– Inventors discovered a new mechanism of action that produced
`certain effects. Id., ¶ 14.
`– Animal model example showing effects. Id., ¶ 15.
`– Human example in specification focused on achieving certain
`effects. Id.
`– In arguments for patentability, file history mentions balance of
`safety and efficacy. Id., ¶ 16.
`– “[A] person of skill in June 2006 would read the claims to require
`that the dose be administered to achieve the effects of the
`claimed benefits, or at least be intended to do so.” Id., ¶ 18.
`Paper 63 at 2‐5.
`
`72
`
`
`
`Chavez Does Not Anticipate
`• Chavez does not anticipate expressly or inherently.
`• Chavez does not disclose claim preambles.
`• Chavez is silent on efficacy for 0.5 mg arm.
`• Dr. Lublin says efficacy is not necessarily result from using 0.5
`mg.
`• No expert testimony from Petitioners.
`
`Dr. Lublin, Ex. 2097 ¶ 8; Paper 64 at 7‐10.
`
`73
`
`
`
`Inherency
`
`• Petitioners cite BMS v. Ben Venue, 246 F.3d 1368
`(Fed. Cir. 2001), and In re Montgomery, 677 F.3d
`1375 (Fed. Cir. 2012), as their primary inherency
`references. (Paper 62 at 5.)
`
`• The majority in Montgomery held that inherency
`cannot be based on Phase III results “published …
`after [the] priority date[.]” 677 F.3d at 1378.
`
`• Petitioners here have submitted no other evidence
`to suggest inherency.
`
`Paper 64 at 7‐8.
`
`74
`
`
`
`Inherency
`
`• For a patented “process” to be inherently anticipated, it
`must be “directed to the same purpose” as the original
`process. BMS, 246 F.3d at 1376; Montgomery, 677 F.3d at
`1381.
`• Here, Chavez describes giving 0.5 mg to RRMS patients for
`“testing,” as the undisputed testimony of Dr. Lublin
`shows. Ex. 2025 ¶ 48.
` But the ’405 Patent uses that dose for a different
`purpose: as a therapy.
`In contrast, BMS and Montgomery involved using known
`processes for known uses: to treat cancer (BMS) or
`hypertension and stroke (Montgomery).
`
`•
`
`Paper 64 at 7‐10.
`
`75
`
`
`
`Dr. Benet’s Animal Scaling Argument is Wrong
`
`• Dr. Benet argues that a person of skill would seize on
`Kataoka’s lowest effective dose in an EAE mouse (0.1 mg/kg)
`and scale up from that using the FDA Guidance to 0.5 mg in
`humans.
`• Dr. Jusko shows the flaws in this methodology.
`o First, the FDA Guidance is only for first‐in‐human use
`before human PK/PD data exists; here, human PK/PD data
`existed.
`o Second, the FDA Guidance is general and does not take
`account of animal PK/PD data with any specific drug; here,
`animal PK/PD data existed.
`o Third, the FDA guidance provides multiple methods for
`dose scaling, the weight of which point toward doses 1.0
`mg or higher.
`Ex. 2095 ¶¶ 1‐44; Paper 63 at 7‐8.
`
`76
`
`
`
`Dr. Benet Misuses FDA Guidance Scaling to Human Dose
`
`By June 2006, fingolimod
`had been used for years
`in humans, yielding
`extensive PK/PD data.
`
`Ex. 1049 at 1; Ex. 2095 ¶¶ 4‐18; Paper 63 at 7‐8.
`
`77
`
`
`
`Dr. Benet’s Animal Scaling Argument Is Wrong
`
`• FDA Guidance: “identifying … ‘pharmacologically active’ doses
`(PAD) ‘depends on many factors and differs markedly among
`pharmacological drug classes and clinical indications;
`therefore, selection of a PAD is beyond the scope of this
`guidance.’”
`
`•
`
`Instead, pharmacologist would use PD data from Webb and
`humans to estimate doses.
` “[P]harmacologists assume that PD markers like
`lymphocyte suppression apply across species, absent
`evidence to the contrary.”
` No such evidence here.
`
`Ex. 2095 ¶ 8 (quoting Ex. 1049 at 12 (adding emphasis); Id. ¶ 9; Paper 63 at 7‐8.
`
`78
`
`
`
`Dr. Benet Misuses FDA Guidance Scaling to Human Dose
`
`Dr. Jusko: “…if a pharmacologist were inclined to try to scale a human
`dose from the Kataoka animal data in June 2006, he would turn to
`actual clearance data in the relevant species. He would find the actual
`human and rat clearance data that was available at the time and would
`use it for scaling. … Scaling from rat to human would have pointed
`toward scaled doses for humans of 1.0 mg or higher.” Ex. 2095, ¶26.
`
`Ex. 1049 at 2; Ex. 2095 ¶¶ 4‐18; Paper 63 at 7‐8.
`
`79
`
`
`
`Dr. Benet Cherry‐Picked Scaling Factors
`
`In choosing how to extrapolate from Kataoka with the FDA
`Guidance, Dr. Benet chose the one formula that would yield
`the lowest estimated human dose.
`
`Ex. 2095 ¶¶ 41; Paper 63 at 8.
`
`80
`
`
`
`Conclusion
`
` Ground I and II should be denied because Petitioners have not carried their
`burden of showing unpatentability. Contemporaneous evidence and expert
`testimony support non‐obviousness of the claimed invention.
` State of art taught away from invention and toward 1.0 mg.
` Skepticism of experts as shown by futility analysis and IRB at Mt. Sinai
`refusing to join clinical trial using 0.5 mg.
` Unexpected results in patent showing EAE animal model results and in
`Phase III trial result with 0.5 mg showing efficacy, and at a level similar to
`1.25 mg.
` Impermissible hindsight arguments by Petitioners’ less qualified experts don’t
`outweigh contemporaneous evidence from multiple sources.
` Ground III not proper under AIA and should be denied.
` Proposed amended claims address all grounds of rejections and are novel and
`non‐obvious over Chavez too. Petitioners have no expert testimony to
`support their opposition.
`
`81
`
`
`
`
`
`
`
`
`IPR2017-00854
`U.S. Patent No. 9,187,405
`
`CERTIFICATE OF SERVICE
`Pursuant to 37 C.F.R. § 42.6, I hereby certify that on May 10, 2018, true and
`
`accurate copies of the foregoing PATENT OWNER NOVARTIS’S CORRECTED
`
`ORAL HEARING DEMONSTRATIVES for IPR2017-00854 was served via
`
`electronic mail, on the following counsel of record for Petitioners:
`
`For Apotex:
`
`For Argentum:
`
`For Sun:
`
`Steven W. Parmelee: sparmelee@wsgr.com
`Michael T. Rosato: mrosato@wsgr.com
`Jad A. Mills: jmills@wsgr.com
`Wilson Sonsini Goodrich & Rosati
`701 Fifth Avenue, Suite 5100
`Seattle, WA 98104
`Telephone: 206-883-2542
`
`Teresa Stanek Rea: trea@crowell.com
`Deborah H. Yellin: dyellin@crowell.com
`Shannon M. Lentz: slentz@crowell.com
`Tyler C. Liu: TLiu@agpharm.com
`Crowell & Moring LLP
`Intellectual Property Group
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