UNITED STATES PATENT AND TRADEMARK OFFICE
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`______________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`______________________
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`
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`APOTEX INC. and APOTEX CORP.,
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`Petitioners,
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`v.
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`NOVARTIS AG,
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`Patent Owner.
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`______________________
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`Case IPR2017-00854
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`U.S. Patent No. 9,187,405
`______________________
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`PRELIMINARY PATENT OWNER RESPONSE
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`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`TABLE OF CONTENTS
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`PRELIMINARY STATEMENT ............................................................................ 1
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`FACTS ...................................................................................................................... 5
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`A. The State of the Art in Fingolimod Research in June 2006 ......................... 6
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`ARGUMENT ..........................................................................................................21
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`1. Fingolimod’s Discovery and Early Research on its Mechanism of
` Action ....................................................................................................... 6
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`2. Fingolimod and Transplant Research ....................................................... 7
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`3. Fingolimod and MS Research .................................................................. 9
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`B. The Inventors’ Neo-Angiogenesis Discovery and the ’405 Patent ............13
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`1. The Invention .........................................................................................13
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`2. Prosecution .............................................................................................15
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`3. The Issued Claims ..................................................................................17
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`C. Apotex’s Petition ........................................................................................17
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`1. Kovarik plus Thompson .........................................................................17
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`2. Chiba plus Budde plus Kappos 2005 .....................................................19
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`3. Kappos 2010 ...........................................................................................20
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`I. Apotex’s Kovarik-Thomson Ground Fails to
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`Provide Any Reason to Question the Examiner’s
` Decision to Allow the Patent over Kovarik ............................................21
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` A. The Board Should Not Rehash Prosecution ............................21
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` B. The Examiner’s Conclusion Was Correct: Kovarik’s
` Loading-Dose Requirement Teaches Away from
` the ’405 Patent ............................................................................23
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` C. Kovarik Further Never Teaches How a 0.5 mg
` Fingolimod Daily Dose Would Be Effective for the
` Claimed Methods ........................................................................29
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` 1. Apotex’s Incorrect Claim Construction ...............................29
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` 2. The Kovarik-Thomson Ground Fails Without
` Apotex’s Fatally Flawed Claim Construction ......................35
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`II. Apotex’s Chiba-Budde-Kappos 2005 Ground
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`Fails For Lack of Expert Support ...........................................................36
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`III. Apotex’s Kappos 2010 Ground Fails as a Disguised
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`112 Attack Improper in an IPR, which is Wrong
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`in Any Event ..............................................................................................45
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`CONCLUSION .......................................................................................................49
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`APPENDIX A: CASES ADDRESSING A PERSON OF SKILL
`IN DOSING PATENT DISPUTES ......................................................................50
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`PRELIMINARY STATEMENT
`The Apotex Petitioners base their challenges on publications selectively
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`recycled from the patent file history plus an opinion from a putative expert who lacks
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`essential expertise. Nothing here supports institution.
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`Apotex, a generic drug maker, challenges U.S. Patent No. 9,187,405. The
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`’405 Patent claims methods for using the immunosuppressant drug fingolimod to
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`treat relapsing-remitting multiple sclerosis (RRMS). Novartis AG owns the Patent,
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`and fingolimod is the active ingredient in Novartis’s Gilenya®, the first solid oral
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`treatment ever approved for RRMS. Gilenya has brought relief to tens of thousands
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`of MS patients in the United States. The U.S. Food and Drug Administration
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`approved Gilenya in 2010 for use with the methods in the ’405 Patent.
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`Before the inventors discovered those methods, scientists had investigated
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`fingolimod primarily for its potential in suppressing organ transplant rejection, not
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`as a multiple sclerosis medicine. A decade of research in transplantation had shown
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`that fingolimod suppressed the immune response by sequestering lymphocytes in
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`lymphatic tissue away from the blood stream. Daily 5.0 mg doses sequestered
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`enough lymphocytes in humans to treat organ rejection.
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`Novartis scientists Peter Hiestand and Christian Schnell uncovered a
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`completely different effect of fingolimod and applied it for use in multiple sclerosis,
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`a debilitating disease in which the immune system attacks the body’s own central
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`nervous system. Hiestand and Schnell discovered that fingolimod inhibits the
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`growth of blood vessels into the lesions that RRMS creates in the nervous system,
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`thereby reducing relapses and slowing progression of the disease. No one before
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`had ever shown that fingolimod had any therapeutic mechanism other than
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`lymphocyte sequestration. Their discovery made possible far lower doses than
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`previously thought could be effective.
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`Novartis put these discoveries into a June 2006 patent application claiming
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`use of fingolimod to treat RRMS with a 0.5 mg daily dose. The USPTO awarded
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`the ’405 Patent in 2015. The Patent reports the discovery that fingolimod suppresses
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`“neo-angiogenesis”—new blood vessel growth—in animal models. Based on that
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`surprising discovery, the Patent claims 0.5 mg daily dosing for subjects in need of
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`reducing, preventing, and/or alleviating RRMS relapses; treating the disease more
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`broadly; and slowing its progression. The claims further exclude “a preceding
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`loading dose regimen,” a step used in other contexts to more rapidly achieve a
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`steady-state of a drug in the body, but unnecessary for this invention.
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`Apotex attacks the ’405 Patent as obvious and anticipated, on three grounds.
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`First, Apotex argues that a publication the Examiner used to reject the claims
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`in prosecution, “Kovarik” (Ex. 1004), plus another publication from the Patent’s
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`face, “Thomson” (Ex. 1005), renders the Patent’s claims obvious.
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`Kovarik is a published patent application for a method of using loading doses
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`with S1P agonist drugs, of which fingolimod is one. The Examiner withdrew his
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`rejection based on Kovarik after Novartis amended the claims to specifically exclude
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`the loading dose that Kovarik requires. Apotex says the Examiner was wrong. A
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`person of skill reading Kovarik supposedly would ignore the loading dose
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`requirement as to MS, based on an opinion from physician Dr. Barbara Giesser.
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`Stripped of its loading-dose focus, Apotex says a person of skill would seize on
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`Kovarik’s hypothetical 0.5 mg maintenance dose for autoimmune diseases to render
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`the ’405 Patent obvious.
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`Where, as here, an Examiner thoroughly considered a publication during
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`prosecution—allowing the claims only after they were amended to circumvent this
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`exact publication—the Board should not rehash the analysis. That alone is reason
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`to reject this ground under 35 U.S.C. § 325(d). Nor is there any question the
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`Examiner was right. Kovarik is entirely about loading doses. The ’405 Patent
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`excludes loading doses. Kovarik thus teaches away from the Patent. Kovarik
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`requires a step the ’405 Patent excludes. The law prohibits seizing on one part of a
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`reference while ignoring the rest. That should end the matter. If more were needed,
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`Kovarik never shows how to use a 0.5 mg daily dose—or any specific dose at all—
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`to reduce, prevent, and/or alleviate RRMS relapses; treat RRMS; or slow
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`progression of the disease, as the Patent’s claims call for. Kovarik is inapposite.
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`Second, Apotex recycles two publications from the face of the Patent and
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`mixes in an older patent to argue that a 0.5 mg daily dose would have been obvious
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`to a person of skill: (i) a single-dose Phase I fingolimod transplantation safety study
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`(“Budde,” Ex. 1008); plus (ii) an abstract discussing a Phase II higher dose
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`fingolimod RRMS study (“Kappos 2005,” Ex. 1007); plus (iii) an early patent on the
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`discovery of fingolimod’s lymphocyte-sequestration mechanism (“Chiba,” Ex.
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`1006). Apotex relies on Dr. Giesser’s declaration to argue that a person of skill
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`would have combined these three references to derive a 0.5 mg daily dose of
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`fingolimod to treat RRMS.
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`Dr. Giesser, however, lacks the expertise needed for that opinion. Dr. Giesser
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`is a physician. She has no expertise in the art of drug dose development. The
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`accompanying declarations from physician Dr. Fred Lublin (Ex. 2003) and
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`pharmacologist Dr. William Jusko (Ex. 2005) explain that pharmacologists with
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`training and expertise in drug kinetics and dynamics—specializations wholly
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`different than Dr. Giesser’s—are the correct experts for this invention. Dr. Giesser
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`has none of that expertise. She is thus unable—and does not purport to—interpret
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`the substantial body of pre-June 2006 fingolimod pharmacokinetic (PK) and
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`pharmacodynamics (PD) data in the art, none of which presaged a 0.5 mg daily dose.
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`Apotex’s failure to provide the right expert on these issues is a facial, and fatal,
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`defect in the Petition.
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`Third, Apotex argues a late 2010 reference reporting fingolimod’s Phase III
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`RRMS trial (“Kappos 2010,” Ex. 1038) anticipates the claims, notwithstanding the
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`Patent’s June 2006 priority date. Apotex says the priority date does not control
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`because the specification allegedly does not support the claim language excluding a
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`loading dose that was added by amendment in 2015.
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`Apotex’s anticipation theory is a ruse to unlawfully smuggle a 112 written
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`description argument into an IPR. The theory is also internally inconsistent. The
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`Patent specification focuses on daily or even less frequent dosing to treat RRMS, a
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`chronic, life-long condition. Apotex’s own putative expert repeatedly asserts that
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`persons of skill would read a reference silent on a loading doses as precluding that
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`dosing regimen. Apotex cannot simultaneously argue that the specification’s alleged
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`silence here provides insufficient support for excluding that regimen.
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`For these and other reasons below, the Board should not institute an IPR.
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`FACTS
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`The facts are from the Petition (Pet.) and filed Exhibits (Ex.), including
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`references on the Patent’s face and the accompanying declarations from Dr. Fred
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`Lublin (Ex. 2003), a physician expert in treating MS (Exs. 2003 ¶¶ 8–18; 2004), and
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`Dr. William Jusko (Ex. 2005), a pharmacologist (Exs. 2005 ¶¶ 7–14; 2006).
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`IPR2017-00854
`U.S. Patent No. 9,187,405
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`A. The State of the Art in Fingolimod Research in June 2006
`1.
`Fingolimod’s Discovery and Early Research on its Mechanism of
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`Action: Scientists discovered fingolimod (also called “FTY720”) in the early 1990’s
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`as part of a new class of structurally distinct immunosuppressing compounds derived
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`from a substance in certain fungi called “myriocin.” Fingolimod’s inventors
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`envisioned the compound could be useful to suppress organ rejection or treat
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`autoimmune disease. (Ex. 2007, U.S. Patent No. 5,604,229 on fingolimod and
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`related compounds and methods.)
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`No one, however, knew any of fingolimod’s mechanisms of action until years
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`later, when Dr. Kenji Chiba, one of fingolimod’s inventors, discovered that
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`fingolimod sequestered lymphocytes in lymphatic tissue out of the blood stream. He
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`called this mechanism “lymphocyte homing,” which caused a low lymphocyte
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`blood-count condition called “lymphopenia.” The USPTO awarded Dr. Chiba U.S.
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`Patent No. 6,004,565 in 1999 for this discovery, the “Chiba” patent cited in the
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`Petition (Ex. 1006).
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`With respect to dosing, the Chiba patent showed that higher fingolimod doses
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`caused greater lymphopenia in animals than lower doses, with no increased toxicity.
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`Chiba Figure 11 showed lymphocyte blood counts in animals for doses of 0.1 mg/kg,
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`1.0 mg/kg, and 10 mg/kg. (Ex. 1006 at Sheet 8 of 11; see also col. 10, l. 1–8.)
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`Lymphocyte counts were consistently lower at higher doses. Elsewhere in the patent
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`(at col. 12, l. 66–col. 13, l. 2), Chiba described that higher doses showed no increased
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`renal or other toxicity in the tested species. In other words, Chiba taught that higher
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`doses yielded greater lymphopenia at no measurable cost.
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`2.
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`Fingolimod and Transplant Research. Chiba further described animal
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`experiments with fingolimod to suppress organ rejection. (See, e.g., id. at col. 12, l.
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`48–col. 13, l. 39.) Subsequent research pursued this potential use in humans. In that
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`work, scientists collected and analyzed large volumes of PK/PD data in animals and
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`humans relevant to dosing fingolimod for use in transplantation.
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`Budde. Novartis scientists first gave fingolimod to humans in a Phase I
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`single-dose transplantation study in the early 2000’s, as reported in the Budde
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`reference cited in the Petition (Ex. 1008). Investigators sought “to measure safety,
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`single-dose pharmacokinetics, and pharmacodynamics in stable renal transplant
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`patients.” (Id. at 1073, Abstract.) Investigators gave kidney transplant patients
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`already taking cyclosporine-A escalating single doses of fingolimod of 0.25, 0.5,
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`0.75, 1.0, 2.0, or 3.5 mg, then watched for adverse reactions compared to placebo.
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`(Id. at 1074.)
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`The Budde authors also gathered copious PK/PD data, including peripheral
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`blood lymphocyte counts. Among other things, they found fingolimod’s
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`“pharmacodynamics were characterized by a reversible transient lymphopenia
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`within 6 h, the nadir being 42% of baseline.” (Id. at 1073, Abstract.) While each
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`dose induced lymphopenia, “the two highest dose groups exhibited a more
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`pronounced decline in lymphocyte numbers.” (Id. at 1079.) Adverse events were
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`few and minor at all doses. The most significant was transient, asymptomatic
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`bradycardia, a slowing of the heart rate. (Id. at 1073, Abstract.)
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`Kahan 2003. After Budde’s single-dose study, investigators conducted a
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`multi-dose Phase I study to assess fingolimod’s safety for prolonged use. Kahan
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`2003 reports that study and the results. (Ex. 1031.)
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`Kahan
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`2003
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`“examined
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`the
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`safety,
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`pharmacodynamics,
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`and
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`pharmacokinetics” for escalating doses of 0.125, 0.25, 0.5, 1.0, 2.5, and 5.0 mg or
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`placebo administered over 28 days in stable renal transplant patients. (Id. at 1079.)
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`In its “results” section, Kahan 2003 reported that fingolimod “doses greater than or
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`equal to 1.0 mg/day produced a significant reduction in peripheral blood lymphocyte
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`count by up to 85%,” with no “major increase in adverse events or a change in renal
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`function” as compared to placebo. (Id.) Doses less than 1.0 mg/day produced
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`materially lower reductions in peripheral lymphocyte blood counts. The study
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`concluded that “[a]t doses up to 5.0 mg/day for 28 days, stable renal transplant
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`patients treated with FTY720 in combination with CsA and prednisone displayed a
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`dose-dependent, reversible decline in peripheral blood lymphocytes without an
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`enhanced incidence of collateral toxicities, except possibly bradycardia.” (Id.)
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`Park. Researchers published another multi-dose stable renal transplant study
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`IPR2017-00854
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`in 2005, the “Park” reference. (Exhibit 1019.) Like the studies that came before it,
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`Park focused on fingolimod’s “lymphocyte homing effect” that “produces peripheral
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`blood lymphopenia.” (Id. at 683.) Investigators studied 23 patients at doses ranging
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`from 0.25 to 2.5 mg/day for between 4 and 12 weeks after transplantation. “The
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`effect of PD was calculated as to the absolute lymphocyte count or its reductions.
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`PK/PD modeling was used to find the best-fit model.” (Id.) The investigators found
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`that fingolimod “produced a dose-dependent increase in mean percent reduction of
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`peripheral lymphocyte counts,” and that a “simple Emax model … was the best-fit
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`PK/PD modeling for FTY720 dose” when “[u]sing lymphopenia as an FTY720 PD
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`surrogate marker[.]” (Id.) Further, “high % reductions (~80%) in peripheral
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`lymphocytes are required to achieve best efficacy[.]” (Id.)
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`3.
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`Fingolimod and MS Research: At the same time some scientists were
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`studying fingolimod in transplant patients, others began to explore fingolimod’s
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`potential in MS animal models, and in early clinical trials.
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`MS is a disease in which the body’s immune system attacks the central
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`nervous system. Symptoms include fatigue; numbness; spasticity; bladder, bowel,
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`and/or sexual dysfunction; fatigue; psychiatric disorders; and the like. It is a chronic
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`life-long condition that tends to strike people in their 20’s to the 40’s, especially
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`women. The cause is unknown and there is no cure. (Exs. 1005, Thompson, at 157–
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`58; 2003 ¶ 44.)
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`As of June 2006, MS was usually categorized in four forms: (1) “relapsing-
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`remitting,” or “RRMS”; (2) “secondary progressive,” or “SPMS”; (3) “primary
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`progressive,” or “PPMS”; and (4) “progressive relapsing,” or “PRMS.” RRMS is
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`the most common. It affects patients in cycles: first with an acute phase; then
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`remission; and then acute relapses. Within the nervous system, this process degrades
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`the myelin sheathing around neurons, disrupting nerve signals and causing the build-
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`up of scar-tissue. Some patients transition into a more progressive form of the
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`disease. At that point, processes possibly separate from the immune system take
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`over, and the disease worsens in a more consistent manner with little or no
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`remissions. (Exs. 1016, David J. Virley, Developing Therapeutics for the Treatment
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`of Multiple Sclerosis, The Journal of the American Soc’y for Experimental
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`NeuroTherapeutics (2005) (“Virley”), at 638; 1005 at 159–60; 1003 ¶ 45.)
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`Animal Studies. Scientists studying MS have long used particular mouse and
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`rat models to approximate and investigate RRMS, called “experimental autoimmune
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`encephalitis” or “EAE” models. EAE “models simulate the clinical and pathological
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`hallmarks of MS and can provide the necessary predictive index for clinical
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`therapeutic application.” (Ex. 1016, Virley, at 639.) These models use rats or mice
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`injected with agents that stimulate an immune attack on the central nervous system
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`to induce an RRMS-like condition. From 2002-2005, different research groups
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`published at least four studies of fingolimod’s effects in EAE models, including
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`Brinkman 2002 (Ex. 2008), Fujino 2003 (Ex. 1028), Webb 2004 (Ex. 2014), and
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`Kataoka 2005 (Ex. 1029). Each is on the face of the ’405 Patent (Ex. 1001 at pages
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`1–2), though none is substantively addressed in the Petition.
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`All four studies focus on lymphocyte homing as fingolimod’s mechanism of
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`action. (Exs. 2008 at 21453 (“FTY720 apparently sequesters lymphocytes from
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`circulation to secondary lymph tissue compartments[.]”); 1028 at 71 (“[T]he
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`protective anti-inflammatory effect of treatment with FTY720 was, to a large extent,
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`due to the inhibition of … T-cell responses and/or their migration into the central
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`nervous system and may be a potential candidate for use in treating patients with
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`MS.”); 2014 at 108 (“It now appears that at least one of the mechanisms by which
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`FTY720 achieves its effects in vivo is by a sequestration of circulating lymphocytes
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`in peripheral lymph nodes.”); 1029 at 439 (“FTY720 … sequesters circulating
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`mature lymphocyte[s] into secondary lymphoid tissues and thymus … and exerts
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`immunomodulating effect[s].”).) None mentions the inhibition of neo-angiogenesis
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`as a potential mechanism.
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`Taken together, the studies show that fingolimod induces lymphopenia in a
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`dose-dependent manner. Consistent with Chiba (above at 6–7), higher doses cause
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`lower lymphocyte blood counts and also reduce EAE symptoms to a greater extent
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`than lower doses. (Exs. 2008 at 21456 (Fig. 4); 1029 at 442 (Fig. 3); 2014 at 118–
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`19 (“[W]e saw a dose-dependent and reversible lymphopenia . . . . In addition, there
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`was a dose-dependent reduction in clinical scores of surviving [EAE] mice.”).)
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`Webb observes that at least 70% lymphopenia is needed for any effect on EAE
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`symptoms. (Ex. 2014 at 118 (“In dose response experiments, we found that a
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`threshold of about 70% depletion of peripheral lymphocytes was required to see any
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`efficacy, and thereafter, the dose-response relationship between clinical benefit and
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`lymphopenia was very steep.”).) Webb further observes a “disconnect” between
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`lymphopenia and EAE suppression, suggesting that mechanisms other than
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`lymphopenia might be involved in treating EAE. (Id. at 118–19.) Webb does not
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`speculate about what those mechanisms might be.
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`Phase II Clinical Study—Kappos 2005. Novartis first tested fingolimod in
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`human RRMS patients in a six-month Phase II trial in 281 patients with two dose
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`arms: 5.0 and 1.25 mg daily. The results are in the Kappos 2005 abstract discussed
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`in the Petition. (Ex. 1007.) This abstract describes how researchers measured
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`fingolimod’s effect on clinical endpoints such as MRI brain scans and neurological
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`tests. Fingolimod reduced lesions and relapses as compared to placebo. “Adverse
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`events were more common in the 5 mg group, with the most frequently reported
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`(>15% patients) being mild headaches and nasopharyngitis.” (Id. at 41) However,
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`“[t]here was no compelling dose-related difference in efficacy on MRI or clinical
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`endpoints.” (Id.)
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`The Inventors’ Neo-Angiogenesis Discovery and the ’405 Patent
`B.
`In early 2006, Novartis scientists Hiestand and Schnell upended a decade’s
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`worth of research focused solely on fingolimod’s ability to sequester lymphocytes
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`in lymphatic tissue. The inventors showed fingolimod could also retard new blood
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`vessel growth into MS lesion sites, with therapeutic benefits in MS animal models.
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`Their discovery is reflected in the ’405 Patent specification. (Ex. 1001 at col. 8, l.
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`61–col. 9, l. 15; col. 10, l. 16–col. 11, l. 2).
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`1.
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`The Invention. The Patent specification describes MS as “an immune-
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`mediated disease of the central nervous system with chronic inflammatory
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`demyelination leading to progressive decline of motor and sensory functions and
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`permanent disability.” (Ex. 1001 at col. 8, l. 61–64.) The “[c]haracteristic
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`pathological features of demyelinating disease include inflammation, demyelination
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`and axonal and oligodendrocyte loss. In addition lesions can also have a significant
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`vascular component.” (Id. at col. 9, l;. 6–9.) With respect to vascularization, “[a]
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`firm link has recently been established between chronic inflammation and
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`angiogenesis[,] and “neovascularization seems to have a significant role in the
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`progression of the disease.” (Id. col. 9, l. 6–12.)
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`The inventors then revealed their discovery “that S1P receptor modulators
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`have an inhibitory effect on neo-angiogenesis associated with demyelinating
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`diseases, e.g., MS.” (Id. col. 9, l. 13–15.) As the specification explains,
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`fingolimod/FTY720 is an “S1P receptor modulator.” (Id. col. 10, l. 22–24.)
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`The specification further describes the EAE animal experiments proving the
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`discovery. Hiestand and Schnell treated some EAE rats with fingolimod, while
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`others received nothing. After 26 days, the rats reached a relapse phase. The
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`inventors then euthanized the rats and used special polymers to create negative-space
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`casts of the rats’ vasculature. The inventors analyzed the casts “using micro
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`computer tomography,” and compared the results of the treated and untreated rats.
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`The inventors’ analysis showed that fingolimod—“Compound A” in the
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`specification—“significantly blocks disease-associated neo-angiogenesis when
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`administered to the animals at a dose of from 0.1 to 20 mg/kg p.o.”—i.e., orally—
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`which in turn “completely inhibits the relapse phases[.]” Moreover, Hiestand and
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`Schnell discovered that this effect could be achieved at even infrequent dosing—
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`“0.3 mg/kg every 2nd or 3rd day or once a week.” (Id. col. 10, l. 36–col. 11, l. 2.)
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`Based on these EAE animal studies, the specification explains how different
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`doses of S1P modulators could be useful in humans, ranging from 0.1 to 50 mg daily.
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`For oral administration, the specification identifies suitable doses from 0.1 mg to 30
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`mg daily, and fingolimod in particular “may alternatively be administered
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`intermittently, e.g. at a dose of 0.5 to 30 mg every other day or once a week.” Finally,
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`the specification explains how fingolimod can be administered with other anti-
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`angiogenic drugs as well, so-called “VEG-F receptor antagonists.” (Id. at col. 11, l.
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`20–42.)
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`2.
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`Prosecution. Novartis wrote up these discoveries and applied for a
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`patent claiming methods of treating MS using 0.5 mg daily dosing. Kevin E.
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`Weddington—an Examiner with over 20 years of experience in examining life
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`sciences patent claims—examined the application. (Exs. 1011 (’405 Patent File
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`Wrapper), at 0040; 2019 at 1, showing Examiner Weddington as the Examiner on a
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`life science patent application in 1984.)
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`During prosecution, Examiner Weddington raised the Kovarik publication as
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`a potential barrier to patentability in an April 6, 2015 Office Action. The Examiner
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`pointed to a review of emerging RRMS treatments—the “Virley” reference—that
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`discussed fingolimod in general terms without regard to dose. The Examiner
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`combined that reference with the example in Kovarik of a 0.5 mg daily dose for
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`autoimmune disease to reject the claims as obvious. (Ex. 1011 at 0051–56.)
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`Kovarik is a 2004 patent application on a method of using loading doses to
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`achieve a steady-state of S1P receptors like fingolimod in the body more rapidly
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`than would be achieved with regulator dosing. (Ex. 1004.) Kovarik’s loading-dose
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`regimen was general; it was not for any particular disease or any particular active
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`molecule. It merely addressed how to use an S1P modulator “in the course of the
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`treatment of transplant patients or patients suffering from autoimmune disease or
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`disorders.” (Id. at 1.) Kovarik’s application contains multiple hypothetical
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`examples of the rates and ratios that might be used for various molecules, in many
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`different diseases. (Id. at 13–18.) The application barely mentions multiple sclerosis
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`at all, listing it only once in a compilation of autoimmune diseases. (Id. at 14 (listing
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`“autoimmune diseases, e.g. multiple sclerosis, lupus nephritis, rheumatoid arthritis,
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`inflammatory bowel diseases or psoriasis”).)
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`In response to the Kovarik rejection, Novartis amended its claims to explicitly
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`exclude any loading dose. (Ex. 1011 at 0032.) Novartis in-house patent counsel
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`Drew Holmes, Ph.D. argued that the amended claims rendered Kovarik irrelevant.
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`(Id. at 0033–34.) As Dr. Holmes pointed out, “Kovarik does not teach or suggest
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`any daily [dose] of FTY720 that does not immediately follow a loading dose
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`regimen and, indeed, relies upon the disclosed loading dose regimen to determine
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`the daily dose that follows it.” In other words, “Kovarik’s mention of a dosage of
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`0.5 mg is limited to the context of a dosage that follows, immediately, the loading
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`dose regimen described therein.” Dr. Holmes explained that the “Kovarik loading
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`dose regimen involves raising stepwise the daily dosage of the S1P receptor …
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`agonist over 3 to 6 days up to 3- to 21-fold the standard daily dosage for the purpose
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`of attaining steady state blood levels of the drug in less than a week.” (Id.)
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`Kovarik thus simply established ratios of loading to daily doses to achieve
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`steady state at a certain rate. It did not teach how to use a specific dose to treat any
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`specific condition, including MS. Accordingly, “[a]pplicants submit that the skilled
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`person reading Kovarik would attach no significance to the suitability of any daily
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`dosage mentioned therein outside the context of an immediately preceding loading
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`dose regimen.” (Id. at 0034.) Examiner Weddington apparently agreed, withdrew
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`the rejection, and allowed the amended claims on August 17, 2015. (Id. at 0011.)
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`3.
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`The Issued Claims. The USPTO issued the Patent on November 17,
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`2015. (Ex. 1001, cover page.) It contains three pairs of independent and dependent
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`claims. All require a 0.5 mg fingolimod daily dose (in base or salt form) as RRMS
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`therapy for a “subject in need,” absent an immediately preceding loading dose
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`regimen. The claims differ in that 1 and 2 are for a subject in need of “reducing or
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`preventing or alleviating relapses” (id. col. 12, l. 49–58); 3 and 4 are for a subject in
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`need of “treating” the disease (id. col. 12, l. 59–67); and 5 and 6 are for a subject in
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`need of “slowing [its] progression” (id. col. 13, l. 1–9).
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`C. Apotex’s Petition
`Apotex filed its Petition on February 2, 2017. Apotex relies on Dr. Giesser’s
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`accompanying declaration (Ex. 1002) to advance three proposed grounds.
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`1.
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`Kovarik plus Thomson: This ground challenges the ’405 Patent as
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`obvious on the theory that Thomson provides basic background about fingolimod’s
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`potential utility in treating RRMS, and Kovarik supposedly specifies a 0.5 mg daily
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`dose. (Pet. 32–47; Ex. 2002 ¶¶ 103–129.) The Thomson review thus serves the
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`same role as the Virley review in the Examiner’s original Kovarik analysis.
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`Apotex does not dispute that Kovarik describes a loading-dose invention, or
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`that the ’405 Patent claims exclude a loading dose. Apotex and Dr. Giesser instead
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`contend a person of skill would seize on one example in Kovarik of a hypothetical
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`0.5 mg maintenance dose for an unspecified autoimmune disease, and
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`simultaneously would ignore its express loading dose requirement. (Pet. at 36.) Dr.
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`Giesser concedes that fingolimod has a long half-life in the body, and that such drugs
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`are often prescribed with loading doses to achieve steady-state in the body as quickly
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`as possible. (Ex. 1002 ¶ 69.) But according to Apotex and Dr. Giesser, RRMS is a
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`chronic condition unsuited to loading doses, which allegedly are used for acute
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`conditions that have an urgent need for a steady-state of the drug in the body. (Pet.
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`37; Ex. 1002 ¶¶ 70–71.)
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`Neither Apotex nor Dr. Giesser explain how Kovarik would teach anyone that
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`0.5 mg of fingolimod daily would reduce, prevent, or alleviate RRMS relapses; treat
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`RRMS; or slow progression of RRMS, as the ’405 Patent claims require. Kovarik
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`merely offers hypothetical dosing regimens to illustrate how to calculate loading
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`doses for S1P modulators, including fingolimod. Kovarik contains no data on how
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`0.5 mg daily would be effective for treating any particular condition.
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`Apotex and Dr. Giesser