IPR2017-01035 (Patent No. 9,320,716)
`Patent Owner Preliminary Response
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
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`MYLAN PHARMACEUTICALS INC.,
`PETITIONER
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`v.
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`COSMO TECHNOLOGIES LIMITED,
`PATENT OWNER
`___________________
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`CASE IPR2017-01035
`Patent 9,320,716
`___________________
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`PATENT OWNER’S PRELIMINARY PATENT OWNER RESPONSE
`UNDER 37 C.F.R. § 42.107
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`Patent Owner Preliminary Response
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
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`MYLAN PHARMACEUTICALS INC.,
`PETITIONER
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`v.
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`COSMO TECHNOLOGIES LIMITED,
`PATENT OWNER
`___________________
`
`
`CASE IPR2017-01035
`Patent 9,320,716
`___________________
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`PATENT OWNER’S PRELIMINARY PATENT OWNER RESPONSE
`UNDER 37 C.F.R. § 42.107
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`Table of Contents
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`IPR2017-01035 (Patent No. 9,320,716)
`Patent Owner Preliminary Response
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`I.
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`II.
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`INTRODUCTION ............................................................................................. 1
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`BACKGROUND ............................................................................................... 8
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`A.
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`Technical Overview Of The Invention .............................................. 8
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`1.
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`2.
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`3.
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`4.
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`Inflammation Associated With Ulcerative Colitis ................... 8
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`Treatment Of Ulcerative Colitis............................................. 10
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`Oral Colonic-Delivery Formulations ..................................... 11
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`Uceris ..................................................................................... 15
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`B.
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`Prosecution History .......................................................................... 18
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`III. CLAIM CONSTRUCTION .............................................................................. 18
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`A.
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`B.
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`“macroscopically homogenous structure” (All Claims) .................. 18
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`“to treat intestinal inflammatory disease” (All Claims) ................... 19
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`IV. EACH OF PETITIONER’S GROUNDS FAILS ................................................. 21
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`A. Grounds 1 And 2: Savastano (Ex. 1008) Does Not Anticipate
`Nor Render Obvious Any Of The Claims ........................................ 22
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`1.
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`2.
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`3.
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`4.
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`Savastano Does Not Teach “a macroscopically
`homogenous structure” (All Claims) ..................................... 24
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`Savastano Does Not Teach A Macroscopically
`Homogenous Structure Comprising “at least one
`lipophilic compound” (Claims 1-11, 22-24, 26-27, 29) ........ 36
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`Savastano Does Not Teach “wherein the
`macroscopically homogenous structure controls the
`release of the budesonide” (All Claims) ................................ 37
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`Savastano Does Not Teach How To Make A
`Formulation With “budesonide in an amount effective
`to treat intestinal inflammatory disease” (All Claims) .......... 42
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`IPR2017-01035 (Patent No. 9,320,716)
`Patent Owner Preliminary Response
`Savastano Does Not Anticipate Or Render Obvious
`Amphiphilic Claims (Claims 6-8, 12-23, 25-26, 28-29) ....... 43
`
`a.
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`Lecithin (Claims 8 and 18) .......................................... 45
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`Savastano Does Not Provide A Motivation Or A
`Reasonable Expectation Of Success ...................................... 47
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`5.
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`6.
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`B.
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`Grounds 3 and 4: Friend (Ex. 1009) Does Not Anticipate Or
`Render Obvious Any Of The Claims ............................................... 48
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`1.
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`2.
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`3.
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`4.
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`5.
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`6.
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`Friend Does Not Teach A Macroscopically
`Homogenous Structure (All Claims) ..................................... 49
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`Friend Does Not Teach A Macroscopically
`Homogenous Structure Comprising “at least one
`lipophilic compound” (Claims 1-11, 22-24, 26-27, 29) ........ 51
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`Friend Teaches Controlled Release Through Bacterial
`Degradation Of A Gum Excipient, Not “wherein the
`macroscopically homogenous structure controls the
`release of the budesonide” (All Claims) ................................ 52
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`Friend Does Not Teach How To Make A Formulation
`With “budesonide in an amount effective to treat
`intestinal inflammatory disease” (All Claims) ...................... 54
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`a.
`
`b.
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`Friend’s Gum Formulation Failed “to treat
`intestinal inflammatory disease” ................................. 54
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`Friend Does Not Enable The Substitution Of
`Budesonide For Dexamethasone
`In The
`Exemplary Formulations ............................................. 56
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`Friend Does Not Anticipate Or Render Obvious
`Amphiphilic Compound (Claims 6-8, 12-23, 25-26,
`28-29) ..................................................................................... 58
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`a.
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`Lecithin (Claims 8 and 18) .......................................... 60
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`Friend Does Not Provide A Motivation Or A
`Reasonable Expectation Of Success ...................................... 61
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`IPR2017-01035 (Patent No. 9,320,716)
`Patent Owner Preliminary Response
`Ground 5: Friend (Ex. 1009) in Combination with Savastano
`(Ex. 1008) Does Not Render Obvious Claims 8 and 18 .................. 61
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`C.
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`V.
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`PETITIONER FAILS TO OVERCOME THE OBJECTIVE EVIDENCE OF
`NON-OBVIOUSNESS .................................................................................... 63
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`A. Others, Including The Pharma Giant In The GI Field
`AstraZeneca, Failed To Meet The Long-Felt Need To
`Develop An Oral Formulation That Could Deliver Drug To
`The Distal Colon .............................................................................. 63
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`B.
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`Uceris Satisfied The Long-Felt Need ............................................... 67
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`VI. THE PETITION SHOULD BE DENIED BECAUSE THE INTER PARTES
`REVIEW PROCESS IS UNCONSTITUTIONAL ................................................ 70
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`VII. CONCLUSION .............................................................................................. 70
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`IPR2017-01035 (Patent No. 9,320,716)
`Patent Owner Preliminary Response
`TABLE OF AUTHORITIES
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` Page(s)
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`Cases
`In re Antonie,
`559 F.2d 618 (C.C.P.A. 1977) ............................................................................ 47
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`Apple v. Virnetx,
`IPR2014-00481, Paper No. 35 (P.T.A.B. Aug. 24, 2015) .............................. 7, 36
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`In re Brimonidine Patent Litig.,
`643 F.3d 1366 (Fed. Cir. 2011) .......................................................................... 47
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`Cephalon Inc. v. Mylan Pharm. Inc.,
`962 F. Supp. 2d 688 (D. Del. 2013) .................................................................... 69
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`Coalition For Affordable Drugs II, LLC v. Cosmo Technologies, Ltd.,
`IPR2015-00988 (Paper 8) (P.T.A.B. Oct. 7, 2015) ............................................ 33
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`Complex Innovations, LLC v. Amgen,
`IPR2016-00085, Paper No. 10 (P.T.A.B. July 14, 2016) ....................... 46, 47, 62
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`Continental Can Co. USA v. Monsanto Co.,
`948 F.2d 1264 (Fed. Cir. 1991) ................................................................ 5, 27, 34
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`In re Cyclobenzaprine Hydrochloride Extended-Release Capsule
`Patent Litig.,
`676 F.3d 1063 (Fed. Cir. 2012) .......................................................................... 21
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`Delphix Corp. v. Actifio, Inc.,
`IPR No. 2015-01678, Paper No. 8 (P.T.A.B. Feb. 20, 2016) ............................. 26
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`Eli Lilly & Co. v. Teva Pharm. USA,
`557 F.3d 1346 (Fed. Cir. 2009) .......................................................................... 69
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`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) .................................................................. 4, 43, 59
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`Leo Pharm. Prod., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 71
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`Martek Biosciences Corp. v. Nutrinova,
`579 F.3d 1363 (Fed. Cir. 2009) .......................................................................... 21
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`Page(s)
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`MaxLinear v. Cresta Tech. Corp.,
`IPR2015-00594, Paper No. 90 (P.T.A.B. Aug. 15, 2016) .............................. 7, 36
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`McCormick Harvesting Mach. Co. v. C. Aultman & Co.,
`169 U.S. 606 (1898) ............................................................................................ 72
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`Mylan Pharmaceuticals v. Yeda Research & Development Co. Ltd.,
`IPR2015-00643, Paper 90 (P.T.A.B., Dec. 2, 2016) .......................................... 21
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`Mytee Prods. v. Harris Research,
`439 Fed. App’x 882 (Fed. Cir. 2011) ................................................................. 40
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`Oil States Energy Servs., LLC v. Greene's Energy Grp., LLC,
`No. 16-712 (June 12, 2017) ................................................................................ 72
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`In re Rijckaert,
`9 F.3d 1531 (Fed. Cir. 1993) ........................................................................ 41, 42
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`In re Spormann,
`363 F.2d 444 (C.C.P.A. 1966) ............................................................................ 42
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`St. Jude Med. v. Access Closure,
`729 F.3d 1369 (Fed. Cir. 2013) .......................................................................... 42
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`Tietex Int’l Ltd. v. Precision Fabrics Group,
`IPR2014-01248, Paper No. 39 (P.T.A.B. Jan. 27, 2016) ................................... 40
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`W.L. Gore & Assocs. v. Garlock,
`721 F.2d 1540 (Fed. Cir. 1983) ...................................................................... 5, 34
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`Ex Parte Ziegler,
`Appeal 2012-010974, 2015 WL 430598 (P.T.A.B. Jan. 20, 2015) .................... 40
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`Rules and Regulations
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`37 C.F.R. § 42.65 ............................................................................................... 26, 51
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`IPR2017-01035 (Patent No. 9,320,716)
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`Other Authorities
`U.S. Constitution ...................................................................................................... 72
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`Page(s)
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`IPR2017-01035 (Patent No. 9,320,716)
`Patent Owner Preliminary Response
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`I.
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`INTRODUCTION
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`Ulcerative colitis (“UC”)
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`is a devastating disease
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`that can cause
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`inflammation throughout the large intestine, i.e., the colon. UC patients suffer from
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`persistent diarrhea, abdominal cramps and pain, rectal bleeding, loss of appetite,
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`weight loss, and fatigue. Unfortunately, there is no cure for UC. If it cannot be
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`managed with medications, the only alternative is surgical removal of the colon.
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`At some point during the course of their disease, most patients must resort to
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`using glucocorticosteroids (“steroids”), a class of powerful anti-inflammatories, to
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`reduce their inflammation. While systemic steroids can reduce colon inflammation,
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`they also cause terrible toxicities that preclude their long-term use, including high
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`blood pressure, glaucoma, memory and psychological effects,
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`increased
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`susceptibility to infections, diabetes, adrenal gland suppression, and cataracts,
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`among others.
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`Pharmaceutical companies, including giants in the field of gastrointestinal
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`(“GI”) disease like AstraZeneca, tried for many years to develop an oral,
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`colonic-delivery formulation that could deliver locally-acting steroids, such as
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`budesonide, directly to the sites of inflammation and thereby avoid the toxicities of
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`systemic administration. While some formulations, such as Entocort CR®, could
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`deliver drug to the small intestine and proximal colon (the portion of the colon
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`immediately after the small intestine), no prior art formulation delivered drug
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`throughout all the sectors of the colon, including the hard-to-reach distal colon (the
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`final portion of the colon).
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`Patent owner fulfilled this unmet need by developing a tablet formulation
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`that delivers budesonide throughout the sectors of the colon, including the distal
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`colon. This formulation is sold as Uceris® and it is covered by the patent at issue,
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`U.S. Pat. No. 9,320,716 (“the ʼ716 patent”). As shown in a pharmaco-scintigraphy
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`study,1 Uceris® delivers budesonide “throughout the whole colon including the
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`sigmoid [, i.e., end of the distal colon].” Ex. 2001 at 34. This extraordinary drug-
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`release profile results from a novel feature of the formulation claimed by the ʼ716
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`patent: a “macroscopically homogenous structure” comprising a hydrophilic,
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`1 In a “pharmaco-scintigraphy” study, scientists tag a drug formulation with a
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`weakly radioactive isotope and track the same during its transit through the
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`gastrointestinal systems of volunteers using a “gamma camera,” while
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`simultaneously measuring plasma levels of absorbed drug. This allows assessment
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`of where in the GI tract, and to what extent, the drug formulation breaks up and
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`releases the active compound. Scintigraphy has been described as an “elegant
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`technique” and the “method of choice” for investigating release of drug
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`formulations in the gastrointestinal tract. Ex. 2002 at 1201.
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`lipophilic and/or amphiphilic compound “wherein
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`the macroscopically
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`homogenous structure controls the release of the budesonide.”
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`None of the art cited by petitioner taught this novel feature. Indeed, the two
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`references in petitioner’s Grounds disclosed very different methods of colonic
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`delivery. The first reference, Savastano (Ex. 1008, U.S. Pat. No. 5,681,584),
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`teaches the use of discrete layers—i.e., a “delay jacket” and “semi-permeable
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`membrane”—and optionally a “release orifice,” to control drug release. The
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`second reference, Friend (Ex. 1009, U.S. Pat. No. 5,811,388), teaches a bioerodible
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`formulation that uses gum to control release through degradation by microbes and
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`enzymes present in the colon. Neither reference teaches a “macroscopically
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`homogenous structure” of particular excipients to control drug release.
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`Petitioner’s only argument that the Savastano and Friend references disclose
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`the key limitation of the ʼ716 patent is to conclude summarily that pharmaceutical
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`“mixing” and compression of ingredients to obtain a “uniform matrix tablet,”
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`without more, necessarily results in a “macroscopically homogenous structure.”
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`Not so.
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`As discussed in detail in Section IV.A.1 below, the homogeneity of a
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`mixture will depend on many factors, including mixing time, the size and shape of
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`the particles of each component (e.g., whether particles are milled or micronized),
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`relative densities of different components, the order of mixing, mixing equipment,
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`whether the mixture is moved during the manufacturing process, and the quantity
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`of an excipient relative to the total amount of all components. If homogeneity is
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`desired for a particular product, additional steps and techniques, such as geometric
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`dilution and comilling, often are necessary. Neither Savastano nor Friend instructs
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`the use of any of these techniques. Indeed, neither reference says anything about
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`achieving homogeneity in any sense, much less macroscopic homogeneity. Neither
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`petitioner nor its expert provides any underlying rationale why the very limited
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`descriptions of the formulation processes in Savastano (e.g., “mix[] together”) and
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`Friend (e.g., “simply blend[]”) necessarily would result in a macroscopically
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`homogenous structure.
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`The omission of any analysis by petitioner is glaring for at least four
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`reasons. First, conclusory assertions, unaccompanied by citation to scientific
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`literature or reasoned explanation, are entitled to no weight. In re Kahn, 441 F.3d
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`977, 988 (Fed. Cir. 2006) (noting that a finding of obviousness “cannot be
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`sustained by mere conclusory statements; instead, there must be some articulated
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`reasoning with some rational underpinning to support the legal conclusion of
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`obviousness”).
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`Second, petitioner is effectively relying on an implicit inherency theory to
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`support its argument. Without any discussion of the particular physical properties
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`of the ingredients (e.g., particle size, density, fineness) or the specific mixing and
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`processing steps they undergo (e.g., mixing time, sequence of mixing, geometric-
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`dilution mixing), petitioner’s argument reduces to the recognition that one can
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`obtain a homogenous blend if the right ingredients are used and the proper steps
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`are taken. But the prior art contains no direction regarding achieving macroscopic
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`homogeneity; it contains only simple directions to mix. It is petitioner’s burden to
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`show that one following that limited direction in the art necessarily would obtain a
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`macroscopically homogenous result, i.e., for all ingredients, under all processing
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`conditions. See, e.g., Continental Can Co. USA v. Monsanto Co., 948 F.2d 1264,
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`1268-69 (Fed. Cir. 1991) (for inherent anticipation “evidence must make clear that
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`the missing descriptive matter is necessarily present in the thing described in the
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`reference, and that it would be so recognized by persons of ordinary skill”); W.L.
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`Gore & Assocs. v. Garlock, 721 F.2d 1540, 1554 (Fed. Cir. 1983) (anticipation
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`“cannot be predicated on mere conjecture respecting the characteristics of products
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`that might result from the practice of processes disclosed in references”). Yet
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`petitioner provides no evidence from which one can reach that conclusion.
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`Third, petitioner’s position in district court litigation undercuts its suggestion
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`that the steps described in the prior art necessarily result in a macroscopically
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`homogenous composition. Indeed, petitioner has taken the exact opposite position
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`regarding whether simple mixing/blending, to make a “uniform” tablet necessarily
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`would result in a “macroscopically homogenous structure.” In arguing for
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`non-infringement of the ʼ716 patent, petitioner asked the court to adopt a finding
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`(from trial in another case) that “uniformity testing to demonstrate blend
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`uniformity, to demonstrate tablet uniformity” after “blending” and “compression
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`steps,” Ex. 2025 at 293:15-19, was insufficient by itself to show that a resulting
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`tablet would have a “macroscopically homogenous” structure. Id. at 335:16-24.2
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`Petitioner contended “[t]he same finding is warranted” with respect to the ’716
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`patent. Ex. 2003 at 4.3
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`2 Patent owner disagrees with the ultimate holding in that trial because, inter alia,
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`there was evidence of record in that case well beyond simple blending and
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`uniformity testing. But, as discussed Section IV.A.1 below, where, as here, the
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`prior art discloses scant details beyond the bare fact of mixing, petitioner should
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`not be heard to argue that what it contends is insufficient to prove infringement
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`sufficient to meet the high burden of showing an alleged inherent property of the
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` is nevertheless
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`prior art.
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`3 Petitioner refused patent owner’s request to submit under seal to the Board an
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`underacted version of petitioner’s relevant statements in this letter, relying on the
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`district court protective order. To the extent patent owner obtains relief from the
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`court, it will so advise the Board and seek leave to file a substitute exhibit.
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`Petitioner’s assertion that “blending,” “compression,” and “uniformity
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`testing” is insufficient to assure macroscopic homogeneity is fatal to its
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`(conclusory) assertion that the general descriptions in Savastano and Friend
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`necessarily would result in such a homogenous composition. Moreover, this Board
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`should, in any event, hold petitioner to its district-court position. See, e.g., Apple v.
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`Virnetx, IPR2014-00481, Paper No. 35 at 10 (P.T.A.B. Aug. 24, 2015) (“Patent
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`Owner made the opposite argument in District Court. Patent Owner cannot now
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`rely on any claim disavowals as clear after it characterizes them as unclear [in
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`District Court].”) (internal citation omitted); MaxLinear v. Cresta Tech. Corp.,
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`IPR2015-00594, Paper No. 90 at 23 (P.T.A.B. Aug. 15, 2016) (holding that the
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`“Favrat” reference was prior art where “Patent Owner admitted before the ITC that
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`Favrat was prior art under § 102(e)”).
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`Finally, petitioner points only to lipophilic lubricants in Friend (Grounds 3
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`and 4) as allegedly satisfying the “one lipophilic compound” limitation in the ʼ716
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`patent claims. But Friend expressly teaches that the lubricant used in its
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`formulations is not blended uniformly with other ingredients. Ex. 1009, col. 16:19-
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`22 (“the ingredients (except for the lubricant) are simply blended together to
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`provide a uniform mixture having the active ingredient uniformly dispersed
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`throughout….” (emphasis added)). Petitioner’s failure to explain why skilled
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`artisans would homogenously mix lubricants with other ingredients when the
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`reference teaches the opposite dooms petitioner’s assertion that Friend anticipates
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`or renders obvious claims that require “at least one lipophilic compound” in the
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`macroscopically homogenous structure.
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`For these reasons, and other deficiencies in the Petition (as will be
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`discussed), petitioner does not establish a reasonable likelihood of prevailing on
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`any of its Grounds.
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`II. BACKGROUND
`A. Technical Overview Of The Invention
`1.
`Inflammation Associated With Ulcerative Colitis
`Ulcerative colitis is intestinal inflammatory disease that affects the large
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`intestine. UC inflammation begins in the rectum and extends proximally
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`(backwards) in an uninterrupted pattern involving part of or the entire colon.
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`IPR2017-01035 (Patent No. 9,320,716)
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`Below is an illustration of typical UC inflammation (image of large intestine
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`anatomy from Exhibit 2034, see also Ex. 2035 at 181, and the extent of
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`inflammation is shown in light and dark red shading):
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`Because UC inflammation can affect the whole colon, see Ex. 2004 at 98
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`(“Inflammation in ulcerative colitis begins in the anal canal, is continuous to a
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`variable degree
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`through
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`the colon”), effective
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`treatment must exert
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`its
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`anti-inflammatory effects throughout the sectors of the colon. This includes the
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`left-sided colon (right side of the illustration above) and sigmoid colon—known
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`together as the “distal colon”—where inflammation is commonly worse. See
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`IPR2017-01035 (Patent No. 9,320,716)
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`Ex. 2005 at 43 (“The most frequent localization of ulcerative colitis (UC) is the
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`distal colon.”); id. at 44 (“In treating active distal UC, efficacy and targeting of the
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`drug to the distal colon are key priorities.”); Ex. 2035 at 181 (identifying sectors of
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`the large intestine); Ex. 2034 at 3 (defining “distal colon” as “[t]he last part of the
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`colon. The distal colon includes the descending colon…and the sigmoid
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`colon….”).
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`Treatment Of Ulcerative Colitis
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`2.
`Non-steroidal anti-inflammatory drugs are inadequate to address UC in
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`nearly half of all UC patients. To treat UC, these individuals have historically
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`resorted to systemically-acting steroids, such as dexamethasone, taken orally or
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`administered intravenously. See Ex. 2006 at 16. Systemic steroids, which act
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`through the bloodstream, can reduce inflammation along the length of the colon.
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`The problem, however, is that maintaining the levels of systemic steroid necessary
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`to reduce inflammation is very toxic to other parts of the body. See Ex. 1009,
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`col. 1:63-66 (“Unfortunately, there are certain side effects the glucocorticoids
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`exhibit if administered systemically and these side effects can be quite
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`significant….”); Ex. 2007 at 1218 (“[S]erious adverse events (AEs) [are]
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`associated with systemic corticosteroid therapy….”). These toxicities affect almost
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`all organ systems in the body and include neuropsychiatric complications,
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`osteoporosis, impaired wound healing, hypertension, diabetes, weight gain,
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`glaucoma, “moon face,” and “buffalo hump.” See, e.g., Ex. 2008 at 205
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`(identifying some toxicities of systemic steroids); Ex. 2009 at 179 (accord).
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`To avoid systemic steroid toxicities, drug formulators have attempted to
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`design oral dosage forms for localized (topical) delivery in the colon, in which the
`
`active ingredient could act on the tissues it contacts while minimizing drug
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`absorption into systemic circulation.
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`3. Oral Colonic-Delivery Formulations
`Throughout the 1980s and 1990s, skilled artisans attempted to design orally
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`administered, colonic-delivery formulations that could deliver drug throughout the
`
`colon to relieve inflammation. Artisans experimented with several different
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`colonic-release mechanisms. See Ex. 1009, col. 2:6-12 (identifying five different
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`categories of colonic-delivery formulations); Ex. 1008, col. 2:61-3:25 (accord).
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`One example formulation used layers—i.e., a “delay jacket” and “semi-
`
`permeable membrane”—and optionally a “release orifice” to control drug release.
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`Below is an illustration of this design:
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`IPR2017-01035 (Patent No. 9,320,716)
`Patent Owner Preliminary Response
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`More detail about this formulation is discussed in Section IV.A when addressing
`
`the Savastano reference (Ex. 1008). Petitioner never suggests this formulation was
`
`ever FDA approved.
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`Another example was a gum-based formulation that relied on bacteria in the
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`colon to enzymatically degrade (i.e., digest) the gum enveloping active drug,
`
`thereby releasing drug as the gum is eroded. More details about this drug release
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`mechanism is discussed in Section IV.B when addressing the Friend reference
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`(Ex. 1009). Petitioner again never suggests this formulation was ever FDA
`
`approved.
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`IPR2017-01035 (Patent No. 9,320,716)
`Patent Owner Preliminary Response
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`Yet another example was a multi-particulate system with individual drug
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`pellets having different controlled-release enteric (pH sensitive) coats that released
`
`drug at different times. Below is an illustration of multiparticulate formulations:
`
`
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`Pellets contained different degrees or types of coating to stagger the release of
`
`drug, such that each pellet controlled release of only that portion of the total dose
`
`of drug that it contained (Figure 1 from Ex. 2010):
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`
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`IPR2017-01035 (Patent No. 9,320,716)
`Patent Owner Preliminary Response
`One such multiparticulate formulation, marketed by AstraZeneca as Entocort EC®,
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`was approved to treat Crohn’s disease, a gastrointestinal disease associated with
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`inflammation in the small intestines and proximal colon, but usually not the distal
`
`colon. See Ex. 2004 at 98 (“Crohn’s disease may occur at any site in the
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`gastrointestinal tract, but more frequently in the terminal ileum and the proximal
`
`colon.”).
`
`As of the priority date, no oral colonic-delivery steroid formulation had been
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`approved in the United States for UC treatment. This was because no one had been
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`able to formulate a colonic-delivery system that delivered drug throughout the
`
`sectors of the colon, including the hard-to-reach distal colon where UC
`
`inflammation begins and is most severe.
`
`Delivering drug to the sectors of the colon, including the distal colon, is
`
`difficult because the oral dosage formulation has to (1) traverse the stomach and
`
`small intestine, and (2) once in the colon, release drug in a controlled manner
`
`throughout the sectors of the colon. To achieve these goals. formulators must
`
`design formulations that can overcome wide variations (both intra- and inter-
`
`patient) in pH, osmotic pressure, viscosity and volume of fluid, enzymatic
`
`conditions, distribution of gut bacteria, mechanical force, and transit time in the
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`gastrointestinal tract. See Ex. 1008, col. 1:59-2:45 (“[T]o reach the colon intact, the
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`dosage form must withstand the rigors of the transit through the gastro-intestinal
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`IPR2017-01035 (Patent No. 9,320,716)
`Patent Owner Preliminary Response
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`tract. These rigors include at least a million-fold variation in hydrogen ion
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`concentration, wide variations in osmotic pressure from the surrounding fluids, a
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`variety of enzymes, and a strong mechanical grinding force.”).
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`Even if a dosage formulation successfully reaches the colon to begin drug
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`delivery, a big challenge in treating patients with UC is ensuring delivery
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`throughout all sectors of the colon, including and especially in the distal colon.
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`For years, these challenges stymied scientists seeking to design an oral
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`dosage form containing a topically-acting steroid for the treatment of UC.
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`Uceris
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`4.
`Patent owner solved the long-felt need by creating a novel oral formulation
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`that delivered topical steroid throughout the sectors of the colon. Patent owner’s
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`unique tablet formulation controls the release of its active ingredient, the steroid
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`budesonide, by using a macroscopically homogenous structure of at least one
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`hydrophilic excipient and at least one lipophilic and/or amphiphilic excipient.4
`
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`4 Independent Claim 1 requires at least one hydrophilic and one lipophilic
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`compound. Independent Claim 12 requires at least one hydrophilic and one
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`amphiphilic compound. Independent Claim 22 requires at least one hydrophilic,
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`one lipophilic, and one amphiphilic compound.
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`IPR2017-01035 (Patent No. 9,320,716)
`Patent Owner Preliminary Response
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`Patent owner rejected prior art formulations that used multiparticulate
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`systems, bacteria-based release systems (e.g., gum-based), and delay layers to
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`control drug release. Instead, patent owner discovered that a single-unit tablet itself
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`can deliver drug throughout the colon if it possesses release-controlling excipients
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`contained in a macroscopically homogeneous structure. Patent owner patented this
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`invention in the ʼ716 patent, and developed its commercial embodiment in an
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`FDA-approved drug called Uceris®. See Ex. 1060 at 2 (Orange Book listing for
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`Uceris®).
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`Uceris® is a colonic-delivery tablet containing 9 mg budesonide and is the
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`only colonic-delivery steroid formulation approved by the FDA for treatment of
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`UC. This approval was, in part, due to pharmaco-scintigraphy data demonstrating
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`that Uceris® delivered drug throughout the sectors of the colon, including the hard-
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`IPR2017-01035 (Patent No. 9,320,716)
`Patent Owner Preliminary Response
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`to-reach distal colon. Below on the left is a scintigraphy image showing
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`approximate drug dosage form breakup with Uceris® (from Figure 1 of Ex. 2001),
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`and on the right, for comparison, is figure of the large-intestine anatomy (Ex. 2035
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`at 181):
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`
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`As illustrated above, approximate drug release from the scintigraphy image (bright
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`spots from the radioactive label) shows spread throughout the colon.
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`The FDA approved Uceris® in 2013 for the treatment of active, mild to
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`moderate ulcerative colitis. Due to the commercial and clinical success of Uceris®,
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`six generic drug manufacturers, including petitioner, have filed Abbreviated New
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`Drug Applications seeking to market generic versions of Uceris® and sought to
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`invalidate Orange Book patents, including the ʼ716 patent, that encompass Uceris®
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`tablets.
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`IPR2017-01035 (Patent No. 9,320,716)
`Patent Owner Preliminary Response
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`Prosecution History
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`B.
`Petitioner’s Grounds rely on the same references that the examiner
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`considered during prosecution. The examiner withdrew an anticipation rejection
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`over Savastano (Ground 1) in this patent family after patent owner explained that
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`Savastano does not disclose “a macroscopically homogenous” structure. See
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`Ex. 2011 at 8. Patent owner explained that Savastano instead taught artisans to
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`employ “both a delay jacket and semi-permeable membrane surrounding the tablet
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`core to control the release of the active ingredient.” Id. The examiner also
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`withdrew an obviousness rejection over Savastano (Ground 2) and another
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`reference not at issue in this proceeding. See Ex. 2012 at 7-8. Additionally, the
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`examiner withdrew an anticipation rejection over Friend (Ground 3) after patent
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`owner amended all claims to add the limitation, “wherein the macroscopically
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`ho
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