IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELA WARE
`
`NOVARTIS PHARMACEUTICALS
`CORPORATION and NOV ARTIS AG,
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`Plaintiffs,
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`e.A. No. 14-1289-RGA
`
`v.
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`PAR PHARMACEUTICAL, !Ne.
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`Defendant.
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`DEFENDANT PAR PHARMACEUTICAL, INc.'S INITIAL INVALIDITY
`CONTENTIONS
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`Pursuant to paragraph I(d) of the Court' s Scheduling Order, Defendant Par Pharmaceutical,
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`Inc., ("Par") provides its initial invalidity contentions with respect to claims 1-3 and 7-10 ofU.S.
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`Patent No. 5,665,772 ("the '772 patent"), claims 1,4-8, 10, and 13 of U.S. Patent No. 6,004,973
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`("the '973 patent"), and claim 7 ofU.S. Patent No. 6,455,518 ("the '518 patent") (collectively, "the
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`Asserted Claims"), presently asserted by Plaintiffs Novartis Pharmaceuticals Corporation and
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`Novartis AG (collectively, "Plaintiffs") as set forth in Plaintiffs' initial infringement contentions
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`served on February 19, 2015.
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`PRELIMINARY STATEMENT
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`Par reserves all rights to amend and supplement these initial invalidity contentions In
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`accordance with the Court's orders, local rules, and the Federal Rules of Civil Procedure as
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`appropriate. Discovery is currently ongoing, and Par' s searches for, analysis of, and application of
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`relevant prior art are ongoing. For at least these reasons, additional prior art not included in these
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`initial invalidity contentions and/or additional facts, documents, and things, whether known or
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`unknown to Par, may become relevant. Par reserves the right to amend, alter, or supplement these
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`1
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`metabolism or excretion of cyclosporin A by rapamycin. (Id.) The animals were treated with
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`either 1 mg/kg of cyclosporin A / 0.02 mg/kg of rapamycin (w/w - 50:1), or 2 mg/kg of
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`cyclosporin A / 0.02 mg/kg ofrapamycin (w/w - 100:1). (Id. , at S224-S225.)
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`B.
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`Bierer
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`B.E. Bierer, et aI., "Two distinct signal transmission pathways in T Iymphocytes are
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`inhibited by complexes formed between an immunophilin and either FK506 or rapamycin," Proc.
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`Nat '/' Acad. Sei., 87:9231-9235 (1990) ("Bierer") qualifies as prior art to the ' 772, '973, and ' 518
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`patents under 35 U.S.C. § 102(b) because it was published in 1990, which is more than one year
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`prior to the earliest claimed U.S. filing dates of the ' 772 patent of September 24,1993, of the '973
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`patent of July 12, 1996, and of the ' 518 patent of July 29, 1997.
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`Bierer states that rapamycin and tacrolimus (FK-506) are immunosuppressants that bind to
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`and inhibit the rotamase activity of the immunophilin FKBP. (Bierer, at 9234.)
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`C.
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`Brookhaven Databank Entry
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`The Brookhaven National Laboratories Protein Databank Entry for
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`the FKBP-
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`12/Rapamycin complex referenced in Van Duyne I ("Protein Databank Entry") qualifies as prior
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`art to the '772, '973, and '518 patents under 35 U.S.C. § 102(b) because it was deposited into the
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`databank in July 1992, which is more than one year prior to the earliest claimed U.S. tiling dates
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`of the '772 patent of September 24, 1993, of the '973 patent of July 12, 1996, and of the '5 18
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`patent ofJuly 29, 1997.
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`The Protein Databank Entry contains the three-dimensional structure of the FKBP-
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`12/rapamycin complex referenced in Van Duyne T, as determined by an X-ray diffraction
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`technique. (See generally Brookhaven Databank Entry.)
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`D.
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`Vezina
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`C. Vezina, et aI., "Rapamycin (AY -22,989), A New Antifungal Antibiotic," J Antibiotics,
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`8
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`tacrolimus and rapamycin and the similarity of the pipecolinyl resonances in the NMR spectra of
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`the two FKBP drug complexes support a common mode of drug binding. (Id., at 841.) Van
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`Duyne concludes that its "investigations provide a structural framework to improve upon the high(cid:173)
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`affinity interactions of a clinically promising immunosuppressant with its predominant cystolic
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`receptor in the T cell." (Id.)
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`H.
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`Van Duyne I
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`G.D. Van Duyne, et aI., "Atomic Structure of the Rapamycin Human Immunophilin
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`FKBP-12 Complex," JAm. Chem. Soc., 113:7433-7434 (1991) ("Van Duyne I") qualifies as prior
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`art to the ' 772, ' 973, and '518 patents under 35 U.S.C. § I02(b) because it was published in 1991 ,
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`which is more than one year prior to the earliest claimed U.S. filing dates of the '772 patent of
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`September 24, 1993, of the '973 patent ofJuly 12, 1996, and of the '518 patent ofJuly 29, 1997.
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`Van Duyne I reports the three-dimensional structure of the binding complex of rapamycin
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`and FKBP-12.
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`11
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`Flew'e I. (a. top) A slC:reoview of the a<carbon tracing of FKBP- 12 and
`rapamycin. The N· and C·terminal Q-<carbonl Ire labeled. (b, bottom)
`A stereodrawing of the bindina: pocket showing all of the bound rapa(cid:173)
`my~in molecule and selected FKBp·12 residues.
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`(Van Duyne J, at Figure \.)
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`Van Duyne I states that the complete refined coordinates of the FKBP-12/rapamycin
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`complex will be deposited in the Brookhaven Protein Databank, and, according to the Databank,
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`such deposit was made in July 1992. (Id. , at 7434.)
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`The protein component of the FKBP-12/rapamycin complex forms a five-stranded
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`antiparallel ~-sheet wrapping with a right-handed twist around a short a-helix. (Id., at 7433 -34.)
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`Rapamycin binds in a cavity between the ~ -sheet and a-helix with the pipecolinyl ring deeply
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`buried in the protein.
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`(Id. , at 7434.) The protein-ligand interface involves atoms from the
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`pyranose ring through the C-28 hydroxyl, with the remainder, including the C-17 to C-22 triene,
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`exposed. (Id.) The C-l ester, the pipecolinyl ring, the C-8 and C-9 carbonyls, and the pyranose
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`ring adopt the following conformation: three hydrogen bonds between this region and FKBP-12
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`(lie-56 NH to C-l carbonyl, Tyr-82 hydroxyl to C-8 carbonyl, and Asp-37 carboxylate to C-10
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`12
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`hydroxyl) and a C-9 carbonyl binding pocket involving C-H"O interactions with &-hydrogens
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`from Tyr-26, Phe-36, and Phe-99.
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`(Id.) Two additional hydrogen bonds are involved in
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`rapamycin binding to FKBP-12.
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`(Id.) The fust is from Glu-54 main chain carbonyl to C-28
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`hydroxyl, which along with the lie-56 NH to C-I carbonyl-hydrogen bond may mimic the
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`interaction of the dipeptide portion of a natural substrate with FKBP-12.
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`(Id.) The second
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`hydrogen bond is from GIn-53 main chain carbonyl to the C-40 hydroxyl; the cyclohexyl group
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`(C-35 to C-42) is bound to the protein through this hydrogen bond. (Id. , at 7433-34.)
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`Van Duyne I states that rapamycin has two-fold higher affinity for FKBP-12 than does the
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`structurally-similar tacrolimus (FK-506). (Id. , at 7434.) Van Duyne I reports a Ki for rapamycin
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`of 0.2 nM and a Kd for tacrolimus of 0.4 nM. (Id.) Van Duyne I states that rapamycin's added
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`anchoring of the cyclohexyl hydroxyl (the C-40 position) via hydrogen bonding to the FKBP-12
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`could partially explain the higher affinity ofrapamycin. (Id.)
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`I.
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`Van Duyne III
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`O.D. Van Duyne, et aI., "Atomic Structures of the Human Immunophilin FKBP-12
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`Complexes with FK506 and Rapamycin," J Mo!. Bioi., 229: 105-124 (1993) ("Van Duyne I1I")
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`qualifies as prior art to the '772 patent at least under 35 U.S.C. §102(a) because it published in
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`January 1993, which is prior to the earliest date of invention that can be established in the U.S. or
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`a NAFTA country of September 24, 1993. See 37 C.F.R. § 1.131 (stating that prior invention may
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`not be established before January I, 1996 in a WTO member country other than a NAFT A
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`country). Van Duyne III qualifies as prior art to the '973 and ' 518 patents under 35 U.S.c. §
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`102(b) because it published in January 1993, which is more than one year prior to the earliest
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`claimed U.S. filing dates of the '973 patent of July 12, 1996 and of the '518 patent of July 29,
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`1997.
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`Van Duyne III provides a detailed description of three-dimensional structures ofrapamycin
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`13
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`NOVARTIS EXHIBIT 2131
`Par v Novartis, IPR 2016-00084
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`
`/s/ Steven J Fineman
`Steven J. Fineman (#4025)
`Katharine C. Lester (#5629)
`RICHARDS LA YTON & FINGER, P.A.
`920 North King Street
`Wilmington, DE 19801
`(302) 651-7700
`fineman@rlf.com
`lester@rlf.com
`Attorneysfor Defendant Par Pharmaceutical,
`Inc.
`
`Of Counsel:
`
`Daniel G. Brown
`LA THAM & W ATKINS LLP
`885 Third A venue
`New York, NY 10022
`(212) 906-1200
`
`Roger J. Chin
`LATHAM & WATKINS LLP
`505 Montgomery Street, Suite 2000
`San Francisco, CA 94111
`(415) 391-0600
`
`Marc N. Zubick
`LATHAM & W ATKINS LLP
`330 North Wabash Avenue, Suite 2800
`Chicago, IL 6061 I
`(312) 876-7700
`
`Parker M. Tresemer
`LA THAM & W A TKINS LLP
`355 South Grand Avenue
`Los Angeles, CA 90071
`(213) 485-1234
`
`Dated: March 26, 2015
`
`33
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`NOVARTIS EXHIBIT 2131
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