Coalition for Affordable Drugs II LLC
`Petitioner
`v.
`NPS Pharmaceuticals, Inc.
`Patent Owner
`
`IPR2015-00990 & IPR2015-01093
`U.S. Patent No. 7,056,886
`
`
`Patent Owner’s Demonstratives
`for June 23, 2016, Oral Argument
`
`
`
`IPRs 2015Ͳ00990, 01093 – Patent Owner’s Demonstrative Exhibits
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`1
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`NPS Ex. 2173
`CFAD v. NPS
`IPR2015-00990
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`§ 103 cannot bar patentability when the invention “is more
`than the PREDICTABLE use of prior art elements according
`to their established functions.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 417
`(2007).
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`Peptide formulation is a HIGHLY UNPREDICTABLE ART.
`
`
`“each molecule has its own unique physical and chemical
`properties which determine in vitro stability. The formulation
`scientist must also be concerned about the in vivo stability of the
`drug. Thus, the development of successful formulations is
`dependent upon the ability to study both the in vitro and in vivo
`characteristics of the drug as well as its intended application.”
`
`(PO Resp., 24-27; Ex. 1024, 2 (Cleland); Carpenter Dec., ¶¶ 66-68; Ob. of Palmieri, No. 14)
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`Peptide ≠ Protein (PO Resp., 27; Palmieri Ob. 16, 30)
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`Peptide ≠ Small Molecule (PO Resp., 10, 27)
`
`Glucagon ≠ GLP-2 or analogs (PO Resp., 43-48)
`
`Serendipity ≠ Predictability (PO Resp., 48)
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`What matters is the path that the person of ordinary skill in the art
`would have followed. Otsuka Pharmaceutical Co., Ltd. V. Sandoz, Inc., 687 F.3d 1280
`(Fed. Cir. 2012)
`The parties agree that the person of ordinary skill in the art has
`knowledge in formulating peptides. (Pet., 21; PO Resp., 24)
`Peptide formulators study these primary physical and
`chemical properties of the subject peptide: (PO Resp., 19-20, 25-26;
`Carpenter Dec., ¶¶ 68-71, 87, 88)
`pH (PO Ob. of Dr. Palmieri, No. 26; Carpenter Dec., ¶¶ 87, 88);
`solubility (PO Ob. of Dr. Palmieri, No. 29; Carpenter Dec., ¶¶ 87, 88);
`degradation pathways (triage) (PO Ob. of Dr. Palmieri, No. 9; Carpenter Dec.,
`¶¶ 87, 88).
`Petitioner did not consider any of these properties. (PO Resp.,
`3, 6, 14, 15, 28-30)
`They all differ for glucagon v. GLP-2 = Unpredictability
`(PO Resp., 43-48)
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`4
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`POSA would have expected Petitioner’s
`application of the prior art to be unpredictable.
`
`(PO Resp., 4-7)
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`No reasonable expectation of success because
`glucagon and GLP-2 are so different.
`
`
`(PO Resp., 4-7)
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`IPRs 2015‐00990, 01093 – Patent Owner’s Demonstrative Exhibits 
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`5
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`Petitioner’s Hypotheses Are All
`INCORRECT
`Glucagon and GLP-2:
`Do NOT share relevant properties (PO Prel. Resp. 14-15, 22-23, n. 9, 24-26;
`PO Resp., 43-45);
`Do NOT have similar physical and chemical profiles or
`degradation pathways (PO Resp., 44-45);
`Do NOT have the same secondary structure (PO Resp., 44-48);
`Are NOT closely related.
`The problems in formulating GLP-2 are vastly different than
`those in formulating glucagon. See Mintz v. Dietz & Watson, Inc., 679 F.3d 1372
`(Fed. Cir. 2012)
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`Glucagon and GLP-2 Have Different Key Properties -
`Different Solubility, pI, and Optimal pH
`Glucagon is soluble and resistant to aggregation at very acidic pH.
`(PO Resp, 10, 19-20)
`GLP-2 precipitates at acidic pH. (PO Resp., 10; Carpenter Dec., ¶¶ 64, 87, 88, 153, 154,
`156)
`Glucagon’s pI ~ 7.0. (PO Resp., 15)
`GLP-2’s pI ~ 4.0. (PO Resp., 15; Carpenter Dec., ¶¶ 64, 87, 88, 155)
`Optimal pH for minimizing aggregation and precipitation is far
`from its pI. (PO Resp., 15; Carpenter Dec., ¶ 155)
`GLP-2 is soluble at pH >5.5, insoluble at pH <5.5. (PO Prel. Resp., 14; PO Resp., 18)
`Glucagon is soluble at pH 2.8. (PO Prel. Resp., 14; PO Resp., 18; Carpenter Dec., ¶ 153)
`Low pH avoids deamidation. (Ob. of Dr. Palmieri, No. 14, Ex. 2171, 505:9-506:11)
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`Glucagon and GLP-2 Have Different
`Degradation Pathways (PO Resp., 9, 44-48; Carpenter Dec., ¶¶ 157-160)
`Degradation Pathways = Intermediates formed upon degradation
`1st Palmieri Dep. (Ex. 2042), 72:16-24; Ob. of Palmieri, No. 8)
`Deamidation of different amino acids form different
`intermediates.
`Deamidation at different positions forms different
`intermediates.
`Oxidation of different amino acids forms different
`intermediates.
`Oxidation at different positions forms different intermediates.
`Each may or may not affect pharmacological activity. (Carpenter Dec., ¶ 65)
`Neither has the same degradation-susceptible amino
`acids at the same positions. (PO Resp., 44; Carpenter Dec., ¶¶ 157-59)
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`Carpenter Dep. (Ex. 1043) 272:12-273:9
`12 Q. Earlier we talked about the
`13 amino acid residues and peptide giving
`14 some indication possibly of chemical
`15 degradation pathways to which that peptide
`16 might be susceptible, no guarantees, but
`17 to which it might be susceptible.
`18
`
`Can you determine the physical
`19 degradation of pathways of a peptide by
`20 looking at its amino acid residues?
`21
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`MR. FEDOWITZ: Objection,
`22 misstates Dr. Carpenter's prior testimony.
`23 A. You -- the prediction of
`24 aggregation is not really something we
`25 know how to do yet.
`2
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`If I get a given protein or a
`3 given peptide, I can have all the sequence
`4 information and I still don't know for
`5 that protein or peptide how sensitive it
`6 may be, the stress, how readily it
`7 aggregates.
`8
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`Literally, that we have to
`9 determine empirically.
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`Keiffer (Ex. 1018) Fig. 3 with degradation-susceptible
`amino acids highlighted
`
`Key - Orange = Deamidation-susceptible asparagine (N). (Carpenter Dec., ¶ 157, 158)
`Pink = Deamidation-susceptible glutamine (Q). (Id.)
`Yellow = Oxidation-susceptible methionine (M). (Id.)
`Purple = Oxidation-susceptible tyrosine (Y). (Id.)
`
`
`Neither has the same degradation-susceptible amino
`acids at the same positions. (PO Resp., 44; Carpenter Dec., ¶¶ 157-59)
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`Glucagon and GLP-2 have:
`Different total number of degradation-susceptible amino acids
`(glucagon = 6;GLP-2 = 5). (PO Resp., 44; Carpenter Dec., ¶¶ 157-58; Ex. 1018 (Keiffer),
`Fig. 3)
`Different number of specific degradation-susceptible amino
`acids, M, N, Y, and Q (glucagon = 1M, 1N, 2Q, 2Y; GLP-2 = 1M,
`3N, 1Q, 0Y). (Id.)
`Different positions of degradation-susceptible amino acids
`(glucagon = positions 10, 13, 20, 24, 27, 28; GLP-2 = positions 10,
`11, 16, 24, 28). (Id.)
`Different amino acids at common degradation-susceptible
`positions (glucagon = Y10, Q24, N28; GLP-2 = M10, N24, Q28).
`(Id.)
`Different degradation-susceptible amino acids (glucagon has Y;
`GLP-2 does not). (Id.)
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`Glucagon and GLP-2 Are Not Closely Related
`Large family of disparate molecules - 17 different members of this superfamily of
`peptide hormones. Ex. 1018 (Keiffer). (Note: Dr. Palmieri thinks all can be formulated the
`same. (PO Resp., 27; Ob. of Palmieri, No. 22)
`From different parts of proglucagon. (Pet., 17; Palmieri Opening Dec., ¶ 36)
`Produced in different cells - Glucagon expressed in hypothalamus, GLP-2 expressed
`in multiple tissues including liver, etc. (PO Prel. Resp., 25-26 ; Ex. 1018 (Keiffer), Fig. 8)
`Different activities -
`GLP-2 binds to GLP-2 receptor, glucagon does not. (PO Prel. Resp., 14)
`GLP-2 has intestinotrophic activity, glucagon maintains blood glucose levels during
`fasting. (PO Prel. Resp., 14, 25)
`67% different amino acid sequence. (PO Prel. Resp., 26)
`Molecular weights are irrelevant – Similar merely means similar number of amino
`acids (See, e.g., oxytocin v. bradykin and cytochrome C (human) v. ribonuclease A
`(bovine pancreas) v. lysozyme (chicken egg white)). (PO Prel. Resp., 22, n. 9)
`Common names are naïve to consider. (Palmieri Reply Dec. (Ex. 1041), ¶ 18; Ob. of Palmieri,
`No. 32)
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`NO Common Secondary Structure
`Common secondary structure (i.e., alpha-helix) is cornerstone of Petition – It fails –
`(A person of ordinary skill in the art would have been motivated to combine these prior art references because
`GLP-2 is structurally similar to glucagon.) (Pet., 49)
`HOWEVER: There is no secondary structure (e.g., alpha-helix) of
`glucagon or GLP-2 in solution or lyophilized form. (Carpenter Dec., ¶ 162; Ob. of
`Palmieri, Nos. 18-21)
`HOWEVER: Glucagon has structural heterogenicity in liquid or
`lyophilized form. (PO Resp., 45-46; Carpenter Dec., ¶ 162)
`HOWEVER: Receptor-induced secondary structure is absent from a
`formulation. (Ex. 2050, 54; Ob. of Palmieri, No. 18; Ex. 2071, 640:8-642:1)
`HOWEVER: Tertiary structure, not secondary structure, determines the
`susceptibility of amino acids to degradation and the activity of the peptide.
`(PO Prel. Resp., 23, n. 10)
`HOWEVER: Maintaining secondary structure is not a prerequisite for
`glucagon stability in lyophilized formulations. (PO Resp., 45; Ex. 2049 (Fang et al.),
`Abstract; Carpenter Dec, ¶ 161)
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`Even if the alpha-helix did exist in glucagon, there is NO indication it
`would exist in GLP-2 (PO Resp., 45-46)
`Lomize (Ex. 1019) Table V Experiment Alpha-Helix Data
`Depicted on Keiffer (Ex. 1018) Fig. 3 Sequences
`
`Only 6 of 15 amino acids are the same - Primary structure
`determines secondary structure.
`Petitioner provided no evidence for an alpha-helix in GLP-2.
`14
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`Even if the alpha-helix did exist in glucagon, there is NO indication it
`would exist in GLP-2 (PO Resp., 45-46)
`Lomize (Ex. 1019) Table V Calculated Alpha-Helix Data
`Depicted on Keiffer (Ex. 1018) Fig. 3 Sequences
`
`Only 7 of 17 amino acids are the same - Primary structure
`determines secondary structure.
`Petitioner provided no evidence for an alpha-helix in GLP-2.
`15
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`There are NO magic excipients;
`A formulator must study each individual
`peptide. (Ob. of Palmieri, No. 14; Palmieri Dep. (Ex. 2171), 487:2-488:1).
`
`Histidine ≠ General stabilizer (PO Resp., 2,5)
`Phosphates ≠ General Buffers (PO Resp., 2,5)
`Mannitol/sucrose ≠ General excipients (PO Resp., 2, 5)
`
`The combination of the 3 for GLP-2
`is NOT predictable (PO Resp., 48)
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`Histidine – a low pH buffer; incompatible with phosphates/GLP-2
`A buffer at low pH - Sodium phosphate buffers crystallize which means the histidine acidic
`buffer acidifies formulations. (PO Resp., 49-50; Carpenter Dec., ¶ 83)
`Tends to crystallize. (PO Resp., 49; Carpenter Dec., ¶¶ 8, 168-69)
`Oxidizes and promotes oxidation. (PO Resp., 50; Carpenter Dec., ¶¶ 83, 171)
`Competes with other buffers. (PO Resp., 50; Carpenter Dec., ¶ 170)
`Phosphates – most problematic buffers; avoid them. (Palmieri Dep. (Ex. 2171),
`454:22-455:11, 503:3-504:3)
`Crystallizes on freezing and changes the formulation’s pH. (Palmieri Dep. (Ex. 2171), 500:24-502:2)
`Inhibiting phosphate buffer crystallization is unpredictable. (Palmieri Dep. (Ex. 2171), 503:3-504:3)
`Need a reduced pH to avoid deamidation. (Palmieri Dep. (Ex. 2171), 505:9-506:11)
`Mannitol/sucrose - capacity of a sugar to protect needs to be investigated
`for each formulation. (Palmieri Dep. (Ex. 2171), 471:25-472:10)
`Crystallizes at high temperatures. (Palmieri Dep., 463:16-464:14)
`Adversely affected by water. (Palmieri Dep., 464:16-465:13, 465:15-466:3)
`Use dissacharides, not monosaccharides. (Palmieri Dep., 466:18-24)
`Mannitol does not protect during lyophilization. (Palmieri Dep., 468:15-469:18)
`Sucrose hydrolizes to reducing sugar which should be avoided. (Palmieri Dep., 471:10-24)
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`The Prior Art Is Deficient
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`Drucker ‘379 (Ex. 1029) (PO Resp., 32-33; Carpenter Dec., ¶¶ 109-115)
`No excipients other than buffered saline or dextrose in liquid
`In vivo stabilization by amino acid substitutions/end blocking groups
`In vitro lyophilization of unformulated peptide
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`Drucker ‘600 (Ex. 1028); (PO Resp., 33; Carpenter Dec., ¶¶ 116-118)
`No excipients other than buffered saline or dextrose in liquid
`In vitro lyophilization of unformulated peptide
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`The Prior Art Is Deficient
`Kornfelt (Ex. 1027); (PO Resp., 35-39; Carpenter Dec., ¶¶ 130-142)
`Glucagon ≠ GLP-2
`Teaches away from physiological pH –
`Histidine shows a buffer effect at pH 2.8. (Ex. 1027, 3:22-27)
`Formulates glucagon at pH 2.8 to “give a minimum for the rate of
`decomposition of glucagon;” cannot formulate glucagon at
`physiological pH. (Ex. 1027, 3:25-26, 4:22-26)
`Example 1 – at pH 2.8 – “The results show that a very pronounced
`stabilization of glucagon is obtained by adding stabilizing agent in
`accordance with the present invention.” (Ex. 1027, 4:50-54)
`Histidine is equivalent to leucine and glycine
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`The Prior Art Is Deficient
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`Osterberg (Ex. 1030); (PO Resp., 33-35; Carpenter Dec., ¶¶ 119-129)
`No peptides
`Histidine ≠ universal stabilizer (possibly multi-functional (buffer/metal ion
`scavenger)).
`
`Sucrose inhibits histidine crystallization during thawing, but lyophilization
`uses sublimation (i.e., solid ---> gas).
`
`Crystallization of L-histidine during freezing/thawing is minimal at pH 6.
`Water/humidity causes amorphous L-histidine to crystallize.
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`There Are Surprising & Unexpected Results
`‘886 Patent Fig. 2 – Histidine with phosphate buffer stabilized GLP-2 analog at
`pH 7.1-7.5. Ex. 1003, 8:12-13. The histidine did not inhibit phosphate buffer in this
`formulation. (Carpenter Dec., ¶ 148; Ex. 1003, Example 2)
`‘886 Patent Fig. 3 – Mannitol and sucrose out-performed trehalose, maltose,
`and lactose when combined with histidine, phosphate buffers, and GLP-2
`analog. (Carpenter Dec., ¶ 149; Ex. 1003, Example 3)
`‘886 Patent Fig. 4 – Lactose gave significant aggregation; mannitol and sucrose
`did not. (Carpenter Dec., ¶ 150; Ex. 1003, Example 3)
`‘886 Patent Figs. 5 and 6 – Histidine, phosphate buffer, and mannitol
`(Formulation 1) showed no GLP-2 analog degradation, but other combinations
`did. (Carpenter Dec., ¶ 150; Ex. 1003, Example 4)
`‘886 Patent Example 6 - pH 7.4, 2 sets of conditions (4oC and 25oC) – GLP-2
`analog with histidine, phosphate buffers, and mannitol was stable at least 6 and
`18 months. (Ex. 1003, Example 6)
`No protection of GLP-2 analog by leucine or glycine. (Carpenter Dec., ¶ 141)
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`No Rebuttal of
`Surprising & Unexpected Results
`Petitioner’s admission against interest –
`Results for [Gly2]GLP-2 are unexpected. “Despite this data being
`unexpected, ….” (Pet. Reply, 11)
`Dr. Palmieri admitted that ‘886 Patent Figs. 5 and 6 show that the
`claimed formulation is the most stable. (Ob. of Palmieri, No. 12)
`Petitioner’s only response –
`Dr. Palmieri, without reason, does not think so. (Ob. of Palmieri, No. 12)
`Dr. Palmieri does not know if reproducible – but he never tried. (Ob.
`of Palmieri, No. 12)
`Not enough testing – but more than in Kornfelt. (Ob. of Palmieri, No. 12)
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`There Is NO Blocking Patent (Ob. of Hofmann, No. 3)
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`Merck v. Teva, 395 F.3d 1364 (Fed. Cir. 2005)
`
`Identical API claimed in both patents
`
`Blocking Patent - 4,621,077
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`Patent/Claims-in-Suit –5,994,329
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`Claims 23 and 37
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`Present IPRs - Patents are of Different Scope (Ob. of Hofmann, No. 3)
`Can practice ‘886 patent with an API that does NOT infringe ‘379 patent
`U.S. Patent No. 7,056,886 Alleged Blocking Patent 5,789,379
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`Secondary considerations may often be the most probative and
`cogent evidence of non-obviousness and act as a check against
`hindsight.
`Leo Pharm. Prods., Ltd. v. Rea, 726 F.3d 1346, 1358 (Fed. Cir. 2013)
`
`Apple Inc. v. ITC, 725 F.3d 1356, 1366 (Fed. Cir. 2013);
`
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`“[T]he concept of commercial success is to evaluate a
`product’s performance in a market….” (Hofmann Dec., ¶ 94)
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`
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`There is a presumption of nexus, and the burden to
`disprove nexus is on Petitioner. Brown & Williamson Tobacco Corp. v. Philip
`Morris Inc., 229 F.3d 1120, 1130 (Fed. Cir. 2000) (“[I]f the marketed product embodies the claimed
`features, and is coextensive with them, then a nexus is presumed and the burden shifts to the party
`asserting obviousness to present evidence to rebut the presumed nexus.”)
`
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`Evidence of Commercial Success
`Petitioner’s admission against interest – The Coalition will file petitions
`on “a big-selling drug.” (PO Prel. Resp., 33; Ex. 2036, 2)
`Significant (18%) patient penetration – Better than other blockbuster
`drugs. (PO Resp., 57; Rausser Dec. ¶ 52; Ob. of Hofmann, Nos. 16-18)
`High pricing, low discounts – 10-13% discount = $376-433,000/year/patient.
`(PO Resp., 57-58; Rausser Dec. ¶¶ 53, 74; Ob. of Hofmann, Nos.10, 11)
`High sales and sales growth – Exceeded expectations. (PO Resp., 58; Rausser Dec. ¶¶
`55, 56)
`Sophisticated customers – Gattex promotion does not drive its sales. (Ob. of
`Hofmann, No. 5; Janssen Pharmaceuticals v. Watson Labs, 2012 U.S. Dist. LEXIS 129099, *69 (D.N.J. Sept. 11,
`2012))
`Patent Owner’s share price beat the markets once Gattex launched –
`> 400% increase (< $10 to > $40) – far better % increase than S&P 500,
`FPHAX, XBI, NBI. (PO Resp., 58; Rausser Dec., ¶ 58, Fig. 7, 62; Hofmann Dec., ¶ 90, Fig.; Ob. of
`Hofmann, Nos. 19, 20)
`Key driver in Shire’s acquisition on the open market – At least $2.8
`billion valuation by third party Shire. (PO Resp., 58-59; Rausser Dec., ¶¶ 62, 63; Ob. of Hofmann,
`No. 21)
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`Evidence of Long-Felt Need
`Short bowel syndrome is a life-long disease – Life threatening,
`severely impairs quality of life, devastating side effects. (PO Resp., 11-12;
`Rausser Dec. ¶¶ 19, 29, 34, 35, 40; Ob. of Hofmann, No. 14)
`Parental nutrition – IV feedings up to 7 days/week, up to 15 or more
`hours/day. (PO Resp., 57; Rausser Dec., ¶¶ 22-23, 63)
`No limit on length of Gattex treatment. (Ex. 2027; Rausser Dec., ¶ 26, 46; Ob. of
`Hofmann No. 14)
`Gattex reduces PN and PN complications (Rausser Dec., ¶ 41) – Mr.
`Hofmann does not think this meets a long-felt need. (Ob. of Hofmann, No. 14;
`Hofmann Dec., ¶ 24)
`Physicians found improvement in quality of life and reduction
`in PN as the best attributes of Gattex - Nothing else did that. (PO
`Resp., 57; Rausser Dec., ¶¶ 45-47; Hofmann Dec, ¶¶ 38-41)
`Only one other drug – Zorbtive is labeled for use for only 4 weeks. (PO
`Resp., 57; Ex. 2083; Rausser Dec., ¶¶ 25, 26, 31, 44, 46; Ob. of Hofmann, No.15)
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`Nexus
`Gattex, the commercial product, is the claimed formulation, not
`just API. (Carpenter Dec., ¶ 73)
`Gattex must be stable to be sold. (Rausser Dec., ¶¶ 64-69)
`Gattex must be stable for > 90 days. (Ob. of Hofmann, No. 7; Ex. 2027)
`No heavy discounting, unusual promotion, predatory pricing,
`rebates, etc. (Rausser Dec., ¶¶ 64, 72-77; Ob. of Hofmann, Nos. 10, 11)
`Petitioner’s burden to disprove assumption of nexus
`Petitioner’s only rebuttal – Dr. Rausser “does not establish a
`nexus” (Hofmann Dec., ¶ 14), “fail[s] to establish a nexus” (id.), “makes no
`effort to establish a nexus” (id. at 22), “fails to show … a nexus” (id. at 33),
`“would not necessarily mean that a nexus exists” (id. at 44), “fails to
`demonstrate the required nexus” (Pet. Reply, 23), “makes no effort to
`address any nexus” (id. at 24)
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`The Carpenter Article (Ex. 1050) Is Merely a Theoretical
`Starting Point for PROTEINS, NOT PEPTIDES
`Read it as a whole (Dr. Palmieri did NOT), not selectively (Ob. of Palmieri, No. 14)
`Unpredictability
`All of these difficulties theoretically can be avoided with a properly prepared lyophilized formulation. (Ex.
`1050, 969, col. 1)
`Rather, our goal is to provide a starting point for the researcher for whom design of stable lyophilized protein
`formulations is still a new and major challenge. (Id. at 970, col. 1)
`However, it must be realized that crystalline excipients when used alone will usually not provide adequate
`stability to most proteins during processing or storage in the dried solid. (Id.)
`Essentially every step from vial filling to final reconstitution of the dried product can damage the protein and
`require formulation components to inhibit degradation. (Id. at 971, col. 1)
`However, every protein has unique physicochemical properties and, hence, unique stabilization requirements.
`Thus, the formulation will have to be "customized" for every protein drug. (Id. at 974, col. 2)
`Even if the formulation design given above appears to be successful for a given protein, there are other
`problems that can lead to failure, especially during long-term storage. (Id. at 974, col. 1)
`In general, the three most important parameters to consider are protein concentration, buffer choice, and
`freezing protocol. (Id. at 971, col. 2)
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`Carpenter Dep. (Ex.1043) 282:2-284:15, 284:18-286:9
`24 formulation that can be lyophilized
`p. 282 - 2 Is it true that given your
`12 So for freezing, because of the
`25 successfully predictable?
`3 book, Carpenter 110, or your article,
`13 mechanism, the bulk concentration matters;
`p. 285 - 2 A. No.
`4 Carpenter 111, that it will be routine and
`14 for drying it is the ratio between the
`3 Q. Why not?
`5 predictable to formulate a peptide to be
`15 sugar and the protein, and we lay that out
`6 stable and to lyophilize?
`4 A. Because we just don't know --
`16 very clearly so people don't get in
`7 A. No, these chapters and review
`5 in fact, you were asking about
`17 trouble by using not enough or too much.
`8 articles are meant to be a starting point.
`6 freeze-drying papers earlier, Matt, I
`18 And in general, I think there
`7 didn't look them up, but we do have a
`19 are several places in here, and I
`9 To put freeze-dried proteins in
`8 couple of more mechanistic ones where
`20 reiterated some today about the caveats
`10 the context of pharmaceutical product,
`9 we're trying to answer that question, what
`21 that every protein is different, every
`11 there is huge literature out there of
`10 degradation pathways can be coupled to
`22 protein has unique physiochemical
`12 people freeze-drying with many compounds
`11 what physical properties of the glass and
`23 properties.
`13 that wouldn't be acceptable and if a
`12 we did all that work and the answer was we
`24 And importantly for medicine,
`14 person starts and does a literature search
`13 don't know.
`25 every protein or peptide has its critical
`15 and wants to learn how to freeze-dry, you
`14 In fact, we got a big shock, we
`p. 284 - 2 quality attributes; what degradation
`16 get very confused very quickly.
`15 did all that, we did the beautiful
`3 pathways are really important, what
`17 And so these were meant to be,
`16 physical studies, we did neutron
`4 effects safety and efficacy.
`18 based on our experience at the time, kind
`17 scattering, and for one of the proteins we
`5 This is a good starting point,
`19 of an initial starting point and to
`18 learned none of that mattered, it was the
`6 but it doesn't necessarily assure success.
`20 provide insights into why excipients do
`19 amount of protein on the surface of the
`7 We mentioned very clearly in
`21 the job you want them to do, like
`20 glass area interface that dictated
`8 here as one of the four criterions, you
`22 mannitol, crystallizing, and being a
`21 everything.
`9 got to know your protein, you got to know
`23 bulking agent, and sucrose and trehalose
`22 So after all these years, these
`10 your peptide, what's the optimal pH,
`24 remaining amorphous and being stabilizers.
`23 things, we think we know kind of broadly
`11 what's the chemical degradation pathways
`25 We also provided detail on the
`24 what to do and, I mean, that wasn't a
`12 that may not be controlled by the general
`p. 283-2 mechanisms by which things worked, quite
`25 chemical problem, just -- actually, it
`13 freeze-drying, methionine oxidation, for
`3 different protecting a protein during
`2 was both, but the surface layer of protein
`14 example, as we say, you want a native
`4 freezing, the thermodynamic physical
`3 dictated degradation.
`15 protein, you want a glass matrix --.
`5 mechanism, than during drying.
`4 Q. So when you go to formulate a
`18 THE WITNESS: Sorry, I'm
`6 And that actually dictates from7 a rational, if you
`5 peptide to be stable or for
`19 lecturing now.
`want to think rational
`6 lyophilization, it is neither predictable
`20 A. So that's just some examples.
`8 formulation; if I have a freezing label
`7 nor is there a reasonable expectation of
`21 Q. So even if you know all of this
`9 protein, I need a fairly high solution
`8 success, is that correct?
`22 information about your peptide, is
`10 concentration of a stabilizer, maybe 300
`9 A. That's right.
`23 formulating into a stable formulation or
`11 millimolar.
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`The Carpenter Article (Ex. 1050) Read as a Whole (Cont’d)
`
`Buffers
`Buffer choice can also be critical. The main culprits here are sodium phosphate and potassium phosphate, which
`can undergo drastic changes in pH during freezing and annealing. (Ex. 1050, 971, col. 2)
`Although other excipients can aid in inhibiting the pH change (24), the best approach is to avoid using sodium
`phosphate or potassium phosphate buffers. (Id.)
`Mannitol and sucrose
`With the goal of obtaining a strong cake structure during a rapid lyophilization cycle, polymers such as dextran
`and hydroxyethyl starch, which have relatively high collapse temperatures, are attractive excipients. (Id. at 972,
`col. 2)
`Sugars and mannitol can contain transition metals, and surfactants (e.g., Tweens) can be contaminated with
`peroxides, all of which can foster oxidation. (Id. at 974, col. 1)
`Further, a recent report showed evidence of a reducing sugar contaminant in mannitol. (Id.)
`However, on occasion during summer, after shipping excessive degradation was found after only 2 weeks
`storage at room temperature. [ ] It was found that mannitol in the formulation was not completely crystallized,
`but rather formed a metastable glass with a Tg of about 45°C. When this temperature was exceeded, which can
`occur during shipping in the summer, the mannitol crystallized. Since mannitol is an anhydrous crystal, the
`water originally “associated” with mannitol was sent to the remaining amorphous phase, which lowered it’s Tg.
`Thus, any stabilization offered by amorphous mannitol was lost, and the water content of the protein phase was
`increased, both effects accelerating the degradation of protein. (Id.)
`
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`The Carpenter Article (Ex. 1050) Read as a Whole (Cont’d)
`
`
`Mannitol and sucrose (cont’d)
`Among the numerous compounds tested it appears that the most effective stabilizers during the lyophilization
`cycle are disaccharides. (Ex. 1050, 972, col. 2)
`However, one group of compounds that should be avoided are the reducing sugars. (Id.)
`As noted earlier, crystalline bulking agents such as mannitol and glycine do not provide protection during
`lyophilization. (Id. at 972, col. 2)
`Trehalose is also more resistant than sucrose to acid hydrolysis. Hydrolysis of these disaccharides produces
`reducing sugars, which must be avoided. (Id. at 973, col. 2)
`Hence, the capacity to protect a protein must be examined for each formulation. (Id. at 973, col. 2)
`First, there are often contaminants in excipients that can lead to rapid chemical degradation of proteins. Sugars
`and mannitol can contain transition metals, and surfactants (e.g., Tweens) can be contaminated with peroxides,
`all of which can foster oxidation (35). Further, a recent report showed evidence of a reducing sugar contaminant
`in mannitol. (Id. at 974, col. 1)
`
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`The Carpenter Book Chapter (Ex. 1049) Is Merely a Theoretical
`Starting Point for PROTEINS, NOT PEPTIDES
`Read it as a whole (Dr. Palmieri did NOT), not selectively (Ob. of Palmieri, No. 14)
`Unpredictability
`However, obtaining a stable lyophilized formulation of a given protein may not necessarily be as
`straightforward as it appears based on the generalizations provided in this review. (Ex. 1049, 202)
`Each protein has unique physicochemical characteristics, which produces its unique “personality.” (Id.)
`Sometimes this personality manifests itself as a protein that "cooperates fully" during formulation development.
`At other times the protein seems to be a "spoiled child who follows or breaks the rules in an apparently illogical
`pattern of frustratingly inconsistent behavior. (Id.)
`Currently, it is not possible to predict if a protein will fall into one of these extremes or somewhere in between,
`which in a way is beneficial to the careers of formulation scientists. (Id.)
`If all that was needed to obtain stable proteins was the purchasing of a "kit of magic excipients" or simply
`following a single, simple recipe, then there would not be much need for highly skilled protein stabilization
`experts in the industry or for further advances in the field from basic researchers. Since this is not the case,
`there is a great need to increase the fundamental understanding of protein formulation and to document by case
`studies the applicability of general rules to individual proteins. (Id.)
`However, as has been the case with liquid formulations, these general approaches of increasing physical
`stability may not be sufficient to inhibit certain pathways of chemical degradation. (Id. at 252)
`Specific formulation conditions (e.g., pH) must be developed to inhibit chemical degradation pathways, which
`might arise even in native proteins. (Id. at 202)
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`The Carpenter Book Chapter (Ex. 1049) Read as a Whole (Cont’d)
`Unpredictability (cont’d)
`To develop a protein formulation that has both acute and long-term storage stability, it is crucial that the
`specific conditions (i.e., pH, specific stabilizing ligands) for optimum protein stability be established and the
`appropriate nonspecific stabilizing additives (i.e., those excipients that generally stabilize any protein) be
`incorporated into the formulation. (Ex. 1049, 201)
`Clearly, simply keeping a protein sample below its Tg is not adequate for storage stability. (Id. at 253)
`Buffers
`If solutes that are destabilizing to the protein are present, then this concentrating effect can contribute to protein
`denaturation. Finally, as noted above, there can be dramatic pH changes during freezing. (Id. at 242)
`For example, the dibasic form of sodium phosphate crystallizes in frozen solution, which results in a system that
`only contains the monobasic salt and has a very low pH. (Id. at 242)
`Other components in a formulation may inhibit the crystallization of dibasic sodium phosphate. However, such
`inhibition is not predictable …. (Id. at 242)
`To minimize problems associated with pH changes sodium phosphate buffer should be avoided whenever
`possible.