DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`June 14, 2023
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`June 14, 2023
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Pet., 1-2, 32, 34-34; Reply, 1-2, 4-6, 11-12.
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`22
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`GC-C and Human Uroguanylin
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`3
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`Human uroguanylin acts as a natural laxative by activating GC-C receptors on the
`intestinal endothelium, drawing water into the intestinal lumen.
`
`EX1020 (Nakazato), Figure 2.
`
`Pet., 1, 6, 17, 24; EX1002 (Peterson), ¶¶58-59; EX1063 (Peterson), ¶9; Reply, 4;
`EX1062 (Waldman), 62:7-67:7; see also EX1016 (Fan), E957; EX1064 (Epstein), ¶¶23-24.
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`GC-C is disposed throughout small and large intestines,
`with higher density in the small intestine.
`
`EX1002 (Peterson), ¶¶58-59.
`
`Pet., 17, 36-37; Reply, 4; EX1063 (Peterson), ¶9; EX1064 (Epstein), ¶24;
`see also EX2021 (WIPO), 3:1-2 (both natural ligands produced throughout the intestinal mucosa).
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Uroguanylin is the body’s endogenous ligand for adding water to the lumen:
`
`EX1064 (Epstein), ¶¶34-35.
`
`EX1062 (Waldman), 57:3-11, 65:9-19.
`
`EX1063 (Peterson), ¶9; EX1002 (Peterson), ¶¶59, 63, 90, 127-28;
`Reply, 4, 6, 20-21; EX2025 (Waldman), ¶39; see also EX1062,
`62:7-63:14, 65:9-19 (endogenous ligand for water secretion).
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`
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`Bausch’s expert Dr. Waldman admits it was known to treat constipation by using
`laxatives to induce water flow into the intestinal lumen:
`
`EX1062 (Waldman), 53:5-14, 51:18-22.
`
`EX2025 (Waldman), ¶¶27, 29-30, 33-34, 37.
`
`POR, 7; Reply, 4-6, 20-21; EX1002 (Peterson),
`¶¶59, 63, 90, 127-28; see also EX1064 (Epstein),
`¶¶33-36; EX1063 (Peterson), ¶¶10-11, 106-07.
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`
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`Petitioner provided fulsome
`obviousness arguments
`against claims 2-6 in
`Grounds 2-4.
`
`Pet., 40-53.
`
`POR failed to provide
`independent arguments
`against these additional
`grounds; instead, they stand
`or fall with claim 1.
`
`POR, 67.
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`8
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`Pet., 40-53; Reply, 1; EX1002 (Peterson), ¶¶181-247.
`
`
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`EX1060 (Davies), 20:3-8.
`
`EX1060 (Davies), 111:17-112:5.
`
`Pet., 11-12; Reply, 1-2; EX1001, 37:1-38:10; EX1002 (Peterson), ¶¶32-33, 44-45, 124.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`9
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`3
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`“A peptide consisting of the amino acid sequence of SEQ ID NO: 20”
`
`Independent claim 1:
`
`Independent claims 2, 3, 6, and dependent claims 4 and 5 rise or fall with Claim 1.
`
`EX1001, 37:1-38:10; Pet., 11-12; Reply, 1; EX1002 (Peterson), ¶¶31-37.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`10
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`A single conservative substitution is all that differentiates Seq ID No. 20 (top sequence)
`from human uroguanylin (bottom sequence):
`
`EX1002 (Peterson), ¶23.
`
`EX1002 (Peterson), ¶25.
`
`EX1002, ¶¶23-25, 73-75; Pet., 7, 17, 20-21; Reply, 14-16.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`11
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`3
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`“[T]he cases establish that if [a challenger]
`has found prior art close enough to the
`claimed invention to give one skilled in the
`relevant chemical art the motivation to make
`close relatives (homologs, analogs, isomers,
`etc.) of the prior art compound(s), then there
`arises what has been called a presumption of
`obviousness or a prima facie case of
`obviousness.”
`In re Dillon, 919 F.2d 688, 696 (Fed. Cir. 1990) (en banc).
`
`Bristol-Myers Squibb v. Teva Pharms.,
`752 F.3d 967, 973 (Fed. Cir. 2014).
`
`Pet., 31; Reply 3; EX1002 (Peterson), ¶¶15-22, 117-25;
`see also KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406 (2007).
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Uroguanylin is naturally produced by the body to draw water into the intestinal
`lumen, is “useful for the control of intestinal absorption,” able to displace ST
`binding, and may “act as a laxative and be useful in patients suffering from
`constipation[.]” EX1005 (Currie), 2:6-24; EX1016 (Fan), E957, E962; EX1020 (Nakazato), 222 & Fig. 2;
`EX1018 (Joo), G635-36, G639-41; EX1019 (Hamra 96), G708; EX1017 (Thomson), 807; EX1002 (Peterson), ¶¶59, 63, 71,
`90, 126-31; EX1064 (Epstein), ¶¶23-24.
`
`Oral administration of human uroguanylin stimulated intestinal fluid secretion
`for treatment of constipation. EX1018, G641-G642; EX1002, ¶¶99, 59-60, 85-86, 107; EX1005, 1:34-44,
`1:50-55, 2:6-24, 2:53-65, 6:11-22; EX1063 (Peterson), ¶10; EX2021 (WIPO), 2:28-3:1.
`
`At relevant intestinal pH, human uroguanylin has enhanced potency over
`guanylin attributed to acidic residues at positions 2 and 3. EX1002, ¶¶61-65, 91;
`EX1021 (Hamra 97), 2705, 2709; EX1063, ¶13.
`
`Currie acknowledged placement and import of uroguanylin’s disulfide bridges
`and that it lacked ST’s toxic potency, but taught its “physiological
`characteristics” made it “important to medical science in the study of regulators
`of guanylate cyclase.” EX1005, 1:47-63, 2:3-7; EX1002, ¶¶60, 86, 88, 105.
`
`Pet., 1, 5, 17-22; Reply, 2, 4-6; EX1002 (Peterson), ¶¶132-38.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`1313
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`3
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`Li narrows substitution choices at position 3 to Glu.
`EX1002 (Peterson), ¶¶137-52.
`
`Conservative substitution likely to retain excellent GC-C activity.
`EX1002, ¶¶73-75.
`
`Conserved in homologous species.
`
`Fine tune pH response.
`
`Eliminate pairing causing aspartimide formation.
`
`Routine synthesis and characterization.
`
`EX1002, ¶¶132-36.
`
`EX1002, ¶¶165-70.
`
`EX1002, ¶¶175-79.
`
`EX1002, ¶¶66-67.
`
`Pet., 21-22, 34-39; Reply, 11-12; EX1063 (Peterson), ¶50.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`14
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`3
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`EX1005 (Currie), 3:8-45.
`
`Intelligent Bio-Systems v. Illumina Cambridge,
`821 F.3d 1359, 1367 (Fed. Cir. 2016).
`
`EX1002 (Peterson), ¶¶66-67; id., ¶¶130-31.
`
`Pet., 21-22, 24, 35-36; Reply, 2; EX1002, ¶¶142-49.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`EX1060 (Davies), 127:5-128:4.
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`EX1060 (Davies), 130:9-20.
`
`Paper 16 (Institution Decision), 20.
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Pet., 21-22, 31, 35-36; Reply, 2-3;
`EX1002 (Peterson), ¶66-67, 130-31,
`147; EX1063 (Peterson), ¶¶114-17.
`16
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`EX1005 and EX1006
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`17
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`Currie (EX1005) taught natural GC-C ligand human uroguanylin:
`• Laxative effect for treating constipation. EX1005, 2:21-25.
`• Enhanced activity over guanylin; not toxic like ST. EX1005, 1:31-44, 3:65-4:9, Fig. 3B.
`• Works on rat intestines. EX1005, 5:5-20, 6:19-32.
`• Synthetic analogues easily and routinely made. EX1005, 3:8-45.
`
`Li (EX1006) taught Glu3-uroguanylin:
`• Glu3 was a conservative and homologous substitution for human uroguanylin
`• Likely to retain enhanced receptor affinity and potency at acidic pH. EX1006, 53-54.
`• Rat uroguanylin (with Glu3 substitution) works on a cell line from human intestines.
`EX1006, 47, 54.
`
`Pet., 22-24, 32-34.
`
`Pet., 24-26, 32-34.
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`The Combination provides:
`• Good reason to make the [Glu3]-analogue of human uroguanylin with a reasonable
`expectation of success.
`
`Pet., 32-34.
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`See also EX1002 (Peterson), ¶¶117-25.
`18
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`Human uroguanylin stimulated laxative activity via GC-C activation:
`
`EX1005, Figure 3B (with key from Figure 3A).
`
`EX1005, 6:11-21.
`
`EX1005, 2:21-25.
`
`Pet., 22-24; EX1002 (Peterson), ¶¶65, 84-87; Reply, 5-6; see also EX1005, 3:7-8 (“The novel peptide of
`this invention can be prepared by known solution and solid phase peptide synthesis methods.”).
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`The prior art provided good reason to make a synthetic analogue of the natural
`human uroguanylin GC-C ligand used by the body to draw water into the intestinal
`lumen.
`
`EX1063 (Peterson), ¶9.
`
`Pet., 22-24; EX1002 (Peterson), ¶¶104-06, 124-38; Reply, 4; EX1063, ¶9.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`20
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`EX1062 (Waldman), 62:7-67:6.
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`
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`Heat stable enterotoxins (STs) were known to have toxic properties;
`
`Human uroguanylin was a desirable alternative.
`
`EX1005, 1:31-44.
`
`EX1063 (Peterson), ¶¶16-19.
`
`Pet., 22-24; EX1002 (Peterson), ¶¶59-65; Reply, 5-6.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`21
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`“They create a massive diarrhea, a
`massive fluid and electrolyte secretion
`event, massive diarrhea, and the bugs
`are expelled into the environment so
`that they can find a new host. That’s
`the purpose of the molecular
`mimicry.”
`
`Dr. Waldman
`
`EX1062 (Waldman), 77:15-79:20.
`
`Pet., 34-39; Reply, 6-7; EX1002 (Peterson), ¶¶59-65.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`
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`EX1006, 52, Fig. 6A (annotated).
`
`Li indicates the conservative replacement
`of Asp3 of uroguanylin with Glu3, as found
`naturally in a mammal closely related to
`humans, was expected to retain relevant
`enhanced receptor affinity of uroguanylin.
`EX1006, 47, 54.
`
`EX1006, 54.
`
`Pet., 24-26; EX1002 (Peterson), ¶¶108-10; EX1006, 45, 53.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Aspartate (Asp) and Glutamate (Glu)
`“are the only amino acids having a
`second carboxyl group within the side
`chain and therefore were known for
`their characteristic, negatively
`charged functional groups.” “[T]he
`only structural difference between
`them is…one additional methylene….”
`EX1002 (Peterson), ¶54.
`
`EX1012 (Nelson), Fig. 5-5.
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Pet., 16-17; Reply, 14-16; EX1002, ¶¶53-54.
`24
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`Hamra 1997: “All uroguanylin peptides have aspartate or glutamate residues at
`these positions” and the “acidic residues” should not be deleted. EX1021, 2709.
`
`EX1021, 2709.
`
`Pet., 34-39; Reply, 16-19; EX1002 (Peterson), ¶¶64-65, 163-65; see also POR, 22, 45-51.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`This conservative substitution was expected to retain or improve activity.
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`EX1002 (Peterson), ¶74.
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`Pet., 21; Reply, 11; see also EX1063 (Peterson), ¶62.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`“In protein engineering the concept of conservative
`mutations is frequently used.”
`
`EX2035 (Jonson), 397.
`
`“In the case of aspartic acid, the obvious replacement
`is glutamic acid…these are certainly the only really
`conservative substitutions that would be possible.”
`EX2041 (Grossman), 37-38.
`
`Substitution would not negatively affect peptide
`structure.
`
`Bausch contends
`conservative substitutions
`simultaneously have
`minimal effect, and yet are
`wildly unpredictable.
`POR, 22, 41-42.
`
`Yet Bausch’s exhibits
`confirm an obvious,
`conservative modification
`was expected to retain
`activity.
`
`Reply, 14-16.
`
`EX2010 (Marx), Fig. 4 (annotated with red coloring).
`
`Pet., 34-39; Reply, 14-16; EX1002 (Peterson), ¶¶73-76, 137-38; see also POR, 40-45.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`POSAs routinely looked to orthologs (i.e., a peptide performing the same
`function in a different species, such as rat uroguanylin).
`
`“[S]killed artisans routinely investigated orthologous
`peptides, the same peptide hormone but in a different
`animal, for potential amino acid substitutions….
`[E]valuating uniformity verses variance in the sequence of
`orthologs across various species was a routine practice[.]”
`EX1002 (Peterson), ¶78; see also EX1025 (Karten).
`
`“[H]omology shows that uroguanylin orthologs generally
`do not vary much among mammals.”
`EX1002, ¶144 (citing EX1006 (Li), Figure 6A (reproduced below)).
`
`EX1006 (Li), Figure 6A.
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Pet., 21; EX1002, ¶¶73-81, 137-38.
`28
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`POSAs understood rat
`uroguanylin was informative to
`human uroguanylin:
`Currie: human uroguanylin
`acted on isolated intestinal rat
`preparation. EX1005, 2:16-24.
`Li: rat uroguanylin activated
`GC-C in human-derived T84
`cells. EX1006, 47, 54.
`
`EX1005 (Currie), 2:16-24.
`
`“[A] skilled artisan would have had good reason to
`look to the amino acids that differ between rat and
`human uroguanylin sequences in identifying
`promising, conservative amino acid substitution in
`designing a synthetic human uroguanylin analog.
`Indeed, a skilled artisan would have known that rat
`uroguanylin was highly likely to stimulate the
`human receptor.”
`
`EX1002 (Peterson), ¶142.
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Pet., 1-2; EX1002, ¶¶139-52.
`29
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`
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`Uroguanylin evolved to have
`enhanced potency in acidic
`mucosa in the intestines.
`
`EX1019 (Hamra 96), Fig. 1.
`
`EX1019, G710; EX1002 (Peterson), ¶62-63; Pet., 18-
`19; Reply, 20-21; EX1063 (Peterson), ¶¶105-06.
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`
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`Human uroguanylin “works better in the acidic environment of the small
`intestine[.]”
`POR, 54.
`
`EX1016 (Fan), E962.
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Pet., 17, 36-37; Reply, 4;
`EX1002 (Peterson), ¶¶65, 166-67.
`31
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`Bausch wrongly asserts Li Fig. 3 teaches Glu3 reduced activity.
`EX1063 (Peterson), ¶¶82-87; 1006 (Li), 49-51.
`• Dr. Davies read but did not analyze Li:
`
`• Dr. Davies mistakenly thought the
`uroguanylin bar graph in Fig. 3 was
`extracted from rat intestines to compare
`its activity to other peptides because a POSA
`would not assay activity of the synthetic standards:
`
`EX1060 (Davies), 139:19-142:5.
`
`EX1060 (Davies), 144:8-20.
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`EX1060 (Davies), 172:19-173:4.
`
`EX1060 (Davies), 172:12-173:19.
`
`Pet., 34-39; Reply, 16-19; EX1060, 139:19-142:5, 160:15-166:12, 168:2-171:22, 172:1-173:19.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`
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`Dr. Davies eventually confirmed Li Fig. 3 uses rat guanylin and opossum
`uroguanylin synthetic standards merely to show whether preincubation makes
`a difference in activity levels. EX1063 (Peterson), ¶¶82-87; 1006, 49-51.
`
`EX1060 (Davies), 184:4-185:1.
`
`EX1060 (Davies), 185:7-186:2.
`
`EX1060 (Davies), 182:14-21.
`Pet., 34-39; Reply, 16-19; see also POR, 22, 45-51.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`
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`Li does not indicate the same amount of each
`peptide was used:
`
`EX1063 (Peterson), ¶87.
`
`This misunderstanding infects testimony of
`both Drs. Davies and Waldman. EX2024 (Davies),
`¶¶75, 79, 161-65; EX2025 (Waldman), ¶57.
`
`Pet., 34-39; Reply, 16-19; see also POR, 22, 45-51.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`34
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`EX1006 (Li), 49 (Fig. 3).
`
`
`
`EX2021 (WIPO), 7:26-8:3 & Fig. 7.
`
`Pet., 34-39; Reply, 16-19; EX1002 (Peterson), ¶¶177-79.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`3
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`POSA expected Glu3 substitution to result in protonated glutamate at higher
`pH for better activity in the less acidic environment further from stomach.
`EX1002 (Peterson), ¶¶157-61; EX1012 (Nelson), 118, Table 5-1.
`
`Bausch’s contention that buried-residue pKa values showed unpredictability is
`erroneous; position 3 is not buried. EX1063 (Peterson), ¶¶102-03; EX2010 (Marx), 235, Fig. 4A-C.
`
`EX2010 (Marx), Fig. 4. (select portions,
`labeled, annotated with red coloring)
`The relative difference between pKas would benefit intestinal absorption.
`EX1063, ¶¶98-100, 104; EX2026 (Peterson), 100:3-13.
`
`Pet., 16-17, 36-37; Reply, 20-21; EX1002, ¶¶55-57, 157, 164-68.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`
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`EX1063 (Peterson), ¶110.
`
`EX1002 (Peterson), ¶¶175-79; Pet., 21-22, 34-39; Reply, 11-12, 21-22.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`
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`EX1002 (Peterson), ¶¶66-67.
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`EX1002, ¶¶120-25, 179; Pet., 21-22; Reply, 2.
`38
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`
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`Oral uroguanylin already shown to naturally add fluid to lumen.
`EX1063 (Peterson), ¶27; EX1018 (Joo), G641-G642; EX2021 (WIPO), 2:28-3:1; EX1002 (Peterson), ¶¶99, 59-60,
`85-86, 107; EX1005 (Currie), 1:34-44, 1:50-55, 2:6-24, 2:53-65, 6:11-22.
`No requirement to expose uroguanylin to pH 4.5 for 24 hours at 37°C.
`No more than 1% interconversion in vivo. EX1063, ¶¶25-27, 29, 31-32, 58;
`EX1064 (Epstein), ¶¶25-31, 39.
`Topoisomerism was easily managed. EX1063, ¶¶23-30, 34-40, 52; EX1064, ¶32;
`EX1002, ¶¶97-98; EX2010 (Marx), 236-39; EX2020 (Klodt), 227-28.
`Purification was straightforward. EX1063, ¶¶34, 40.
`Marx taught the ionizable side chains at positions 2 and 3 “may be involved
`in the control of stabilization of the two isomers.” EX2010, 236, 238.
`No reference says not to make uroguanylins because of topoisomerism.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Pet., 34-39; Reply, 7-11.
`39
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`
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`EX1018 (Joo), G641-G642.
`
`EX2021 (WIPO), 2:28-3:1.
`
`EX2010 (Marx), 229.
`
`EX2010 (Marx), 239.
`
`Pet., 48; Reply, 4, 7-8, 19; EX1063 (Peterson), ¶27; EX1002 (Peterson), ¶¶95-99, 59-60, 85-86, 107.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`
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`Bausch overstates the likelihood of interconversion.
`EX1063 (Peterson), ¶¶24-27, 29, 31-32, 58.
`
`EX1063 (Peterson), ¶25.
`
`Reply, 11-14; EX1064 (Epstein), ¶¶37-41; see POR, 39-40.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`
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`POSA would anticipate at most 1% conversion following oral administration.
`EX1063 (Peterson), ¶¶24-27, 29, 31-32, 58.
`
`EX1063 (Peterson), ¶26.
`
`EX2010 (Marx), Figure 6C (annotated by Dr. Peterson, EX1063 ¶26).
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Pet., 34-39; Reply, 11-14; see POR, 39-40.
`42
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`
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`Topoisomerism was addressable via formulation. EX1063 (Peterson), ¶¶27-28, 34-40, 52.
`
`EX1063 (Peterson), ¶28.
`
`EX1063 (Peterson), ¶40.
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`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Pet., 34-39; Reply, 11-14; see POR, 39-40.
`43
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`
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`Topoisomeric purification was straightforward. EX1063 (Peterson), ¶¶27-28, 34-40, 52.
`
`EX1060 (Davies), 114:19-115:10.
`
`EX2011 (Chino), 29.
`
`EX2010 (Marx), 230.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Pet., 34-39; Reply, 11-14; see POR, 39-40.
`44
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`
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`POSA knew the ionizable terminal carboxylic acid side chains at positions 2
`and 3 were points of interest for stabilizing uroguanylin. EX2010 (Marx), 236, 238.
`
`EX2010 (Marx), 236.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Pet., 34-39; Reply, 11-14; see POR, 39-40.
`45
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`
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`Bausch’s references instead called for “systematic substitution of amino acids
`contained in uroguanylin and guanylin.” EX2010 (Marx), 236.
`
`EX2010 (Marx), 236.
`
`EX1063 (Peterson), ¶33.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
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`Pet., 34-39; Reply, 11-14; see POR, 39-40.
`46
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`
`
`Bausch argues a POSA necessarily would have
`modified enterotoxin. POR, i-ii, 2-3, 26, 41.
`
`The Board already cautioned Bausch against this.
`
`Paper 16 (Institution Decision), 20-23.
`
`Petitioner need only identify “some reason” to
`modify a known compound.
`Bristol-Myers Squibb v. Teva Pharms., 752 F.3d 967, 973 (Fed. Cir. 2014).
`
`Altana Pharma AG. v. Teva
`Pharms., 566 F.3d 999,
`1007-08 (Fed. Cir. 2009)
`(impermissible to require
`prior art “point to only a
`single lead compound”).
`
`In re Fulton, 391 F.3d 1195,
`1200 (Fed. Cir. 2004) (no
`requirement “that the
`combination is the most
`desirable combination
`available”).
`
`Pet., 31; Reply, 2-4; EX1002 (Peterson), ¶¶29, 122-23, 126-79.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`47
`
`
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`48
`
`
`
`Dr. Shailubhai’s testimony confirmed the
`cGMP values of Table 4 can’t be read to
`conclude a statistical difference existed
`between tested peptides.
`
`Bausch contends
`plecanatide is unexpectedly
`more active in producing
`cGMP than uroguanylin.
`POR, 60-64.
`
`Yet the difference is within
`the level of experimental
`error. No real, material
`difference was shown.
`EX1063, ¶¶118-35.
`
`EX1061, 33:19-34:15.
`EX1061 (Shailubhai), 33:19-34:15.
`Pet., 31-32, 50, 54; Reply, 24-26; EX1002 (Peterson), ¶253; see also POR, 40-45.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`49
`
`
`
`Any nominal difference reflects experimental variability, not unexpected results.
`EX2023, ¶¶9, 16; EX1063, ¶¶126-29; EX2027, 20.
`
`EX1063 (Peterson), ¶¶126-29 (annotating and comparing
`Table 1, EX2027, 20 (left) with Table 4, EX1001 (right)).
`
`Pet., 31-32, 50, 54; Reply, 24-26; see also POR, 40-45.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`50
`
`
`
`Dr. Davies glosses over the error-riddled data, arguing observed differences were
`not real differences; merely “a different way to interpret the data.”
`EX1060, 57:8-10, 54:2-4, 68:8-18; EX1063, ¶¶124-29.
`
`EX1060 (Davies), 74:8-17.
`
`Pet., 31-32, 50, 54; Reply, 24-26; see also POR, 40-45.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`51
`
`
`
`Bausch’s Table 2 reports human uroguanylin was ~20% more active.
`
`EX2023, ¶24 (Table 2).
`Bausch’s Table 3 reports plecanatide was the least active of the tested peptides.
`
`EX2023, ¶29 (Table 3).
`
`EX1063 (Peterson), ¶¶134-41; EX1060 (Davies), 79:9-82:19;
`Pet., 31-32, 50, 54; Reply, 24-26; see also POR, 40-45.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`52
`
`
`
`Variation in nominal values for the same peptides at the same concentrations
`was as high as 29-59%; yet even a two-fold variation is common and does not
`show unexpected results. EX1063 (Peterson), ¶¶135-36; EX2028, 14, Table 3.
`
`EX1060 (Davies), 79:9-82:19.
`
`Pet., 31-32, 50, 54; Reply, 24-26; see also POR, 40-45.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`53
`
`
`
`Bausch’s data shows experimental error is greater than the asserted 56% improvement.
`
`EX1063 (Peterson), ¶131.
`
`EX1063 (Peterson), ¶136 (Data of EX2023 Table 3 at T=0;
`full scale (left) and zoomed-in on nominal differences (right)).
`
`EX1063 (Peterson), ¶135.
`
`Pet., 31-32, 50, 54; Reply, 24-26; see also POR, 40-45.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`54
`
`
`
`Table 1 was amended, eliminating the purported 10-fold potency difference.
`EX1063 (Peterson), ¶124; EX2027, 20.
`
`EX1060 (Davies), 66:1-70:5.
`
`EX1069, 30.
`
`Pet., 31-32, 50, 54; Reply, 24-26; see also POR, 40-45.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`55
`
`EX2027, 20.
`
`
`
`No material difference in
`kind after boiling peptides
`(95°C) for 90 minutes).
`Reply, 26-27; EX1063 (Peterson), ¶140.
`
`Glu3’s cGMP values drifted
`~7% higher after heat
`treatment.
`EX1063 (Peterson), ¶¶137-140.
`
`EX1067, 129.
`
`EX1001, 16:19-28; EX1060 (Davies), 47:3-22.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Reply, 26-27.
`56
`
`
`
`Bausch’s presentation of data as %
`of starting activity gives false
`impression of significant or material
`differences.
`Reply, 26-27; EX1063 (Peterson), ¶¶136-43.
`
`Uroguanylin and Glu2 have initial
`cGMP values 6-13% greater than
`Glu3.
`Reply, 26-27; EX1063 (Peterson), ¶¶136-43 & n.8.
`
`EX1063 (Peterson), ¶141.
`
`EX1063 (Peterson), ¶136.
`
`EX2028, 14, Table 3.
`
`Pet., 31-32, 50, 54; Reply, 26-27; EX1063, ¶¶136-43 & n.8; POR, 64-65.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`57
`
`
`
`Bausch has not shown relevance of topoisomeric interconversion at pH 3 at
`37°C for 16 hours:
`
`EX1063 (Peterson), ¶177.
`
`EX1067, 130; Pet., 31-32, 50, 54; Reply, 27-28; EX1063, ¶¶24-29, 31-32, 162, 167, 177.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`58
`
`EX1063 (Peterson), ¶25.
`
`
`
`Acidic residues at positions 2 and 3 contributed to stabilization.
`
`EX1063 (Peterson), ¶178.
`Sterical bulk reduces topoisomeric conversion.
`
`EX2020 (Klodt), 228.
`Substituting Glu3 thus provided no unexpected difference in kind.
`
`Pet., 31-32, 50, 54; Reply, 27-28; EX1002 (Peterson), ¶253; EX1063, ¶178.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`59
`
`
`
`Indicia of reliability, including error bars and evaluation of statistical
`significance between peptides, absent from Bausch reports .
`EX1063 (Peterson), ¶¶166-67; EX1067, 93-94, 120-22, 140.
`
`EX1067, 121 (Annex A).
`
`EX1067, 121, Table 1.
`
`EX1067, 121, Figure 1.
`
`Pet., 31-32, 50, 54; Reply, 24-26; see also POR, 40-45.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`60
`
`
`
`Indicia of reliability, including error bars and evaluation of statistical
`significance between peptides, absent from Bausch reports.
`EX1063 (Peterson), ¶¶166-67; EX1067, 93-94, 120-22, 140.
`
`EX1067, 122 (Annex A).
`
`EX1067, 122, Table 2.
`
`EX1067, 122, Figure 2.
`
`Pet., 31-32, 50, 54; Reply, 24-26; see also POR, 40-45.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`61
`
`
`
`Bausch has not shown the same HPLC protocol was capable of resolving both
`peaks for both peptides.
`
`EX1063 (Peterson), ¶¶146-47
`(annotating EX2028, 10, Fig. 1).
`
`EX1067, 91.
`
`EX1063, ¶¶146-47; EX1067, 90-91 ;Pet., 31-32, 50, 54; Reply, 27-28.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`62
`
`
`
`Claim 1 recites no topoisomer limitation:
`
`EX1060 (Davies), 20:3-8;
`see also id., 111:17-112:13, 108:22-110:15.
`
`“[N]o principle of law…would
`authorize us to read into a claim an
`element which is not present.”
`McCarty v. Lehigh Valley R.R. Co.,
`160 U.S. 110, 116 (1895).
`
`Unexpected results must be
`“commensurate in scope with the
`claims.”
`
`DuPont v. Synvina,
`904 F.3d 996, 1012 (Fed. Cir. 2018).
`
`Bausch’s later patents state the ’786 patent synthetic methods
`produce mixed topoisomers. EX1068 (’346 patent), 3:30-41.
`Pet., 11, 14, 32-34; Reply, 22-24; EX1002 (Peterson), ¶¶44-45, 117-19.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`63
`
`
`
`Bausch previously argued plecanatide in “the form in which it is therapeutically
`administered” was compared to uroguanylin as “a mixture of isoforms.”
`EX1063 (Peterson), ¶¶148-49, 152; EX1067, 102-03, 139-40.
`
`EX1067, 139-40.
`But Bausch could have—and should have—compared the active form of
`uroguanylin against the active form of plecanatide.
`EX1063 (Peterson), ¶168; EX1060 (Davies), 114:19-116:10, 41:6-17, 43:12-19.
`
`EX1067, 125-26.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet., 11, 14, 32-34; Reply, 22-24.
`64
`
`
`
`EX1005, EX1006, and EX1007
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`65
`
`
`
`Currie & Li obviated Glu3-human uroguanylin (Plecanatide; SEQ ID NO: 20)
`as previously discussed.
`
`Currie also taught:
`Human uroguanylin could be used for its natural purpose as a laxative to
`treat constipation in human patients. EX1005, 2:20-24.
`Uroguanylin and its analogs act in the intestinal endothelium. EX1005, 1:20-25.
`
`Narayani taught:
`Unit doses of peptides in gelatin capsules facilitates passage through the
`stomach and drug delivery to the intestine. EX1007, 47.
`
`Combination taught:
`Good reason to use a capsule as a unit dose of Glu3 analog of human
`uroguanylin to deliver the peptide to the intestine.
`
`Pet., 40-42; EX1002 (Peterson), ¶¶181-89, 190-201.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`66
`
`
`
`It was known to deliver peptide drugs to the intestine while avoiding degradation
`in the stomach using natural polymer coating (e.g., alginate).
`
`EX1007, 40.
`
`EX1007, 47
`
`Pet., 26-27; EX1002 (Peterson), ¶¶111-12, 181-89, 190-201.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`67
`
`
`
`Narayani taught:
`Unit doses of peptides in polymer-coated gelatin capsules facilitates
`passage through the stomach and drug delivery to the intestine. EX1007, 47.
`
`Plain meaning of “excipient” includes coating agents:
`
`EX1043 (Baldrick), 210.
`
`Pet., 14, 42-45; EX1002 (Peterson), ¶¶202-09.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`68
`
`
`
`EX1005, EX1006, EX1007, and EX1008
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`69
`
`
`
`Currie, Li, and Narayani obviated unit dose forms of Glu3-human uroguanylin
`(Plecanatide; SEQ ID NO: 20), including as capsules, to treat constipation as
`previously discussed.
`
`Campieri taught:
`Using steroidal anti-inflammatory agents (prednisolone, budesonide) to
`treat intestinal inflammation. EX1008, 213.
`Application in treatment of Chrohn’s disease, a chronic inflammatory
`disorder. EX1008, 209.
`
`Combination taught:
`Good reason to include an anti-inflammatory agent in a capsule dose of
`Glu3 analog of human uroguanylin.
`
`Pet., 45-50; EX1002 (Peterson), ¶¶113-14, 210-14, 215-27.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`70
`
`
`
`POSA knew administration of budesonide
`and prednisolone would promptly treat
`symptoms of inflammatory bowel disease.
`
`Campieri orally administered the
`steroids as tablets, consistent with a
`capsule.
`
`EX1008, 213.
`
`EX1008, 209.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet., 27-28; EX1002, ¶¶113-14.
`71
`
`
`
`EX1005, EX1006, and EX1009
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`72
`
`
`
`Currie & Li obviated Glu3-human uroguanylin (Plecanatide; SEQ ID NO: 20)
`as previously discussed.
`
`Ekwuribe taught:
`Benefits of peptide conjugates comprising PEG attached to the peptide.
`EX1009, [57], 33:50-55 (claim 15); EX1002 (Peterson), ¶¶234, 237-39.
`
`Combination taught:
`Good reason to conjugate polyethylene glycol (PEG) to plecanatide.
`
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`
`Pet., 50-53; EX1002, ¶¶232-36, 237-47.
`73
`
`
`
`Ekwuribe teaches advantages to
`modifying peptides so physiological
`activities are maintained.
`
`EX1009, 1:46-59.
`
`Ekwuribe conjugated the peptide
`insulin to PEG, then to a linker with
`more PEG, providing a hydrophilic
`environment.
`
`EX1009, 13:44-53.
`
`Ekwuribe further teaches PEGylation
`“endow[s] the polymer-peptide with
`high aqueous solubility” and provided
`“increased stability against
`denaturation and enzymatic digestion.”
`
`EX1009, 14:50-55, 2:60-3:1.
`
`Pet., 27-28; EX1002 (Peterson), ¶¶113-14, 232-36, 237-47.
`DEMONSTRATIVE EXHIBIT – NOT EVIDENCE
`74
`
`
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