Ground 1: Claims 1, 14, and 15 Are Anticipated By ‘241 Patent as Characterized
`by Patent Owner’s Admissions
`
`Claims of the ‘921
`Patent
`1. A compound which is
`1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-
`carbamoyl-benzofuran-
`5yl)-piperazine
`hydrochloride in its
`crystalline modification,
`wherein the compound
`is an anhydrate, hydrate,
`solvate or
`dihydrochloride.
`
`The ‘241 Patent (Ex. 1004) and Patent Owner’s
`Admissions (Ex. 1001)
`“A compound according to claim 1, wherein said
`compound is…(c) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine or a
`physiologically acceptable salt thereof.” Ex. 1004, cl.
`2.
`“Analogously to Example 3, starting from 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5yl)-piperazine reaction with 2-chloro-1-
`methylpyridinium methane-sulfonate gives 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5yl)-piperazine, m.p. 269-272° (hydrochloride).” Ex.
`1004, Example 4.
`“In the following Examples, “working-up in
`conventional manner” means: Water is added if
`necessary, extraction is carried out with methylene
`chloride, the organic phase is separate off, dried over
`sodium sulfate and filtered, the filtrate is evaporated
`and the residue is purified by chromatography on silica
`gel and/or by crystallization.” Ex. 1004 at 9:4-9.
`“1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5yl)-piperazine, its physiologically
`acceptable salts thereof (U.S. Pat. No. 5,532,241,
`column 7, lines 30-58), a process (U.S. Pat. No.
`5,532,241, Example 4) by which it/they can be
`prepared and their use in treating certain medical
`disorders are known from U.S. Pat. No. 5,532,241 and
`WO 00/72832.” Ex. 1001 at 1:35-41.
`“Former 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride
`having a melting point of 269-272°C. was a mixture of
`amorphous 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride,
`crystallized 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`
`
`Argentum EX1014
`Page 1
`
`

`

`14. A method of treating
`a patient suffering from
`a depressive disorder, an
`anxiety disorder, a
`bipolar disorder, mania,
`dementia, a substance-
`related disorder, a
`sexual dysfunction, an
`eating disorder, obesity,
`fibromyalgia, a sleeping
`disorder, a psychiatric
`disorder, cerebral
`infarct, tension, side-
`effects in the treatment
`of hypertension, a
`cerebral disorder,
`chronic pain,
`acromegaly,
`hypogonadism,
`secondary amenorrhea,
`premenstrual syndrome
`and undesired puerperal
`lactation, or
`combinations thereof,
`comprising
`administering to the
`patient in need thereof
`an effective amount of a
`compound of claim 1.
`15. A pharmaceutical
`composition comprising
`a compound according
`to claim 1, and one or
`more conventional
`auxiliary substances
`
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride
`and the free base 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine.” Ex. 1001 at
`1:65-2:5.
`See Claim 1 above.
`
`“The compounds of the formula I and their
`physiologically acceptable salts can be used for the
`therapeutic treatment of the human or animal body and
`for controlling diseases. They can be used for treating
`disorders of the central nervous system, such as
`tension, depressions and/or psychoses, and side-effects
`in the treatment of hypertension (e.g., with α-
`methyldopa). The compounds can also be used in
`endocrinology and gynecology, e.g., for the therapeutic
`treatment of acromegaly, hypogonadism, secondary
`amenorrhea, premenstrual syndrome and undesired
`puerperal lactation, and also for the prophylaxis and
`therapy of cerebral disorders (e.g., migraine),
`especially in geriatrics in a manner similar to certain
`ergot alkaloids and for controlling the sequelae of
`cerebral infarction (apoplexia cerebri), such as stroke
`and cerebral ischemia.” Ex. 1004 at 8:24-38.
`
`See Claim 1 above.
`“A pharmaceutical composition comprising a
`compound according to claim 1 and a pharmaceutically
`acceptable carrier.” Ex. 1004, cl. 16.
`“The invention further relates to the use of the
`
`Page 2
`
`

`

`and/or carriers.
`
`compounds of the formula I and their physiologically
`acceptable salts for the manufacture of pharmaceutical
`preparations, especially by a non-chemical route. For
`this purpose, they can be converted into a suitable
`dosage form together with at least one excipient or
`adjunct and, if appropriate, in combination with one or
`more additional active ingredients.” Ex. 1004, 7:59-65.
`
`
`Ground 2: Claims 1, 14, and 15 Are Obvious over the ‘241 Patent as Characterized
`by Patent Owner’s Admissions in view of Bartoszyk
`
`Claims the ‘921 Patent
`
`1. A compound which is
`1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-
`carbamoyl-benzofuran-
`5yl)-piperazine
`hydrochloride in its
`crystalline modification,
`wherein the compound
`is an anhydrate, hydrate,
`solvate or
`dihydrochloride.
`
`The ‘241 Patent (Ex. 1004) and Patent Owner’s
`Admissions (Ex. 1001) and Bartoszyk (Ex.1005)
`“A compound according to claim 1, wherein said
`compound is…(c) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine or a
`physiologically acceptable salt thereof.” Ex. 1004, cl.
`2.
`“Analogously to Example 3, starting from 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5yl)-piperazine reaction with 2-chloro-1-
`methylpyridinium methane-sulfonate gives 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5yl)-piperazine, m.p. 269-272° (hydrochloride).” Ex.
`1004, Example 4.
`“In the following Examples, “working-up in
`conventional manner” means: Water is added if
`necessary, extraction is carried out with methylene
`chloride, the organic phase is separate off, dried over
`sodium sulfate and filtered, the filtrate is evaporated
`and the residue is purified by chromatography on silica
`gel and/or by crystallization.” Ex. 1004 at 9:4-9.
`“1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5yl)-piperazine, its physiologically
`acceptable salts thereof (U.S. Pat. No. 5,532,241,
`column 7, lines 30-58), a process (U.S. Pat. No.
`5,532,241, Example 4) by which it/they can be
`
`Page 3
`
`

`

`prepared and their use in treating certain medical
`disorders are known from U.S. Pat. No. 5,532,241 and
`WO 00/72832.” Ex. 1001 at 1:35-41.
`“Former 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride
`having a melting point of 269-272°C. was a mixture of
`amorphous 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride,
`crystallized 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride
`and the free base 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine.” Ex. 1001 at
`1:65-2:5.
`“1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine or a physiologically
`acceptable salt thereof is used for the manufacture of a
`medicament for the treatment of sub-type anxiety
`disorders chosen from the sub-types panic disorder
`with or without agoraphobia, agoraphobia, obsessive-
`compulsive spectrum disorders, social phobia,
`posttraumatic stress disorder, acute stress indication or
`generalized-anxiety disorder, bipolar disorders, mania,
`dementia, substance-related disorders, sexual
`dysfunctions, eating disorders, obesity, anorexia and
`fibromyalgia. A preferred salt is 1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride.” Ex. 1005 at abstract.
`“A typical model for Agoraphobia is named Elevated
`Plus Maze… Normal animals… avoid entering the
`open arms and stay only a [sic.] for a very brief period
`on open arms. 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine or one of its
`physiologically acceptable salts, in particular 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine hydrochloride, following oral application
`dose-dependently increased both the number of entries
`and the time spend on open arms….” Ex. 1005 at 3:20-
`4:5.
`
`Page 4
`
`

`

`“A typical model for OCSD including OCD is the
`Marble Burying Test… 1-[4-(5-cyanoindol-3-yl)butyl]-
`4-(2-carbamoyl-benzofuran-5-yl)-piperazine or one of
`its physiologically acceptable salts, in particular 1-[4-
`(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5-yl)-piperazine hydrochloride… inhibits mable [sic.]
`burying in mice….” Ex. 1005 at 5:23-6:8.
`“A model for social phobia is the Social Interaction
`Test… 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine or one of its
`physiologically acceptable salts, in particular 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine hydrochloride, increase the time spent in
`social interaction….” Ex. 1005 at 6:19-7:2.
`“In a typical model for neophobia, mice deprived from
`food for 18h are given access to unfamiliar food in a
`novel environment… 1-[4-(5-cyanoindol-3-yl)butyl]-4-
`(2-carbamoyl-benzofuran-5-yl)-piperazine or one of its
`physiologically acceptable salts, in particular 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine hydrochloride… increased food
`intake…” Ex. 1005 at 7:29-8:6.
`“A typical model for acute stress indication is the Four
`Plate Test… Normal mice… accept only a few
`footshocks. 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride… increased the number of punished
`crossings…” Ex. 1005 at 10:1-15.
`“A typical model for generalized anxiety disorders is
`the Light-Dark Choise Test… Normal mice… spent
`most time in the dark compartment. 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine or one of its physiologically acceptable
`salts, in particular 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride… increase the number of transitions and
`time spent in lit compartment….” Ex. 1005 at 10:20-
`11:9.
`
`Page 5
`
`

`

`“Additionally… 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine also has
`activity against bipolar disorders and/or mania…. 1-[4-
`(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5-yl)-piperazine or one of its physiologically
`acceptable salts, in particular 1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride, inhibit the hyperactivity… to the same
`degree as do lithium and valproate, the standard
`treatments…” Ex. 1005:13:1-16.
`“Additionally… 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine also has
`activity against dementia, including Alzheimer’s
`disease and multi-infarct… Typical models… are the
`Passive Avoidance test in rats… and the testing of
`memory functions in the Morris Water Maze in aged
`rats… 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine or one of its
`physiologically acceptable salts, in particular 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine hydrochloride, following oral application
`of 10 mg/kg p.o. enhanced memory… 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine hydrochloride is administered to old
`rats… When tested at day 7, the latencies to find the
`platform in the first attempt are… not differing from
`vehicle treated young rats…” Ex. 1005 at 15:15-18:15.
`“Additionally… 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine also has
`activity against eating disorders including anorexia
`nervosa and bulimia nervosa and/or obesity…. A
`typical model is named Cumulative Food Intake… 1-
`[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine hydrochloride… result in a
`reduced development of body weight at higher doses.
`On the other hand, the lower doses… result in
`increased body weight.” Ex. 1005 at 23:24-24:20.
`“Rapid procedures to test pain-relieving properties of
`drugs are the abdominal constriction (writhing) test…
`
`Page 6
`
`

`

`14. A method of treating
`a patient suffering from
`a depressive disorder, an
`anxiety disorder, a
`bipolar disorder, mania,
`dementia, a substance-
`related disorder, a
`sexual dysfunction, an
`eating disorder, obesity,
`fibromyalgia, a sleeping
`disorder, a psychiatric
`disorder, cerebral
`infarct, tension, side-
`effects in the treatment
`of hypertension, a
`cerebral disorder,
`chronic pain,
`acromegaly,
`hypogonadism,
`secondary amenorrhea,
`premenstrual syndrome
`and undesired puerperal
`lactation, or
`combinations thereof,
`comprising
`administering to the
`patient in need thereof
`an effective amount of a
`compound of claim 1.
`15. A pharmaceutical
`composition comprising
`a compound according
`to claim 1, and one or
`more conventional
`
`For example, 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride… reduced abdominal contrictions…
`and… reduced the formalin-induced pain response…”
`Ex. 1005 at 28:10-17.
`See Claim 1 above.
`
`“The compounds of the formula I and their
`physiologically acceptable salts can be used for the
`therapeutic treatment of the human or animal body and
`for controlling diseases. They can be used for treating
`disorders of the central nervous system, such as
`tension, depressions and/or psychoses, and side-effects
`in the treatment of hypertension (e.g., with α-
`methyldopa). The compounds can also be used in
`endocrinology and gynecology, e.g., for the therapeutic
`treatment of acromegaly, hypogonadism, secondary
`amenorrhea, premenstrual syndrome and undesired
`puerperal lactation, and also for the prophylaxis and
`therapy of cerebral disorders (e.g., migraine),
`especially in geriatrics in a manner similar to certain
`ergot alkaloids and for controlling the sequelae of
`cerebral infarction (apoplexia cerebri), such as stroke
`and cerebral ischemia.” Ex. 1004 at 8:24-38.
`
`See Claim 1 above.
`“A pharmaceutical composition comprising a
`compound according to claim 1 and a pharmaceutically
`acceptable carrier.” Ex. 1004, cl. 16.
`
`Page 7
`
`

`

`auxiliary substances
`and/or carriers.
`
`
`
`“The invention further relates to the use of the
`compounds of the formula I and their physiologically
`acceptable salts for the manufacture of pharmaceutical
`preparations, especially by a non-chemical route. For
`this purpose, they can be converted into a suitable
`dosage form together with at least one excipient or
`adjunct and, if appropriate, in combination with one or
`more additional active ingredients.” Ex. 1004, 7:59-65.
`
`1. A compound which is
`1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-
`carbamoyl-benzofuran-
`5yl)-piperazine
`hydrochloride in its
`crystalline modification,
`wherein the compound
`is an anhydrate, hydrate,
`solvate or
`dihydrochloride.
`
`Ground 3: Claims 1 and 11 are Obvious over the ‘241 Patent as Characterized by
`Patent Owner’s Admissions, Pavia, and Byrn
`Claims of the ‘921
`The ‘241 Patent (Ex. 1004) and Patent Owner’s
`Patent
`Admissions (Ex. 1001) in view of Pavia (Ex. 1032)
`and Byrn (Ex. 1012)
`“A compound according to claim 1, wherein said
`compound is…(c) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine or a
`physiologically acceptable salt thereof.” Ex. 1004, cl.
`2.
`“Analogously to Example 3, starting from 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5yl)-piperazine reaction with 2-chloro-1-
`methylpyridinium methane-sulfonate gives 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5yl)-piperazine, m.p. 269-272° (hydrochloride).” Ex.
`1004, Example 4.
`“In the following Examples, “working-up in
`conventional manner” means: Water is added if
`necessary, extraction is carried out with methylene
`chloride, the organic phase is separate off, dried over
`sodium sulfate and filtered, the filtrate is evaporated
`and the residue is purified by chromatography on silica
`gel and/or by crystallization.” Ex. 1004 at 9:4-9.
`“1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5yl)-piperazine, its physiologically
`acceptable salts thereof (U.S. Pat. No. 5,532,241,
`
`Page 8
`
`

`

`column 7, lines 30-58), a process (U.S. Pat. No.
`5,532,241, Example 4) by which it/they can be
`prepared and their use in treating certain medical
`disorders are known from U.S. Pat. No. 5,532,241 and
`WO 00/72832.” Ex. 1001 at 1:35-41.
`“Former 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride
`having a melting point of 269-272°C. was a mixture of
`amorphous 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride,
`crystallized 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride
`and the free base 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine.” Ex. 1001 at
`1:65-2:5.
`“Organic compounds that are solid at room temperature
`are usually purified by crystallization. The general
`technique involves dissolving the material to be
`crystallized in a hot solvent (or solvent mixture) and
`cooling the solution slowly….” Ex. 1032 at 522-531.
`“The most useful methcxl to compare X-ray powder
`diffraction data obtained from different samples and on
`the same instrumentation is to overlay and align the
`respective films or plots….” Ex. 1012 at 63.
`“A compound according to claim 1, wherein said
`compound is…(c) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine or a
`physiologically acceptable salt thereof.” Ex. 1004, cl.
`2.
`“Analogously to Example 3, starting from 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5yl)-piperazine reaction with 2-chloro-1-
`methylpyridinium methane-sulfonate gives 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5yl)-piperazine, m.p. 269-272° (hydrochloride).” Ex.
`1004, Example 4.
`“In the following Examples, “working-up in
`
`Page 9
`
`11. A pharmaceutical
`composition comprising
`a compound which is 1-
`[4-(5-cyanoindol-3-
`yl)butyl]-4-(2
`carbamoyl-benzofuran-
`5-yl)-piperazine
`hydrochloride anhydrate
`in its crystalline
`modification IV, and
`one or more
`conventional auxiliary
`substances and/or
`carriers.
`
`

`

`conventional manner” means: Water is added if
`necessary, extraction is carried out with methylene
`chloride, the organic phase is separate off, dried over
`sodium sulfate and filtered, the filtrate is evaporated
`and the residue is purified by chromatography on silica
`gel and/or by crystallization.” Ex. 1004 at 9:4-9.
`“1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5yl)-piperazine, its physiologically
`acceptable salts thereof (U.S. Pat. No. 5,532,241,
`column 7, lines 30-58), a process (U.S. Pat. No.
`5,532,241, Example 4) by which it/they can be
`prepared and their use in treating certain medical
`disorders are known from U.S. Pat. No. 5,532,241 and
`WO 00/72832.” Ex. 1001 at 1:35-41.
`“Example 4 of U.S. Pat. No. 5,532,241 describes the
`preparation of 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine hydrochloride
`by reacting 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carboxybenzofuran-5-yl)piperazine at first with 2-
`chloro-1-methylpyridinium methanesulfonate in N-
`methylpyrrolidine and then with dried NH3. Customary
`working up gives the free base 1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-carboxybenzofuran-5-yl)piperazine. 700
`mg of the base are dissolved in 30 ml 2-propanol under
`heating and then treated with 0.1 n 2-propanolic HCL-
`solution (Merck-Art. No. 1.00326) until precipitation of
`hydrochloride is complete. The precipitate was filtered
`off and washed with diethylether and dried at room
`temperature to yield 1-[4-(5-cyanoindol-3-yl)butyl]-4-
`(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride having a melting point of 269-272°C.”
`Ex. 1001 at 1:42-57.
`“Former 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride
`having a melting point of 269-272°C. was a mixture of
`amorphous 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride,
`crystallized 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride
`
`Page 10
`
`

`

`and the free base 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine.” Ex. 1001 at
`1:65-2:5.
`“A pharmaceutical composition comprising a
`compound according to claim 1 and a pharmaceutically
`acceptable carrier.” Ex. 1004, cl. 16.
`“The invention further relates to compositions,
`especially pharmaceutical preparations, containing at
`least one compound of the formula I and/or one of their
`physiologically acceptable salts. These preparations
`can be used as drugs in human or veterinary medicine.
`Possible excipients are organic or inorganic substances
`which are suitable for enteral (e.g.,oral), parenteral or
`topical administration and which do not react with the
`novel compounds, examples of such excipients being
`water, vegetable oils, benzyl alcohols, polyethylene
`glycols, gelatin, carbohydrates such as lactose or
`starch, magnesium stearate, talc and petroleum jelly.
`Tablets, coated tablets, capsules, syrups, juices, drops
`or suppositories are used in particular for enteral
`administration, solutions, preferably oily or aqueous
`solutions, as well as suspensions, emulsions or implants
`are used for parenteral administration, and ointments,
`creams or powders are used for topical administration.
`The novel compounds can also be lyophilized and the
`resulting lyophilizates used, e.g., to manufacture
`injectable preparations.” Ex. 1004, 7:66-8:15.
`“Possible excipients are organic or inorganic
`substances which are suitable for enteral (e.g.,oral),
`parenteral or topical administration and which do not
`react with the novel compounds… Tablets, coated
`tablets, capsules, syrups, juices, drops or suppositories
`are used in particular for enteral administration,
`solutions, preferably oily or aqueous solutions, as well
`as suspensions, emulsions or implants are used for
`parenteral administration, and ointments, creams or
`powders are used for topical administration. The novel
`compounds can also be lyophilized and… used, e.g., to
`manufacture injectable preparations.” Ex. 1004 at 8:3-
`
`Page 11
`
`

`

`16.
`“Organic compounds that are solid at room temperature
`are usually purified by crystallization. The general
`technique involves dissolving the material to be
`crystallized in a hot solvent (or solvent mixture) and
`cooling the solution slowly….” Ex. 1032 at 522-531.
`“The most useful methcxl to compare X-ray powder
`diffraction data obtained from different samples and on
`the same instrumentation is to overlay and align the
`respective films or plots….” Ex. 1012 at 63.
`
`
`Ground 4: Claims 1, 12, 14, and 15 are Obvious over the ‘241 Patent as
`characterized by Patent Owner’s Admissions in view Bartoszyk, Pavia and Byrn
`
`Claims the ‘921 Patent
`
`1. A compound which is
`1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-
`carbamoyl-benzofuran-
`5yl)-piperazine
`hydrochloride in its
`crystalline modification,
`wherein the compound
`is an anhydrate, hydrate,
`solvate or
`dihydrochloride.
`
`The ‘241 Patent (Ex. 1004) and Patent Owner’s
`Admissions (Ex. 1001) and Bartoszyk (Ex.1005)
`“A compound according to claim 1, wherein said
`compound is…(c) 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine or a
`physiologically acceptable salt thereof.” Ex. 1004, cl.
`2.
`“Analogously to Example 3, starting from 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5yl)-piperazine reaction with 2-chloro-1-
`methylpyridinium methane-sulfonate gives 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5yl)-piperazine, m.p. 269-272° (hydrochloride).” Ex.
`1004, Example 4.
`“In the following Examples, “working-up in
`conventional manner” means: Water is added if
`necessary, extraction is carried out with methylene
`chloride, the organic phase is separate off, dried over
`sodium sulfate and filtered, the filtrate is evaporated
`and the residue is purified by chromatography on silica
`gel and/or by crystallization.” Ex. 1004 at 9:4-9.
`“1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`
`Page 12
`
`

`

`benzofuran-5yl)-piperazine, its physiologically
`acceptable salts thereof (U.S. Pat. No. 5,532,241,
`column 7, lines 30-58), a process (U.S. Pat. No.
`5,532,241, Example 4) by which it/they can be
`prepared and their use in treating certain medical
`disorders are known from U.S. Pat. No. 5,532,241 and
`WO 00/72832.” Ex. 1001 at 1:35-41.
`“Former 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride
`having a melting point of 269-272°C. was a mixture of
`amorphous 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride,
`crystallized 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine hydrochloride
`and the free base 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5yl)-piperazine.” Ex. 1001 at
`1:65-2:5.
`“1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine or a physiologically
`acceptable salt thereof is used for the manufacture of a
`medicament for the treatment of sub-type anxiety
`disorders chosen from the sub-types panic disorder
`with or without agoraphobia, agoraphobia, obsessive-
`compulsive spectrum disorders, social phobia,
`posttraumatic stress disorder, acute stress indication or
`generalized-anxiety disorder, bipolar disorders, mania,
`dementia, substance-related disorders, sexual
`dysfunctions, eating disorders, obesity, anorexia and
`fibromyalgia. A preferred salt is 1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride.” Ex. 1005 at abstract.
`“A typical model for Agoraphobia is named Elevated
`Plus Maze… Normal animals… avoid entering the
`open arms and stay only a [sic.] for a very brief period
`on open arms. 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine or one of its
`physiologically acceptable salts, in particular 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine hydrochloride, following oral application
`
`Page 13
`
`

`

`dose-dependently increased both the number of entries
`and the time spend on open arms….” Ex. 1005 at 3:20-
`4:5.
`“A typical model for OCSD including OCD is the
`Marble Burying Test… 1-[4-(5-cyanoindol-3-yl)butyl]-
`4-(2-carbamoyl-benzofuran-5-yl)-piperazine or one of
`its physiologically acceptable salts, in particular 1-[4-
`(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5-yl)-piperazine hydrochloride… inhibits mable [sic.]
`burying in mice….” Ex. 1005 at 5:23-6:8.
`“A model for social phobia is the Social Interaction
`Test… 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine or one of its
`physiologically acceptable salts, in particular 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine hydrochloride, increase the time spent in
`social interaction….” Ex. 1005 at 6:19-7:2.
`“In a typical model for neophobia, mice deprived from
`food for 18h are given access to unfamiliar food in a
`novel environment… 1-[4-(5-cyanoindol-3-yl)butyl]-4-
`(2-carbamoyl-benzofuran-5-yl)-piperazine or one of its
`physiologically acceptable salts, in particular 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine hydrochloride… increased food
`intake…” Ex. 1005 at 7:29-8:6.
`“A typical model for acute stress indication is the Four
`Plate Test… Normal mice… accept only a few
`footshocks. 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride… increased the number of punished
`crossings…” Ex. 1005 at 10:1-15.
`“A typical model for generalized anxiety disorders is
`the Light-Dark Choise Test… Normal mice… spent
`most time in the dark compartment. 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine or one of its physiologically acceptable
`salts, in particular 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine
`
`Page 14
`
`

`

`hydrochloride… increase the number of transitions and
`time spent in lit compartment….” Ex. 1005 at 10:20-
`11:9.
`“Additionally… 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine also has
`activity against bipolar disorders and/or mania…. 1-[4-
`(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-
`5-yl)-piperazine or one of its physiologically
`acceptable salts, in particular 1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride, inhibit the hyperactivity… to the same
`degree as do lithium and valproate, the standard
`treatments…” Ex. 1005:13:1-16.
`“Additionally… 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine also has
`activity against dementia, including Alzheimer’s
`disease and multi-infarct… Typical models… are the
`Passive Avoidance test in rats… and the testing of
`memory functions in the Morris Water Maze in aged
`rats… 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine or one of its
`physiologically acceptable salts, in particular 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine hydrochloride, following oral application
`of 10 mg/kg p.o. enhanced memory… 1-[4-(5-
`cyanoindol-3-yl)butyl]-4-(2-carbamoyl-benzofuran-5-
`yl)-piperazine hydrochloride is administered to old
`rats… When tested at day 7, the latencies to find the
`platform in the first attempt are… not differing from
`vehicle treated young rats…” Ex. 1005 at 15:15-18:15.
`“Additionally… 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine also has
`activity against eating disorders including anorexia
`nervosa and bulimia nervosa and/or obesity…. A
`typical model is named Cumulative Food Intake… 1-
`[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5-yl)-piperazine hydrochloride… result in a
`reduced development of body weight at higher doses.
`On the other hand, the lower doses… result in
`
`Page 15
`
`

`

`increased body weight.” Ex. 1005 at 23:24-24:20.
`“Rapid procedures to test pain-relieving properties of
`drugs are the abdominal constriction (writhing) test…
`For example, 1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-
`carbamoyl-benzofuran-5-yl)-piperazine
`hydrochloride… reduced abdominal contrictions…
`and… reduced the formalin-induced pain response…”
`Ex. 1005 at 28:10-17.
`See claim 1 above.
`“Organic compounds that are solid at room temperature
`are usually purified by crystallization. The general
`technique involves dissolving the material to be
`crystallized in a hot solvent (or solvent mixture) and
`cooling the solution slowly….” Ex. 1032 at 522-531.
`“The most useful methcxl to compare X-ray powder
`diffraction data obtained from different samples and on
`the same instrumentation is to overlay and align the
`respective films or plots….” Ex. 1012 at 63.
`“1-[4-(5-cyanoindol-3-yl)butyl]-4-(2-carbamoyl-
`benzofuran-5yl)-piperazine or a physiologically
`acceptable salt thereof is used for the manufacture of a
`medicament for the treatment of sub-type anxiety
`disorders chosen from the sub-types panic disorder
`with or without agoraphobia, agoraphobia, obsessive-
`compulsive spectrum disorders, social phobia,
`posttraumatic stress disorder, acute stress indication or
`generalized-anxiety disorder, bipolar disorders, mania,
`dementia, substance-related disorders, sexual
`dysfunctions, eating disorders, obesity, anorexia, and
`fibromyalgia. A preferred salt is 1-[4-(5-cyanoindol-3-
`yl)butyl]-4-(2-carbamoyl-benzofuran-5yl)-piperazine
`hydrochloride.” Ex. 1005 at abstract; cls. 1-10.
`“The compounds of the formula I and their
`physiologically acceptable salts can be used for the
`therapeutic treatment of the human or animal body and
`for controlling diseases. They can be used for treating
`disorders of the central nervous system, such as
`tension, depressions and/or psychoses, and side-effects
`
`Page 16
`
`12. A method of treating
`a patient suffering from
`a depressive disorder, an
`anxiety disorder, a
`bipolar disorder, mania,
`dementia, a substance-
`related disorder, a
`sexual dysfunction, an
`eating disorder, obesity,
`fibromyalgia, a sleeping
`disorder, a psychiatric
`disorder, cerebral
`infarct, tension, side-
`effects in the treatment
`of hypertension, a
`cerebral disorder,
`chronic pain,
`acromegaly,
`hypogonadism,
`secondary amenorrhea,
`premenstrual syndrome
`and undesired puerperal
`lactation, or
`combinations thereof,
`comprising
`administering to the
`patient in need thereof
`the pharmaceutical
`composition of claim
`11.
`
`

`

`in the treatment of hypertension (e.g., with α-
`methyldopa). The compounds can also be used in
`endocrinology and gynecology, e.g., for the therapeutic
`treatment of acromegaly, hypogonadism, secondary
`amenorrhea, premenstrual syndrome and undesired
`puerperal lactation,