Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 1 of 17 PageID #: 1464
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`HOSPIRA, INC.,
`
`
`
`
`
`AMNEAL PHARMACEUTICALS LLC,
`
`
`
`
`
`v.
`
`
`
`
`
`
`
`
`
`
`
`Plaintiff,
`
`Defendant.
`
`)
`)
`)
`)
`)
`)
`)
`)
`)
`)
`
`
`
`
`
`
` Civil Action No. 15-697-RGA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`HOSPIRA’S OPENING POST-TRIAL BRIEF ON INFRINGEMENT
`
`
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 2 of 17 PageID #: 1465
`
`
`I.
`
`II.
`
`III.
`
`TABLE OF CONTENTS
`
`INTRODUCTION ...............................................................................................................1
`
`PERSON OF ORDINARY SKILL IN THE ART ...............................................................1
`
`AMNEAL INFRINGES EACH ASSERTED CLAIM........................................................2
`
`A.
`
`B.
`
`The Amneal Products Are Disposed Within A “Sealed Glass Container” ..............2
`
`The Amneal Products Infringe The 2% Limitation .................................................4
`
`1.
`
`2.
`
`Amneal’s Product Specification Requests FDA Approval for
`Infringing Products. .....................................................................................5
`
`Amneal’s Stability Data Also Establish Infringement. ................................7
`
`IV.
`
`CONCLUSION ..................................................................................................................14
`
`
`
`
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 3 of 17 PageID #: 1466
`
`I.
`
`INTRODUCTION
`
`Hospira asserts four patents covering its inventive ready-to-use dexmedetomidine
`
`formulation. (D.I. 95, Ex. A ¶¶ 9-11; JTX 1-4.) Amneal seeks FDA approval to market a
`
`copycat version of Hospira’s embodiment of the patents, Precedex Premix. (D.I. 95, Ex. A ¶ 18;
`
`Tr. 5:6-9; PTX-63.51-52.) At the parties’ August 21-24, 2017, trial, Hospira asserted the
`
`following claims (Tr. 3:15-21, 249:4-8):
`
`• Claims 3 and 4 of U.S. Patent No. 8,242,158 (“the ‘158 patent”);
`• Claim 4 of U.S. Patent No. 8,338,470 (“the ‘470 patent”);
`• Claim 5 of U.S. Patent No. 8,455,527; and
`• Claim 6 of U.S. Patent No. 8,648,106 (“the ‘106 patent”).
`
`With two exceptions, Amneal admits that it infringes all claim limitations. (See D.I. 95,
`
`Ex. A ¶¶ 21-27; Tr. 3:22-4:8, 271:5-272:7.) The two limitations in dispute are: (1) whether the
`
`Amneal products are disposed within a “sealed glass container,” as required by each asserted
`
`claim;1 and (2) whether the Amneal products “when stored in the glass container for at least five
`
`months exhibit[] no more than about 2% decrease in the concentration of dexmedetomidine”
`
`(hereinafter, “the 2% limitation”), as recited in the ‘106 patent.
`
`At trial, Hospira proved by a preponderance of the evidence that Amneal infringes both
`
`limitations.
`
`II.
`
`PERSON OF ORDINARY SKILL IN THE ART
`
`Contrary to Amneal’s proffer of a non-POSA statistician, infringement is determined
`
`from the perspective of a person of ordinary skill in the art (“POSA”). E.g., Sundance, Inc. v.
`
`DeMonte Fabricating Ltd., 550 F.3d 1356, 1361 (Fed. Cir. 2008) (finding patent law expert “not
`
`qualified to testify as an expert witness on the issues of infringement or validity” because
`
`
`1 Amneal has stipulated that it infringes Claim 5 of the ‘527 patent, but the dispute remains with
`respect to the other asserted claims. (D.I. 95, Ex. A ¶¶ 26-27, Ex. B ¶ 44.)
`
`
`
`1
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 4 of 17 PageID #: 1467
`
`“[t]hese issues are analyzed in great part from the perspective of a person of ordinary skill in the
`
`art”). Hospira’s infringement expert, Dr. Linhardt, explained that a POSA has an advanced
`
`degree in science, chemistry, pharmacology or pharmaceutical development. (Tr. 268:6-20.) Dr.
`
`Linhardt based his definition on his experience, explaining that he has trained numerous POSAs
`
`over the course of his 35-year career who have gone on to play key roles in the pharmaceutical
`
`industry. (Tr. 268:21-269:10, 246:15-247:3; see also JTX-52.2, 52.47-64.)2
`
`III. AMNEAL INFRINGES EACH ASSERTED CLAIM
`
`Amneal’s ANDA No. 207551 seeks FDA approval to market generic versions of
`
`Precedex Premix in 50 mL and 100 mL glass vials (“the Amneal Products”). (D.I. 95, Ex. A ¶
`
`18.) Both the 50 mL and 100 mL Amneal Products infringe each asserted claim.
`
`In a Hatch-Waxman case, it is an act of infringement to submit an ANDA seeking
`
`approval to market a drug product covered by a patent. 35 U.S.C. § 271(e)(2). A patentee must
`
`prove infringement by a preponderance of the evidence. E.g., Eli Lilly & Co. v. Teva Parenteral
`
`Med., Inc., 845 F.3d 1357, 1364 (Fed. Cir. 2017). Specifically, a patentee must prove that
`
`infringement is more likely than not. O2 Micro Int’l Ltd. v. Beyond Innovation Tech. Co., 449 F.
`
`App’x 923, 928 (Fed. Cir. 2011).
`
`A.
`
`The Amneal Products Are Disposed Within A “Sealed Glass Container”
`
`The first limitation to which Amneal would not stipulate for purposes of infringement is
`
`that its products meet the “sealed glass container” limitation found in every asserted claim. Put
`
`
`2 Amneal’s validity expert, Dr. Yaman, did not opine on infringement issues and never saw
`Amneal’s ANDA submission. (Tr. 606:12-19.) Nonetheless, he and Hospira’s Dr. Linhardt
`agree that a POSA holds an advanced degree in pharmaceutical sciences with knowledge of
`product formulation. (See Tr. 270:21-271:4 (Linhardt); 506:23-508:10 (Yaman).)
`
`
`
`
`2
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 5 of 17 PageID #: 1468
`
`to its proofs at trial, Hospira proved that the Amneal Products are “disposed within a sealed glass
`
`container” under any proposed construction of the term.3
`
`Amneal’s ANDA documents prove that the Amneal Products are “sealed.” ANDA
`
`Module 3.2.P.7 describes Amneal’s container closure systems and how they are sealed, including
`
`information about packaging configuration and sizes, a comparison to Hospira’s Precedex
`
`Premix packaging, and integrity testing. (PTX 64.5-13.) Unsurprisingly for a pharmaceutical
`
`seeking FDA approval, the Amneal Products are sealed and passed integrity testing. (Tr. 273:11-
`
`20 (“They show a stopper system that ensures the product remains sterile during storage.”).) For
`
`example, its proposed 50 mL and 100 mL products passed the industry-standard dye ingress
`
`test—demonstrating that the container closure systems are “sealed.” (PTX-65.2-3, 10-11; see
`
`also PTX-63.64 (describing container closure system for 50 mL and 100 mL products as
`
`designed to “achieve the target shelf-life and to ensure integrity and storage during shipping”).)
`
`The unrebutted testimony of Hospira’s expert, Dr. Linhardt, also explained how the
`
`Amneal Products are disposed within sealed glass containers. (See, e.g., Tr. 273:3-276:8.) After
`
`describing the primary closure system noted above, Dr. Linhardt showed that the products also
`
`
`3 Hospira argued that the meaning of “sealed glass container” is a “glass container closed to
`maintain sterility by having a seal or other closure that passes closure integrity testing,” and
`Amneal argued the meaning is “a container that is closed tightly to prevent unwanted materials
`entering or exiting the glass container.” (Tr. 266:1-6, 584:14-19.) Although Amneal’s meaning
`is inappropriately broad for a pharmaceutical composition, the Amneal Products nonetheless
`meet the limitation under either construction, as shown herein. (See also Tr. 277:17-21.)
`
`After hearing the evidence, the Court proposed possible alternate constructions, including “a
`container that is closed tightly to maintain sterility.” (Tr. 1176:2-21.) So long as this
`construction includes the limitation of “glass,” Hospira agrees that this proposed meaning is
`supported by the record because a sealed container in this context maintains sterility. (See, e.g.,
`JTX-4.7 at 9:9-15; PTX-5.216; Tr. 36:13-37:1; 78:18-79:1 (Roychowdhury); Tr. 633:2-19
`(Yaman).)
`
`
`
`3
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 6 of 17 PageID #: 1469
`
`contain a further seal. (Tr. 276:9-277:21 (“These additional seals actually are important to
`
`understand that the product has [not] been tampered with as well.”); see also Tr. 413:19-415:16.)
`
`Amneal provided no evidence to rebut either its ANDA documents or Dr. Linhardt’s
`
`testimony. The Amneal Products meet the “sealed” limitation, and Amneal infringes the ‘158,
`
`‘470, and ‘527 patents. Intervet Am., Inc. v. Kee-Vet Labs., Inc., 887 F.2d 1050, 1055 (Fed. Cir.
`
`1989) (“A patent is infringed if a single claim is infringed.”).
`
`B.
`
`The Amneal Products Infringe The 2% Limitation
`
`The “2% limitation” is recited only in Claim 6 of the ‘106 patent. The limitation is
`
`highlighted below:
`
`1. A ready to use liquid pharmaceutical composition for parenteral
`administration
`to a subject, comprising dexmedetomidine or a
`pharmaceutically acceptable salt thereof disposed within a sealed glass
`container, wherein the liquid pharmaceutical composition when stored in
`the glass container for at least five months exhibits no more than about
`2% decrease in the concentration of dexmedetomidine.
`
`6. The ready to use liquid pharmaceutical composition of claim 1,
`wherein the dexmedetomidine or pharmaceutically acceptable salt
`thereof is at a concentration of about 4 µg/mL.
`
`
`(JTX-4.15.)
`
`As explained by both parties’ witnesses, this claimed stability refers to stability at
`
`dexmedetomidine’s storage conditions (i.e., room temperature). (Tr. 415:17-416:17 (Linhardt);
`
`691:6-692:12 (Yaman); see also Tr. 92:7-13 (Roychowdhury).)
`
`Amneal infringes the 2% limitation for two independent reasons. First, Amneal’s
`
`product specification includes infringing products. This constitutes infringement as a matter of
`
`law under Sunovion Pharm. v. Teva Pharm., 731 F.3d 1271 (Fed. Cir. 2013) (hereinafter,
`
`“Sunovion”). Second, Amneal’s stability data submitted to the FDA confirm that the Amneal
`
`Products will meet this limitation.
`
`
`
`4
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 7 of 17 PageID #: 1470
`
`1.
`
`Amneal’s Product Specification Requests FDA Approval for
`Infringing Products.
`
`Infringement here is mandated by the Federal Circuit’s ruling in Sunovion. Specifically,
`
`Amneal’s specification provides that the Amneal Products will stay within 90%-110%
`
`dexmedetomidine potency—i.e., no more than 10% dexmedetomidine loss—over their proposed
`
`two-year shelf life. (JTX-76.4; Tr. 278:23-279:16, 284:1-6; see also Tr. 88:1-6, 255:1-16, 658:2-
`
`11.) In other words, Amneal seeks approval to market products losing as little as 0% over two
`
`years, and losing no more than 10% over twenty-four months. Where, as here, “an ANDA
`
`specification defines a compound such that it meets the limitations of an asserted claim, then
`
`there is almost never a genuine issue of material fact that the claim is infringed.” Sunovion, 731
`
`F.3d at 1280.
`
`In Sunovion, the patent claimed 0-0.25% of an impurity. Id. at 1277-78. The Federal
`
`Circuit focused its infringement inquiry on the accused ANDA product specification because
`
`“[w]hat [the ANDA applicant] has asked the FDA to approve as a regulatory matter is the subject
`
`matter that determines whether infringement will occur.” Id. at 1278; see also id. at 1279
`
`(“What a generic applicant asks for and receives approval to market, if within the scope of a
`
`valid claim, is an infringement.”). In contrast to the claimed range of 0-0.25%, the ANDA
`
`applicant’s specification provided for 0-0.6% impurity. Id. at 1278. Further, the ANDA
`
`applicant certified that it would not market any product having 0-0.25% impurity, and would
`
`instead only market products falling in the 0.3%-0.6% range of its product specification. Id.
`
`Nonetheless, the Federal Circuit held that the proposed ANDA defined an infringing
`
`product because it included infringing products within its 0-0.6% range—specifically, products
`
`having the claimed 0-0.25% impurity range. Id. The court explained that “if a product that an
`
`ANDA applicant is asking the FDA to approve for sale falls within the scope of an issued patent,
`
`
`
`5
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 8 of 17 PageID #: 1471
`
`a judgment of infringement must necessarily ensue.” Id. at 1278; see also id. (“In this case,
`
`Reddy’s request for approval of levororotatory amounts from 0.0-0.6% is within the scope of the
`
`‘less than 0.25%’ limitation of the ‘673 patent claims. Reddy’s amended ANDA specification
`
`seeking FDA approval for generic eszopiclone products with 0.0-0.6% levorotatory isomer
`
`mandates a finding of infringement.”).
`
`Similarly, Amneal’s ANDA specification range includes Hospira’s claimed range. Its
`
`90%-110% dexmedetomidine potency over 24 months means 0-10% dexmedetomidine loss over
`
`24 months, and so, at most, Amneal specifies a 0-10% dexmedetomidine loss over at least 5
`
`months. About 2% falls within 0%-10%. Thus, included within the range that Amneal seeks is
`
`the ‘no more than about 2%’ dexmedetomidine loss over at least five months’ limitation that
`
`Hospira’s patent claims. For this reason alone, under Sunovion, Amneal infringes.
`
`In fact, here, Amneal’s infringement is even clearer than in Sunovion. Amneal’s range is
`
`not just over-lapping with Hospira’s claim limitation—it mirrors the claim limitation.
`
`Specifically, Amneal’s specified loss of no more than 10% over 24 months mathematically
`
`equates to no more than 2.08% over 5 months (5/24 x 10% = 2.08%). Therefore, Amneal’s
`
`specification matches the claimed loss of ‘no more than about 2%’, such that the specification
`
`defines an infringing product even without applying the ‘overlapping range’ principle of
`
`Sunovion. As illustrated below, Amneal necessarily infringes Hospira’s ‘106 patent:
`
`
`
`6
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 9 of 17 PageID #: 1472
`
`
`
`2.
`
`Amneal’s Stability Data Also Establish Infringement.
`
`Even setting aside Sunovion, Amneal infringes claim 6 of the ‘106 patent because the
`
`stability data that Amneal submitted to the FDA demonstrate that the Amneal Products exhibit
`
`no more than about 2% decrease in the concentration of dexmedetomidine over at least five
`
`months.
`
`a) Amneal’s Stability Study
`
`As required by the FDA, Amneal conducted a stability study of its 50 mL and 100 mL
`
`products to demonstrate that its products would remain within specification over the proposed
`
`two-year shelf life. (JTX-56; Tr. 280:10-17.) In Amneal’s words, the study was conducted to
`
`assess the “stability characteristics[,] storage conditions, [and] shelf life” of its products. (PTX-
`
`93.4, Tr. 280:18-24.) Among other properties, the study tracked dexmedetomidine potency (i.e.,
`
`concentration) in samples of the Amneal Products over time. (Tr. 282:21-283:9.)
`
`Amneal studied stability under both long-term conditions (standard storage conditions of
`
`25°C) and accelerated conditions (elevated temperature of 40°C), per industry standard. (Tr.
`
`
`
`7
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 10 of 17 PageID #: 1473
`
`281:1-14; see also 574:1-6 (Yaman).) Amneal collected data up to the six-month time point for
`
`accelerated conditions and up to eighteen months for long-term conditions. (JTX-56; Tr. 284:7-
`
`12.)
`
`As noted earlier, stability under long-term conditions is the relevant property when
`
`assessing the stability of a product. (Tr. 255:1-16, 415:17-416:17 (Linhardt); 691:6-692:12
`
`(Yaman); see also Tr. 92:7-13 (Roychowdhury).) But drug product sponsors also study stability
`
`under accelerated conditions to collect stability data in a shorter time; the sponsor can then
`
`correlate the accelerated stability data to stability over a longer time period under long-term
`
`conditions using the well-known Arrhenius equation. (Tr. 100:6-101:14 (Roychowdhury);
`
`255:17-256:9, 297:22-298:10, 412:9-413:9, 417:2-11 (Linhardt); Tr. 702:7-704:4 (Yaman).)
`
`This equation teaches that a 10°C increase in temperature doubles a rate of loss, so, for example,
`
`three months at 35°C correlates to six months of storage at 25°C. (Tr. 298:11-299:11.) This is
`
`why six months of accelerated data is typically used when assessing the stability of a product
`
`with a proposed twenty-four month shelf life. (Tr. 100:6-101:14; see also JTX-56.17.)
`
`Amneal’s study collected data from products placed in an upright orientation as well as in
`
`an inverted orientation. (Tr. 282:15-20.) While upright orientation matches the expected storage
`
`handling for a product, a drug product sponsor also studies stability in an inverted orientation to
`
`assess how the product will behave if stored incorrectly (as might happen, for example, during
`
`shipping). (281:15-282:14.)
`
`Amneal’s stability study submitted to the FDA included eight data sets (see JTX 56; Tr.
`
`281:1-282:20):
`
`Product
`50 mL
`50 mL
`50 mL
`
`Conditions
`Long-term conditions
`Long-term conditions
`Accelerated conditions
`
`Orientation
`Upright
`Inverted
`Upright
`
`
`
`8
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 11 of 17 PageID #: 1474
`
`50 mL
`100 mL
`100 mL
`100 mL
`100 mL
`
`Accelerated conditions
`Long-term conditions
`Long-term conditions
`Accelerated conditions
`Accelerated conditions
`
`
`Analysis of this full set of stability data demonstrates that the Amneal Products infringe the 2%
`
`Inverted
`Upright
`Inverted
`Upright
`Inverted
`
`limitation.
`
`b) Analysis of Amneal’s Stability Data
`
`Dr. Linhardt—the only POSA to analyze Amneal’s stability data and the only POSA to
`
`opine on infringement at all—concluded that the data prove infringement. (Tr. 279:17-280:5.)
`
`To appropriately analyze the data as a POSA would, Dr. Linhardt performed regression analysis.
`
`(Tr. 284:13-285:9, 286:2-13.) He explained that POSAs, himself included, routinely employ
`
`regression analysis for this purpose. (Tr. 289:10-17, 389:7-16, Tr. 407:7-10.) Regression
`
`analysis takes into account all possible data points and creates a best approximation of the rate of
`
`loss, and so is viewed as more accurate than simply looking at individual stability data points in
`
`isolation. (Tr. 289:18-290:12, 344:2-9, 344:18-345:3; see also Tr. 98:4-16, 99:2-5.) Because
`
`any statistical aspects of this analysis are rudimentary, they are within the expertise of a POSA;
`
`the analysis does not require the input of an expert statistician. (Tr. 269:11-270:20, 288:14-20,
`
`351:7-352:7.)
`
`For his regression analysis, Dr. Linhardt used standard regression software to plot the
`
`stability data for each of Amneal’s eight stability data sets. (Tr. 286:6-15, 473:19-474:14.) The
`
`analysis could have equally been performed by hand or with a scientific calculator—the exercise
`
`is simply one of plotting data points and fitting a line to best match the data. (Tr. 286:6-18,
`
`288:22-289:9.) The fitted line is represented by an equation in the form of y = m*x + b, where
`
`‘y’ is the dexmedetomidine concentration and ‘x’ is the number of months. (Tr. 288:4-8.) Using
`
`
`
`9
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 12 of 17 PageID #: 1475
`
`this equation for a line, a dexmedetomidine concentration at a given time-point—and,
`
`consequently, the relative loss of dexmedetomidine over time—can be calculated. (Tr. 288:4-8,
`
`293:12-294:8.)
`
`Dr. Linhardt performed this regression analysis using two rate models for each of the
`
`eight data sets (yielding 16 calculations): zero-order and first-order. (Tr. 294:19-295:23.) Dr.
`
`Linhardt explained that the choice of model depends on the mechanism of loss of
`
`dexmedetomidine, and there are two possible mechanisms here—adsorption of dexmedetomidine
`
`to the glass container surface, and degradation of dexmedetomidine via oxidation. (Tr. 294:9-
`
`295:10.) Because adsorption typically follows a zero-order model while oxidation follows a
`
`first-order model, Dr. Linhardt employed both models to account for both possible mechanisms
`
`of loss. (Tr. 295:24-296:20.) Using either model, the data showed infringement.
`
`Using the results of his regression analysis, Dr. Linhardt identified the equation showing
`
`the largest loss of dexmedetomidine from among Amneal’s tests—i.e., the data set of primary
`
`interest in determining whether there exists a data set showing non-infringement. (Tr. 286:14-
`
`287:15, 291:14-292:5, 301:13-16.) The 50 mL long-term test showed the most significant loss.
`
`Dr. Linhardt computed the loss for this test using the line equation, and found less than 2% loss
`
`at five months under either the zero-order or first-order models. (Tr. 288:9-13, 294:1-8.) For
`
`example, the zero-order model demonstrated that the 50 mL long-term test showed 1.8% loss in
`
`dexmedetomidine concentration after five months of storage. (Tr. 294:1-8.)
`
`Dr. Linhardt then calculated the loss for all of the other data sets. (Tr. 291:17-292:5.)
`
`For the 100 mL long-term test, he computed the loss at five months. For the accelerated
`
`conditions tests, Dr. Linhardt computed the loss at two months because, under the Arrhenius
`
`equation, that time period equates to approximately five months of storage at long-term
`
`
`
`10
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 13 of 17 PageID #: 1476
`
`conditions. (Tr. 297:22-299:11.) For all of these tests, Dr. Linhardt similarly found that the
`
`dexmedetomidine loss at five months was no more than about 2%. (Tr. 291:14-292:16, 296:21-
`
`297:3.)
`
`As a final check, Dr. Linhardt looked at the actual individual stability data points at two
`
`months for accelerated conditions and six months for long-term conditions (Amneal did not
`
`collect data at the five-month mark). (Tr. 301:20-302:2.) These individual data points further
`
`confirm that the Amneal Products exhibit no more than about 2% decrease in the concentration
`
`of dexmedetomidine when stored for at least five months. (Tr. 301:20-302:2; see JTX-56.5 (50
`
`mL inverted accelerated conditions showing ≤0.5% loss at 2-, 3-, and 4-month time-points);
`
`JTX-56.9 (50 mL inverted long-term conditions showing no loss at 18-month time-point); JTX-
`
`56.11 (100 mL inverted accelerated conditions showing no loss at 2-, 3-, and 4-month time-
`
`points); JTX-56.15 (100 mL inverted long-term conditions showing no loss at 18-month time-
`
`point).)
`
`So, no matter which way he analyzed the data, Dr. Linhardt found that the Amneal
`
`Products infringe the 2% limitation. (Tr. 300:20-302:7.) And Dr. Linhardt was the only POSA
`
`to analyze Amneal’s stability data: Amneal offered no evidence from a POSA to the contrary.4
`
`Indeed, Amneal similarly concluded that its stability data demonstrate that the Amneal
`
`Products exhibit “no significant change” in concentration over eighteen months of long-term
`
`storage and six months of accelerated storage. (JTX-56.17, Tr. 300:10-15.) This statement,
`
`made in the context of Amneal seeking to establish a twenty-four month shelf life for its 90%-
`
`110% potency specification, further indicates that the Amneal Products will lose no more than
`
`about 2% of dexmedetomidine in five months. (See Tr. 299:22-300:15.)
`
`
`4 Nor could it, because Amneal asserts that every 4 µg/mL dexmedetomidine composition
`disposed in a sealed glass container meets the 2% limitation. (E.g., 543:11-17, 549:19-550:2.)
`
`
`
`11
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 14 of 17 PageID #: 1477
`
`Instead of evidence from a POSA, Amneal offered only the opinions of a non-POSA
`
`statistician, Dr. Bloch, who opined that more data was needed to form an opinion as to whether
`
`Amneal infringed. (Tr. 434:2-7, 465:15-19, 471:13-16.) He did not opine that Amneal does not
`
`infringe. (465:15-19.) Essentially, Dr. Bloch opined that a statistician could not draw a
`
`conclusion as to the stability of Amneal’s products based on the data available in Amneal’s
`
`stability study. (Tr. 433:2-13 (“And I believe that no statistician could conclude that
`
`infringement has occurred on this issue based on the data that was analyzed.”), 459:6-14, 463:21-
`
`464:3.)
`
`But Dr. Bloch’s opinion that more data is needed stands in direct contradiction to
`
`Amneal’s position before the FDA, where it is using this very data to represent that its product is
`
`sufficiently stable to stay within specification over a two-year shelf life. (PTX 93.4; JTX-56.17;
`
`see also Tr. 469:8-470:7, 472:9-21 (“Now, when they submit data to the FDA, they believe that
`
`backs up that which they are trying to get approval for, so I think from that perspective, I
`
`certainly believe they believe it was sufficient.” (Bloch)).) Dr. Bloch’s opinion is also belied by
`
`Amneal’s position in this litigation, where it stated that discovery of samples of its products was
`
`not necessary because its ANDA “sufficiently describes Amneal’s proposed product” and,
`
`therefore, discovery of samples would be “duplicative of information in Hospira’s possession”
`
`(i.e., the ANDA documents). (JTX-83.13-14; Tr. 422:6-423:6.) Consistently, Dr. Linhardt—
`
`who, again, was the only POSA to analyze Amneal’s stability data—agreed with Amneal,
`
`concluding that, while more data would have been preferable, there was sufficient data to
`
`demonstrate that Amneal infringes the 2% limitation. (Tr. 357:20-359:16, Tr. 393:21-394:6.)
`
`Dr. Bloch offered two other criticisms of Dr. Linhardt’s analysis, but, if anything, Dr.
`
`Bloch’s testimony actually further supports a finding of infringement.
`
`
`
`12
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 15 of 17 PageID #: 1478
`
`First, Dr. Bloch opined that Dr. Linhardt’s calculations for the tests other than the 50 mL
`
`long-term test were incorrect. (Tr. 453:7-21.) But he offered competing calculations for only
`
`two of Dr. Linhardt’s sixteen calculations: (1) a zero-order model for the 100 mL product at
`
`long-term conditions in an upright orientation, and (2) another unidentified test at accelerated
`
`conditions. (Tr. 453:20-454:3, 490:9-11.)
`
`For the 100 mL long-term test, Dr. Bloch’s calculation was 1.4% loss at five months—
`
`still well within the claimed range. (Tr. 455:17-24.) In his other calculation, Dr. Bloch said he
`
`calculated 2.9% loss, but this was at five months of accelerated conditions and so is irrelevant
`
`for infringement. (Tr. 445:2-9, 457:12-458:6, 490:4-11.) As both parties’ POSAs explained, the
`
`relevant time point is five months at long-term conditions; five months at accelerated conditions
`
`equates to over a year of storage at long-term conditions. (Compare supra p. 8 with Tr. 445:2-9.)
`
`In any event, Dr. Bloch’s calculations show that the Amneal Products will infringe the
`
`2% limitation at least in some instances, which establishes infringement. E.g., Broadcom Corp.
`
`v. Emulex Corp., 732 F.3d 1325, 1333 (Fed. Cir. 2013) (“It is well settled that an accused device
`
`that ‘sometimes, but not always, embodies a claim nonetheless infringes.’”); see also Sunovion,
`
`731 F.3d at 1278 (finding infringement where specification provided for both products having
`
`the claimed impurity level as well as products not having the claimed impurity level). Tellingly,
`
`while relying on these isolated calculations, Dr. Bloch provided no opinion on whether Amneal’s
`
`data as a whole showed more or less than about 2% decrease in the concentration of
`
`dexmedetomidine over five months of storage. (Tr. 490:15-491:16 (“I didn’t do that, because I
`
`would have to ask the scientist. . . . A good idea, but how to combine it, I am not sure.”).)
`
`Second, Dr. Bloch faulted Dr. Linhardt for considering zero-order and first-order models
`
`of loss, on the theory that only one of the models can actually be correct. (Tr. 447:20-448:4.)
`
`
`
`13
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 16 of 17 PageID #: 1479
`
`Yet, Dr. Linhardt showed that regardless of which model applies, the result is the same—Amneal
`
`infringes. (Tr. 410:3-10.) While Dr. Bloch suggested that a mixed zero-order / first-order model
`
`might be appropriate, he admitted that he had no idea what model applies because he is not a
`
`POSA. (Tr. 447:20-448:4 (“I’m not a POSA. I can’t judge what is right.”), 479:11-24, 481:2-
`
`24.) More importantly, whether a mixed model applies is irrelevant. Because the zero-order
`
`model showed no more than about 2% loss, and the first-order loss also showed no more than
`
`about 2% loss, a mixed zero-order / first-order model would necessarily also show no more than
`
`about 2% loss. (See Tr. 481:19-24.)
`
`Notwithstanding Dr. Bloch’s testimony, Hospira proved by a preponderance of the
`
`evidence that Amneal’s stability study demonstrates infringement of the 2% limitation. Amneal
`
`infringes the ‘106 patent.
`
`IV. CONCLUSION
`
`Amneal infringes each asserted claim. Hospira requests that the Court enjoin FDA
`
`approval and the manufacture, use, offer for sale, sale, or importation into the United States of
`
`the Amneal Products until the expiry of the patents-in-suit. See 35 U.S.C. § 271(e)(4) (“For an
`
`act of infringement described in [35 U.S.C. § 271(e)(2)] . . . the court shall order the effective
`
`date of any approval of the drug . . . involved in the infringement to be a date which is not earlier
`
`than the date of the expiration of the patent which has been infringed.”).
`
`
`
`14
`
`

`

`Case 1:15-cv-00697-RGA Document 101 Filed 09/18/17 Page 17 of 17 PageID #: 1480
`
`Dated: September 18, 2017
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Respectfully Submitted,
`
`HOSPIRA, INC.
`
`By: /s/ Ryan P. Newell
`
`CONNOLLY GALLAGHER LLP
`Arthur G. Connolly, III (# 2667)
`Ryan P. Newell (# 4744)
`The Brandywine Building
`1000 West Street, Suite 1400
`Wilmington, Delaware 19801
`Telephone: (302) 757-7300
`aconnolly@connollygallagher.com
`rnewell@connollygallagher.com
`
`Bradford P. Lyerla
`Sara T. Horton
`Yusuf Esat
`Chad J. Ray
`JENNER & BLOCK LLP
`353 N. Clark Street
`Chicago, IL 60654-3456
`Telephone: 312 222-9350
`Facsimile: 312 527-0484
`blyerla@jenner.com
`shorton@jenner.com
`yesat@jenner.com
`
`Attorneys for Plaintiff Hospira, Inc.
`
`15
`
`