`
`Michael R. Griffinger
`Sheila F. McShane
`GIBBONS P.C.
`One Gateway Center
`Newark, New Jersey 07102-5310
`Telephone No.: (973) 596-4500
`Facsimile No.: (973) 596-0545
`
`Of Counsel:
`Edgar H. Haug
`Angus Chen
`Nicholas F. Giove
`Leann M. Clymer
`FROMMER LAWRENCE & HAUG LLP
`745 Fifth Avenue
`New York, New York 10151
`Telephone No.: (212) 588-0800
`Facsimile No.: (212) 588-0500
`
`Attorneys for Plaintiffs
`Cornerstone Therapeutics Inc.,
`Cornerstone BioPharma, Inc.,
`and EKR Therapeutics, LLC
`
`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`
`
`CORNERSTONE THERAPEUTICS INC.,
`CORNERSTONE BIOPHARMA, INC., and
`EKR THERAPEUTICS, LLC,
`
`
`
`)
`)
`)
`
`)
`) Civil Action No. 1:13-cv-05723-NLH-AMD
`
`)
`)
`)
`)
`)
`)
`
`
`
`
`
`
`
`
`
`v.
`
`Plaintiffs,
`
`
`
`SANDOZ INC.
`
`
`
`
`
`Defendant.
`
`
`
`PLAINTIFFS’ RESPONSES TO DEFENDANT’S INVALIDITY CONTENTIONS
`
`
`
`
`
`
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`EKR Therapeutics, LLC Exhibit 2014 Page 1
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`

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`
`
`D.
`
`Objective Indicia of Nonobviousness
`
`Evidence relating to objective indicia of nonobviousness must be considered before
`
`determining whether the claimed invention would have been obvious to one of skill in the art at
`
`the time of invention. Here, relevant objective indicia of nonobviousness include, without
`
`limitation: the commercial success of the claimed inventions, the long-felt but unmet medical
`
`need for the claimed inventions, the unexpected results created by the claimed inventions,
`
`skepticism of others, the failure of others to develop the claimed inventions, copying of the
`
`claimed invention by others (including copying by Defendant), and industry praise.
`
`Plaintiffs further state, and Defendant does not dispute, that a nexus exists between the
`
`elements of the asserted claims and the stated objective evidence of nonobviousness. Cardene®
`
`I.V. Premixed Injection is a commercially available embodiment of the asserted claims. See,
`
`e.g., Plaintiffs’ Disclosures Pursuant to L. Pat. R. 3.1(g) and 3.2(e). Accordingly, there is
`
`presumptively a nexus between the commercial success (and other secondary considerations) of
`
`Cardene® I.V. Premixed Injection and the claimed inventions. Defendant has offered no
`
`evidence to rebut the presumption of a nexus.
`
`Plaintiffs reserve the right to supplement and/or amend its disclosure of objective
`
`evidence of nonobviousness as discovery progresses, including fact and expert discovery.
`
`Plaintiffs incorporate by reference its expert declarations, reports, and corresponding testimony.
`
`Plaintiffs also incorporate by reference the objective evidence of nonobviousness presented to
`
`the Patent Office during prosecution of the patents in suit, including that Cardene® I.V. Premixed
`
`Injection had surprising and unexpected results and fulfilled a long-felt but unmet medical need.
`
`(See, e.g., CRTXCAR0001357-64). Specifically, Plaintiffs assert that the claimed invention: (i)
`
`provides a ready to use formulation of nicardipine hydrochloride that is room temperature stable
`
`for more than one year; (ii) is a premixed injection that requires no dilution before administration
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`to a patient; (iii) improves the hospital’s response time in treating cardiovascular emergencies
`
`where immediate lowering of a patient’s blood pressure is required; (iv) decreases the probability
`
`of dosing errors by health care professionals; and (v) minimizes safety concerns and the
`
`possibility of microbial contamination from breaking the ampul neck and/or diluting the
`
`concentrated nicardipine hydrochloride injection. (See, e.g., ’102 patent, col.1, ll.39-57).
`
`1.
`
`Long-Felt but Unmet Need
`
`Before the launch of Cardene® I.V. Premixed Injection there was a long-felt need for a
`
`nicardipine hydrochloride premixed injection product that did not require dilution and could be
`
`immediately administered to patients during an emergency. Premixed injection formulations are
`
`particularly valuable for calcium channel blockers indicated for short-term treatment of
`
`hypertension when oral therapy is not feasible, e.g., when a patient’s blood pressure requires
`
`immediate lowering in an emergency room setting. Acute hypertensive emergencies, especially
`
`stroke-related, require immediate attention. (See CRTXCAR0004504). For example, gaining
`
`early control of elevated blood pressure is beneficial for stroke patients that have experienced
`
`intracerebral hemorrhage and may reduce the incidence of hematoma growth, which most
`
`frequently occurs within one to six hours of the initial stroke, thus improving clinical outcomes.
`
`(See CRTXCAR0004984). Cardene® I.V. ampuls were shown to achieve the target blood
`
`pressure within the first hour of treatment in significantly more patients when compared to other
`
`injectable medications used for lowering blood pressure. (Id.).
`
`Every second counts when treating a patient that has experienced a stroke. “Every
`
`minute in which a large vessel ischemic stroke is untreated, the average patient loses 1.9 million
`
`neurons and 14 billion synapses.” (CRTXCAR0007961). The availability of ready to use
`
`formulations of antihypertensive intravenous solutions, such as Cardene® I.V. Premixed
`
`
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`Injection, saves valuable time when treating a stroke patient. (See, e.g., CRTXCAR0007758;
`
`CRTXCAR0005324; CRTXCAR0004716; CRTXCAR0005484; CRTXCAR0007089).
`
`Nicardipine hydrochloride infusion is safer and more effective for treatment of acute
`
`hypertension as compared to other drugs, including labetalol and nitroprusside. (See, e.g.,
`
`CRTXCAR0005116; CRTXCAR0005279; CRTXCAR0005309). Cardene® I.V. has fewer drug
`
`interactions, which is important when hypertensive patients arrive in the emergency room unable
`
`to communicate what drugs they have recently taken. (See, e.g., CRTXCAR0006120;
`
`CRTXCAR0008075). Cardene® I.V. also provides for smoother control of blood pressure. (See
`
`CRTXCAR0004716; CRTXCAR0004729). And Cardene® I.V. does not have a negative impact
`
`on blood flow to the brain, which is critical when treating a stroke patient.
`
`(CRTXCAR0005324). A patient that has had a stroke must receive a thrombolytic drug to
`
`dissolve the blood clot in the brain within 3 hours of stroke onset; after this time period, the
`
`physician cannot use a thrombolytic. (See CRTXCAR0006140). But thrombolytics may not be
`
`administered if the patient’s blood pressure must be lowered. (See CRTXCAR0006135;
`
`CRTXCAR0005324). Physicians prefer to use an infusion of nicardipine hydrochloride to lower
`
`the patient’s blood pressure in these situations because of its safety and efficacy. (See
`
`CRTXCAR0005324).
`
`Despite: (i) the known benefits of nicardipine hydrochloride over other anti-hypertensive
`
`drugs; and (ii) the known delay (and other disadvantages) associated with the administration of
`
`concentrated formulations, no ready to use formulation of nicardipine hydrochloride existed
`
`before the launch of Cardene® I.V. Premixed Injection. (See CRTXCAR0000009). After
`
`Cardene® I.V. Premixed Injection launched, it was shown to provide significant benefits over
`
`Cardene® I.V. ampuls. The ready to use Cardene® I.V. Premixed Injection product is safer than
`
`
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`concentrated IV products that require dilution before administration, including Cardene® I.V.
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`ampuls. (See CRTXCAR0005312; see also CRTXCAR0000009). Cardene® I.V. Premixed
`
`Injection, when compared to bolus injections of labetalol for management of acute hypertension
`
`in the emergency department, was shown to be 2.7 times more likely to achieve the target blood
`
`pressure range within 30 minutes of initiating treatment. (CRTXCAR0005490). Doctors noted a
`
`difference in time to drug delivery of “as long as 5 to 10 minutes” due to the preparation time
`
`required to mix and prepare Cardene® I.V. ampuls. (CRTXCAR0006138).
`
`Surveys of hospital pharmacists confirm that Cardene® I.V. Premixed Injection filled a
`
`long-felt need for many hospital emergency and pharmacy departments by providing doctors and
`
`their patients with a ready to use formulation of nicardipine hydrochloride intravenous solution.
`
`(See CRTXCAR0004504; CRTXCAR0005197). One study comparing Cardene® I.V. ampul and
`
`Premixed Injection with labetalol showed that immediate bolus administration of labetalol,
`
`which is not available in a premixed bag and must be reconstituted by the pharmacy to be
`
`administered as an infusion, “may be more problematic than its use as a continuous infusion.”
`
`(CRTXCAR0008075). Finally, the need for a quick response time in hypertensive emergencies,
`
`especially in stroke patients, and the relative frequency of emergency room visits for
`
`cardiovascular complaints generally increases the need for effective and convenient treatments to
`
`quickly lower blood pressure. (See CRTXCAR000537-5328).
`
`There was a long felt need for a ready to use nicardipine hydrochloride injectable product
`
`that: (i) eliminates admixture errors; (ii) is immediately available for rapid intervention (iii) saves
`
`pharmacy time and labor; (iv) reduces waste (extended beyond-use dating, no ampul breakage,
`
`no compounding errors); (v) can be stored in automated dispensing cabinets at point of care; (vi)
`
`improves door-to-dose time; (vii) complies with USP <797>; (viii) requires fewer supplies and
`
`
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`equipment (e.g., diluents, filter-tip needles); (ix) promotes standardized dosing; and (x) offers a
`
`safe alternative to after-hours compounding. (See CRTXCAR0005197).
`
`There are numerous other disadvantages associated with the concentrated ampul
`
`formulation of Cardene® I.V. as compared to the Cardene® I.V. Premixed Injection, including
`
`the lag time between the doctor prescribing Cardene® I.V. and the diluted drug product being
`
`administered to the patient (CRTXCAR0005315). Further, breaking the Cardene® I.V. ampul
`
`neck may result in exposing both patients and health care providers to broken glass and an
`
`increased risk of injury. Moreover, because Cardene® I.V. requires dilution before
`
`administration to the patient, there is an increased risk of dosing errors, resulting in either an
`
`overdose or an underdose, as well as potential adverse effects on the stability of the reconstituted
`
`solution if an inappropriate diluent is used. (See CRTXCAR0000009). And once diluted,
`
`solutions prepared from a Cardene® I.V. ampul must be discarded within 24 hours due to
`
`stability issues. (See SAN_NIC_0001635; see also CRTXCAR0000009).
`
`The health care industry has explicitly noted issues with the time required to prepare a
`
`nicardipine hydrochloride solution from a concentrated ampul, including when compared to
`
`labetalol which may be administered immediately upon patient admission to the emergency
`
`department as a bolus injection. (CRTXCAR0004716). One group of investigators noted that
`
`the longer time between patient admission and treatment with nicardipine as compared to
`
`labetalol “was due to the time taken to mix and set up an infusion system for nicardipine.”
`
`(CRTXCAR0004726). Other physicians noted that “slow pharmacy delivery” of Cardene® I.V.
`
`and other intravenous antihypertensive medications “was the major reason for the delay in
`
`achieving target MAP [mean arterial pressure]” and obtain control of blood pressure in patients
`
`following intracranial hemorrhage. (CRTXCAR0004726). The introduction of ready to use
`
`
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`Cardene® I.V. Premixed Injection reduced this delay and improved treatment outcomes.
`
`(CRTXCAR0004726). In fact, the authors noted that many of the patients in another study (at
`
`CRTXCAR0005324) received the ready-to-use Cardene® I.V. Premixed Injection and “achieved
`
`better BP control than did patients treated with labetalol.” (CRTXCAR0004726).
`
` A general “good rule” in any operating room is to have a vasodilator, such as
`
`nicardipine hydrochloride, ready for use as an intravenous infusion at any time.
`
`(CRTXCAR0007899). Cardene® I.V. Premixed Injection also provides increased safety to
`
`patients by supporting dosage standardization, and eliminating dilution errors and the risk of
`
`microbiological contamination associated with the manipulations necessary to prepare
`
`intravenous infusions from concentrated Cardene® I.V. ampuls. (CRTXCAR0000009).
`
`Additionally, Cardene® I.V. Premixed Injection provides cost and time savings to the hospital by
`
`improving efficiency, saving time and labor costs associated with dilution of Cardene® I.V.
`
`ampuls, including the costs of after-hours compounding, and also reduces medical waste.
`
`(CRTXCAR0004505-06). Thus, the development of Cardene® I.V. Premixed Injection, a long
`
`term stable, ready to use nicardipine hydrochloride intravenous product satisfied a long-felt
`
`medical need.
`
`2.
`
`Commercial Success
`
`The commercial success of Cardene® I.V. Premixed Injection evidences the
`
`nonobviousness of the asserted claims. First, the unit sales and dollar sales of Cardene® I.V.
`
`Premixed Injection are substantial considering the related competition from the Cardene® I.V.
`
`ampul and generic nicardipine hydrochloride for injection vial products that are currently
`
`marketed. Second, the commercial success of Cardene® I.V. Premixed Injection cannot be
`
`explained by factors unrelated to the elements of the claimed inventions, such as aggressive
`
`marketing or pricing. The sales of Cardene® I.V. are largely attributable to the elements of the
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`claimed invention, e.g., a ready to use, room temperature stable, nicardipine hydrochloride
`
`premixed injection formulation.
`
`3.
`
`Unexpected Results and Skepticism of Others
`
`The claimed invention gave rise to surprising and unexpected results, including a ready to
`
`use, premixed nicardipine hydrochloride injectable product suitable for long term storage at
`
`room temperature. The biggest hurdle when developing a ready to use, premixed injectable
`
`formulation is obtaining a formulation that is long term stable, especially at room temperature.
`
`One of ordinary skill in the art would have had no expectation of success in formulating a stable
`
`form of a low concentration premixed injectable drug product as claimed by the patents in suit.
`
`Nicardipine hydrochloride is present in the Cardene® I.V. Premixed Injection product at a
`
`lower concentration than the Cardene® I.V. ampul product. Degradation and sorption are of
`
`greater concern with a low concentration formulation like Cardene® I.V. Premixed Injection
`
`because even a relatively small amount of sorption (or a small increase in total impurities) may
`
`result in a significant percentage loss of potency (or a significant percentage increase in total
`
`impurities).
`
`Nicardipine hydrochloride is subject to hydrolysis and is known to degrade in the
`
`presence of water. (CRTXCAR000621; CRTXCAR0006627; CRTXCAR0006658). Thus, a
`
`person of ordinary skill in the art would have expected that the increased water to drug ratio in
`
`the ready to use Cardene® I.V. Premixed Injection formulation would have caused increased
`
`degradation of the nicardipine hydrochloride drug substance. A person of ordinary skill in the art
`
`would not have expected the Cardene® I.V. Premixed Injection formulation to be long term
`
`stable at room temperature.
`
`
`
`Further, a POSA would not have been motivated to adjust the pH of a ready to use
`
`nicardipine hydrochloride premixed injection solution to a range of pH 3.6 to 4.7. Nicardipine
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`hydrochloride is slightly basic with a pKa of about 7.0 and is only about 28% ionized at
`
`physiological pH 7.4. (CRTXCAR0006873; CRTXCAR0008083). Increasing the pH from 3.5
`
`in the concentrated Cardene® I.V. ampul to a pH from about 3.6 to about 4.7 in the ready to use
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`Cardene® I.V. Premixed Injection formulation would lead to lower ionization, lower polarity,
`
`and increased lipophilicity of nicardipine hydrochloride. (CRTXCAR0007030).
`
`In addition, increasing the pH level for a nicardipine hydrochloride aqueous solution
`
`would result in exponentially less aqueous solubility. (See, e.g., CRTXCAR0007011;
`
`CRTXCAR0007041; CRTXCAR0007247). The partition coefficient (log P), or diffusion
`
`coefficient (log K), for nicardipine free base is about 4.2. Nicardipine free base is about 10,000
`
`times more soluble in n-octanol than in water. (CRTXCAR0007144; see also
`
`CRTXCAR0006882). Increasing the pH level of a nicardipine hydrochloride aqueous solution
`
`also converts more of the nicardipine hydrochloride salt to the free base. And nicardipine free
`
`base is more lipophilic and less soluble in water than nicardipine hydrochloride. This can result
`
`in physical instability and precipitation of the drug substance. A POSA would not be motivated
`
`to increase the pH of a nicardipine hydrochloride aqueous solution because it could affect the
`
`stability of a ready to use, nicardipine hydrochloride premixed injection solution.
`
`
`
`A POSA at the time of the invention would not have been motivated to use non-polar
`
`polymer containers for a long term, room temperature stable, ready to use, nicardipine
`
`hydrochloride premixed injection solution at a pH from about 3.6 to about 4.7. Lipophilic drugs,
`
`such as nicardipine hydrochloride, are known to adsorb or absorb to non-polar polymers. (See
`
`CRTXCAR0007173). Figures 5A and 5B of the patents in suit demonstrate that nicardipine
`
`hydrochloride premixed injection solution had a minimal drop in drug potency in non-polar
`
`
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`polymer bags as compared to PVC bags. A POSA would expect a greater level of sorption of
`
`nicardipine to a non-polar polymer container.
`
`Nicardipine hydrochloride is susceptible to oxidation. (See, e.g., SAN_NIC_0001575;
`
`CRTXCAR0006793). A higher pH level of the premixed nicardipine hydrochloride aqueous
`
`solution claimed in the patents in suit would increase the potential for oxidative degradation of
`
`the drug substance. (See CRTXCAR0007056). Non-polar polymers, such as polyethylene and
`
`polypropylene, are permeable to oxygen. (See, e.g., CRTXCAR0006827; CRTXCAR0007056;
`
`CRTXCAR0007337). Thus, a POSA would not have been motivated to increase the pH level of
`
`the premixed nicardipine hydrochloride aqueous solution, and/or to use a polyethylene or other
`
`non-polar polymer container for a ready to use, nicardipine hydrochloride premixed injection
`
`solution.
`
`
`
`Further, nicardipine hydrochloride is a difficult molecule from a manufacturing
`
`perspective. Nicardipine hydrochloride is a dihydropyridine molecule, which is known to
`
`thermally degrade. (CRTXCAR0007156; CRTXCAR0007102). The photosensitivity of
`
`nicardipine hydrochloride is also well-known. These instabilities can lead to the formation of
`
`impurities in an aqueous nicardipine hydrochloride solution. (See CRTXCAR0006807;
`
`CRTXCAR0006888; CRTXCAR0006898; CRTXCAR0006901; CRTXCAR0006919;
`
`CRTXCAR0007459; CRTXCAR0007635). Drug processing, dilution, and manufacturing are
`
`unpredictable arts. Developing a long term, room temperature stable, ready to use nicardipine
`
`hydrochloride premixed injection formulation is especially difficult and unpredictable.
`
`An injectable drug product formulation must be sterile. Failure to maintain sterility
`
`during the drug product manufacturing process can result in purity and stability issues, including
`
`chemical degradation and pathogenic toxicity. The FDA suggests that terminal sterilization is
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`the preferred manufacturing method when making a sterile product. (See CRTXCAR0007396).
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`“It is a well-accepted principle that sterile drugs should be manufactured using aseptic
`
`processing only when terminal sterilization is not feasible.” (CRTXCAR0007396). Thus, a
`
`POSA would be motivated to make a ready to use, nicardipine hydrochloride premixed injection
`
`product that was terminally sterilized.
`
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`These unexpected results further evidence the nonobviousness of the claimed inventions.
`
`4.
`
`Failure of Others
`
`The nicardipine hydrochloride active pharmaceutical ingredient has been available in the
`
`United States since 1988, yet no one successfully developed a premixed aqueous solution that is
`
`ready to administer parenterally without further dilution until the inventors of the patents in suit.
`
`Cardene® I.V. Premixed Injection is the first and only FDA-approved premixed, ready to
`
`administer nicardipine hydrochloride injectable drug product. This is especially notable given
`
`the success of Cornerstone’s concentrated nicardipine hydrochloride injection formulation,
`
`Cardene® I.V., which was approved on January 30, 1992. Finally, actual failed attempts by
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`pharmacists to make ready to use, nicardipine hydrochloride premixed injection formulations
`
`suitable for long term storage at room temperature confirm the nonobviousness of the claimed
`
`invention. (See, e.g. SAN_NIC_0001501; SAN_NIC_0001507; SAN_NIC_0001515).
`
`Other nicardipine hydrochloride products have been available worldwide since at least
`
`1985. In fact, Defendant Sandoz marketed a nicardipine hydrochloride injectable under the
`
`tradename Loxen in Europe, and marketed a generic version of the Cardene® I.V. ampul in the
`
`United States. (See e.g., CRTXCAR0006142). However, it was not until late 2012 that Sandoz
`
`submitted an ANDA for a generic version of Cardene® I.V. Premixed Injection. (See, e.g.,
`
`SAN_NIC_000001; CRTXCAR0006102).
`
`In fact, the Baaske reference demonstrates the failure of others in making a ready to use,
`
`nicardipine hydrochloride premixed injection that is stable for at least one year at room
`
`temperature. (See SAN_NIC_0001575). A POSA at the time of the invention would not have
`
`been motivated to simply dilute the concentrated Cardene® I.V. ampul because it was known that
`
`diluted nicardipine hydrochloride is susceptible to instability, degradation, and sorption. (See,
`
`e.g., SAN_NIC_0004756; SAN_NIC_0004762). Baaske demonstrates that dilution of
`
`concentrated Cardene® I.V. ampuls causes more drug sorption and degradation upon long term
`
`storage at room temperature conditions. (See SAN_NIC_0001575). Diluting a concentrated
`
`drug into a ready to use solution is not a predictable process.
`
`5.
`
`Copying
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`Failed attempts by others to attempt to copy Plaintiffs’ ready to use, long term stable,
`
`nicardipine hydrochloride premixed injection is further objective evidence of nonobviousness.
`
`Specifically, so-called compounding pharmacies, such as Ameridose and PharMEDium, among
`
`others, have attempted to copy—without success—Plaintiffs’ Cardene® I.V. Premixed Injection.
`
`(See, e.g., SAN_NIC_0001472; SAN_NIC_0001497; SAN_NIC_0001501; SAN_NIC_0001507;
`
`SAN_NIC_0001515; see also CRTXCAR0006037; CRTXCAR0006039; CRTXCAR0006041;
`
`CRTXCAR0006045; CRTXCAR0006052; CRTXCAR0006057; CRTXCAR0006063;
`
`CRTXCAR0006065; CRTXCAR0006067; CRTXCAR0006071; CRTXCAR0006074). The
`
`products purportedly being manufactured by these pharmacies, including Ameridose and
`
`PharMEDium, are attempts to essentially copy Plaintiffs’ patented, FDA approved, Cardene®
`
`I.V. Premixed Injection, but without the stability, safety, and efficacy assurances provided by the
`
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`FDA’s review and approval process of an NDA or ANDA. (See, e.g., SAN_NIC_0001472;
`
`SAN_NIC_0001497; SAN_NIC_0001501; SAN_NIC_0001507; SAN_NIC_0001515; see also
`
`CRTXCAR0006037; CRTXCAR0006039; CRTXCAR0006041; CRTXCAR0006045;
`
`CRTXCAR0006052; CRTXCAR0006057; CRTXCAR0006063; CRTXCAR0006065;
`
`CRTXCAR0006067; CRTXCAR0006071; CRTXCAR0006074).
`
`Notably, New England Compounding Center (“NECC”), another compounding pharmacy
`
`owned by the same people as Ameridose, was investigated after injectable drug products it
`
`manufactured, which were contaminated with meningitis, infected and killed many people across
`
`the United States. (See, e.g., CRTXCAR0006039; CRTXCAR0006041; CRTXCAR0006045;
`
`CRTXCAR0006067; CRTXCAR0006071). In fact, Barry Cadden, the chief pharmacist at
`
`Ameridose and NECC, had his pharmacist license revoked. (See CRTXCAR0006042;
`
`CRTXCAR0006047). NECC was eventually shut down, has filed for bankruptcy, and federal
`
`authorities have opened a criminal investigation into NECC’s pharmacy compounding practices.
`
`(CRTXCAR0006071; CRTXCAR0006050; CRTXCAR0006047).
`
`Ameridose was discussed during Congressional hearings held on the meningitis outbreak
`
`associated with products manufactured by NECC. (CRTXCAR0006067; CRTXCAR0008032).
`
`Indeed, discussing the same 2008 FDA inspection report produced by Defendant in support of
`
`their invalidity contentions, Senators voiced concerns about FDA findings that Ameridose
`
`“products were shipped immediately without waiting for test results showing they were sterile.”
`
`(CRTXCAR0006068; see also SAN_NIC_0001507). And Ameridose did not perform potency
`
`tests to confirm the strength of products shipped to customers. (CRTXCAR0008058). FDA
`
`finally issued a Form 483 inspection observation report to Ameridose in November 2012.
`
`
`
`359
`
`EKR Therapeutics, LLC Exhibit 2014 Page 14
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`

`

`
`
`(CRTXCAR0008073; CRTXCAR0008012). FDA summarized its findings of Ameridose’s
`
`practices as follows:
`
`[Ameridose] fails to test finished product for product for potency,
`failed to investigate complaints for ineffective products, failed to
`investigate violations of their own environmental sampling plan
`and fails to adequately maintain equipment and facilities used to
`manufacture sterile drug products.
`
`Ameridose recalled its injectable drug products after the FDA inspection because FDA “could
`
`not be assured of the sterility of those products.” (CRTXCAR0006075; see also
`
`CRTXCAR0006063; CRTXCAR0006065; CRTXCAR0006039). Ameridose has also shut
`
`down their facility. (CRTXCAR0006037; CRTXCAR0006063; CRTXCAR0008073).
`
`Similarly, the FDA recently issued Form 483 inspection observation reports after visiting
`
`two PharMEDium pharmacies. (See CRTXCAR0006052; CRTXCAR0006057). Some of the
`
`relevant observations include PharMEDium’s:
`
`
`
` “failure to perform endotoxin testing on all finished sterile injectable drug
`products.” (CRTXCAR0006052).
`
` “several of the firm’s finished drug products contain active drug ingredients that
`the manufacturer’s label declares to protect from light. These finished drug
`products processed by this firm are placed into clear plastic containers.”
`(CRTXCAR0006054).
`
` “stability test methods used to assign expiration dating of finished sterile
`injectable drug products are not stability indicating. The firm’s stability testing
`procedures do not include sterility, impurity, or degr[a]dant product testing.”
`(CRTXCAR0006055; CRTXCAR0006060).
`
` “failure to perform finished product potency/sterility testing on each lot of
`finished injectable drug product processed/distributed.” (CRTXCAR0006060).
`
`Compounding pharmacies such as Ameridose and PharMEDium have attempted to copy the
`
`inventions claimed in the patents in suit. Such attempted copying evidences the nonobviousness
`
`of the claimed inventions—even though none of the compounding pharmacies were able to
`
`duplicate the stability of the claimed formulations.
`
`
`
`360
`
`EKR Therapeutics, LLC Exhibit 2014 Page 15
`
`

`

`
`
`6.
`
`Industry Praise
`
`Cardene® I.V. Premixed Injection has been widely praised by physicians and the
`
`pharmaceutical industry. (See, e.g., CRTXCAR0005484). A phase four, randomized,
`
`comparative effectiveness trial to determine the efficacy and safety of Cardene® I.V. Premixed
`
`Injection versus bolus labetalol for management of hypertension in the emergency department
`
`setting concluded that Cardene® I.V. Premixed Injection is superior as a first-line intervention in
`
`clinically critical conditions, like intracranial hemorrhage, where rapid blood pressure reduction
`
`is considered optimal. (CRTXCAR0005484).
`
`Doctors, pharmacists, and other health care providers report that ready to use Cardene®
`
`I.V. Premixed Injection was an improvement over the Cardene® I.V. ampul. (See, e.g.,
`
`CRTXCAR0005331). When asked whether a premixed aqueous solution of Cardene® I.V.
`
`would be preferable, a pharmacist responded: “It takes about 5 minutes to admix Cardene IV, so
`
`we should save some time with [the] premixed bag. Ampules are a pain to work with.”
`
`(CRTXCAR0005358). And the ready to use Cardene® I.V. Premixed Injection has also been
`
`praised by the healthcare industry when compared to other antihypertensive medications used in
`
`emergency situations, including labetalol and nitroprusside. (See, e.g., CRTXCAR0005484;
`
`CRTXCAR0004716; CRTXCAR0006120).
`
`V.
`
`L. Pat. R. 3.4A(c)
`
`Attached as Exhibits A – D are Plaintiffs’ claim-by-claim responses to the charts
`
`provided by Defendant pursuant to Local Patent Rule 3.3(c). In its response corresponding to
`
`each asserted claim, Plaintiffs incorporate by reference Sections I-IV, supra. In its response
`
`corresponding to each dependent claim, Plaintiffs incorporate by reference its responses to any
`
`claim(s) from which it depends. To the extent that Defendant’s contentions for an asserted claim
`
`reference another claim (e.g., “See discussion for claim __”), these contentions are vague and
`
`
`
`361
`
`EKR Therapeutics, LLC Exhibit 2014 Page 16
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`

`

`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF NEW JERSEY
`
`CORNERSTONE THERAPEUTICS INC.,
`CORNERSTONE BIOPHARMA, INC., and
`EKR THERAPEUTICS, LLC,
`
`)
`)
`)
`
`)
`) Civil Action No. 1:13-cv-05723-NLH-AMD
`
`)
`)
`)
`)
`)
`)
`
`
`
`
`
`
`
`
`
`v.
`
`Plaintiffs,
`
`
`
`SANDOZ INC.
`
`
`
`
`
`Defendant.
`
`
`
`
`
`CERTIFICATE OF SERVICE
`
`
`
`I hereby certify that on this 28th day of April 2014, a true and correct copy of “Plaintiffs’
`
`Responses to Defendant’s Invalidity Contentions” was served on the following counsel by
`
` s/ Leann M. Clymer
` Leann M. Clymer
`
`
`
`electronic mail:
`
`Counsel for Sandoz Inc.
`
`Matthew M. D’Amore
`David J. Austin
`Sarah L. Prutzman
`Hui Liu
`MORRISON & FOERSTER LLP
`250 West 55th Street
`New York, New York 10019-9601
`Telephone: (212) 468-8168
`
`
`
`
`
`
`
`
`
`01427553.DOCX
`
`EKR Therapeutics, LLC Exhibit 2014 Page 17
`
`