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Par Pharmaceutical, Inc. v. Hospira, Inc.

United States District Court, D. Delaware

November 13, 2019

PAR PHARMACEUTICAL, INC., PAR STERILE PRODUCTS, LLC, and ENDO PAR INNOVATION COMPANY, LLC, Plaintiffs,
v.
HOSPIRA, INC., Defendant.

          FINDINGS OF FACT AND CONCLUSIONS OF LAW

          Joseph F. Bataillon, Senior United States District Judge.

         This matter is before the Court after a bench trial from June 28, 2019, to July 3, 2019. This is a patent infringement action brought under the Hatch-Waxman Act, 21 U.S.C. § 355, et seq. Defendant Hospira Inc. (“Hospira”) filed an Abbreviated New Drug Application ("ANDA"), No. 208908, with the Food and Drug Administration (“FDA”), seeking approval to engage in the manufacturing and sale of a generic version of the plaintiffs' Adrenalin® brand epinephrine injection 1 mg/mL product, which is indicated for emergency treatment of allergic reactions, including anaphylaxis. The plaintiffs, Par Pharmaceutical, Inc. (“Par Pharm”), Par Sterile Products, LLC (“Par Sterile”), and Endo Par Innovation Company, LLC (“EPIC”) (collectively, "Par") allege that Hospira's ANDA infringes its patents, United States Patent Nos. 9, 119, 876 (“the '876 Patent”) and 9, 295, 657 (“the '657 Patent”). Hospira challenges the validity of Par's patents.

         I. REGULATORY BACKGROUND

         The Hatch-Waxman Act was passed in 1984 to respond to two problems created by the statutes that then regulated patents and pharmaceuticals. Eli Lilly and Co. v. Medtronic, Inc., 496 U.S. 661, 669 (1990). The first arose from the fact that inventors ordinarily applied for patent protection for newly discovered drugs well before securing regulatory approval, even though marketing was prohibited until regulatory approval was obtained. Warner-Lambert Co. v. Apotex Corp., 316 F.3d 1348, 1357 (Fed. Cir. 2003). Because the FDA generally took much longer to approve a New Drug Application (“NDA”) than the Patent and Trademark Office (“PTO”) took to grant a patent, the seventeen-year patent term was substantially eroded by the time the patentee could market its product obtain the benefit of his invention. Id.

         The second problem was the requirement that a generic manufacturer obtain its own NDA-providing its own safety and efficacy data-if it wanted to market a product. Id. At that time, manufacturing or using a patented product solely for the purpose of conducting tests and developing the necessary information to apply for regulatory approval later was an act of infringement under 35 U.S.C. § 271(a). Id. Because it took a substantial amount of time for a generic manufacturer to obtain data and secure regulatory approval, requiring those manufacturers to wait until after the patent expired to begin testing and other pre-approval activities resulted in a de facto extension of the patent term. Id.

         The Hatch-Waxman Act was designed to address both of these problems by restoring time lost to innovators during pre-patent testing and regulatory approval, while at the same time enabling generic manufacturers to be ready to enter the market once the patents expired. Id. To further the overall goal of getting generics to market faster, Hatch-Waxman authorized the filing and approval of Abbreviated New Drug Applications and provided a mechanism through which patent-holders could adjudicate patent infringement claims prior to a product coming on the market. Id.; Sunovion Pharm., Inc. v. Teva Pharm. USA, Inc., 731 F.3d 1271, 1279 (Fed. Cir. 2013) (noting that the Hatch-Waxman framework envisions resolution of the infringement issue earlier, and generally before ANDA approval). Under Hatch-Waxman, generic manufacturers had to show bioequivalence to a patented drug, but no longer had to prove the safety and efficacy of a generic version of a drug, they could effectively “piggy-back” on the patent holder's showing of safety and efficacy. Generic manufacturers are also allowed to test and seek approval to market the generic formulation during the patent term. Id.

         Under the infringement adjudication mechanism of the Act, patentees and NDA holders are required to list patents that claim the approved drug or its approved use in the FDA's Approved Drug Products with Therapeutic Equivalence Evaluations publication (the “Orange Book”). Id.; see21 U.S.C. § 355(b)(1). ANDA applicants are required to either certify that no unexpired patent is listed for its proposed generic formulation, or that the listed patent is either invalid or would not be infringed by the manufacture, use, or sale of the drug by the ANDA applicant (“a paragraph IV certification”). Id.; 21 U.S.C. § 355(j)(2)(A)(I-IV).

         The filing of an ANDA with a paragraph IV certification constitutes an act of artificial patent infringement under 35 U.S.C. § 271(e)(2)(A), which allows litigation to commence before actual sale of an accused product has occurred. Vanda Pharm. Inc. v. West-Ward Pharm. Int'l Ltd., 887 F.3d 1117, 1126 (Fed. Cir. 2018); see also Sunovion, 731 F.3d at 1279 (“Although no traditional patent infringement has occurred until a patented product is made, used, or sold, under the Hatch-Waxman framework, the filing of an ANDA itself constitutes a technical infringement for jurisdictional purposes”). Patent holders benefit from the Act because the patent term was extended for products subject to a regulatory review before commercial marketing or use, if the permission for the commercial marketing or use of the product after such regulatory review period was the first permitted commercial marketing or use of the product. Id. at 1358.

         II. FINDINGS OF FACT

         A. Background

         The following facts are gleaned from the parties' agreed facts in the Pretrial Order and from the evidence adduced at trial. (D.I. 192-1, Pretrial Order, Exhibit (“Ex.”) 1, Statement of Uncontested Issues of Fact (“Agreed Facts”); D.I. 223 to D.I. 226, Trial Transcript (“Tr.”)).

         The dispute between the parties involves injectable epinephrine formulations and long-standing problems of stability and shelf-life. Epinephrine is a well-known drug used to treat allergic reactions and anaphylaxis for over 100 years. Joint Trial Exhibit (“JTX”) 48; D.I. 225, Tr. at 452. Older epinephrine formulations, including Par's original Adrenalin® formulation and Hospira's ampoule and Abboject® products, pre-date the current FDA regulatory regime and were sold without FDA approval under statutory “grandfather” provisions. D.I. 225, Tr. at 527. Although the “grandfathered” drugs had been sold for many years, they did not meet modern pharmaceutical standards in terms of quality, stability, and absence of impurities. D.I. 223, Tr. at 159.

         In 2006, the FDA began a drug safety initiative regarding the marketing of unapproved drugs. D.I. 224, Tr. at 215-16; Filing No. 225, Tr. at 527. Under the initiative, the FDA required registration of unapproved products for listing in the Orange Book. Id. Accordingly, the scientists at Par's predecessor company, JHP Pharmaceuticals LLC (“JHP”), began working to develop a product that would meet the FDA's new requirements. Plaintiff's Trial Exhibit (“PTX”) 1, '876 Patent, col.1, ll. 53 to 62. Par's Adrenalin® was the first epinephrine injection product approved by the Food FDA for use in a clinical setting available in the United States. D.I. 192-1, Agreed Facts ¶ 3. Par's NDA No. 204200 was approved by FDA on December 7, 2012 (Id.).

         Though it approved the product, the FDA asked JHP for a post marketing commitment that it would try to reduce the levels of impurities in Adrenalin®. PTX 191 at 3. The impurities were the result of degradation, a process whereby the amount of the active ingredient, and thereby the potency, of the product decreases and the amount of potentially toxic compounds increases. The primary degradants in epinephrine products are epinephrine sulfonic acid (ESA) and D-epinephrine, an enantiomer of the active ingredient L-Epinephrine.[1] PTX 1, '876 Patent at col. 1, ll.53-56.

         The record shows there are three epinephrine degradation pathways-oxidation, racemization, and sulfonation. D.I. 223, Tr. at 165, 173, 179. Patrick Irish, a scientist at JHP, testified it was very difficult to come up with a set of components in a formulation that could minimize one degradation pathway without exacerbating another degradation pathway. D.I. 223, Tr. at 163. The difficulty was that there were unintended consequences of the experiments-solving one issue would create another problem. D.I. 225, Tr. at 452-56.

         Par's efforts to improve the 2012-FDA-approved product eventually led to a supplemental NDA, No. 204200-04, that was approved on September 12, 2016, and to the two patents that are the subject of this case. D.I. 223, Tr. at 69; D.I. 192-1, Agreed Facts ¶ 2-3. Par's predecessor, JHP, filed Application Serial No. 14/657, 990 with the PTO on March 13, 2015, and it issued as the '876 Patent on September 1, 2015. D.I. 192-1, Agreed Facts ¶ 2. JHP filed Application Serial No. 14/818, 121 with the PTO on August 4, 2015, and it issued as the '657 Patent on March 29, 2016. Id. at 3. The '657 Patent is a continuation of the application that issued as the '876 Patent. Id. at 2-3. Both patents are titled “Epinephrine Formulations.” Id. The '657 Patent and the '876 Patent share a common specification. Id. Vinayagam Kannan, Patrick Irish, and Michael Bergren are the named inventors of the '657 and '876 Patents. Id. The '876 Patent covers the composition of the inventive formulations and the improved impurity profile (JTX 1). The '657 Patent covers using those formulations to treat patients (JTX 2).

         The improved formulation of Adrenalin® is the embodiment of the asserted claims of the patents at issue and has a shelf life of twenty-four months. D.I. 192-1, Agreed Facts ¶ 3; JTX 7, FDA correspondence at 2. The '876 and '657 Patents are listed in the Orange Book for the listing for Adrenalin® brand epinephrine injection. Id. at 4.

         Hospira had also committed to the FDA in 2007 that it would remediate its unapproved products-Epinephrine Injection USP Ampul and Epinephrine Injection USP Abboject. JTX 95, 2015 Epinephrine Injection USP Project Technical Review (“2015 PTR”) at 2. Dr. Zhang was the main formulation scientist responsible for the generic product and he testified that Hospira began developing its ANDA Product sometime in 2009. D.I. 223, Tr. at 215, 318: JTX 95, 2015 PTR at 6. After several unsuccessful efforts, Hospira submitted ANDA No. 208908 to the FDA in 2017, seeking approval to engage in the commercial manufacture and sale of a generic version of Adrenalin® epinephrine injection, 1 mg/mL (“Hospira's ANDA Product”) prior to the expiration of the '876 and '657 Patents.[2] D.I. 192-1, Agreed Facts ¶ 5.

         B. Infringement

         Par asserts that Hospira's ANDA product infringes claims 1-3, 5, and 10-19 of each patent (“the asserted claims”) Independent claim 1 of the '876 Patent claims:

1. A composition comprising:
in the range of about 0.5 to 1.5 mg/mL of epinephrine and/or salts thereof,
in the range of about 6 to 8 mg/mL of a tonicity regulating agent,
in the range of about 2.8 to 3.8 mg/mL of a pH raising agent, in the range of about 0.1 to 1.1 mg/mL of an antioxidant,
in the range of about 0.001 to 0.010 mL/mL of a pH lowering agent, and in the range of about 0.01 to 0.4 mg/mL of a transition metal complexing agent, wherein the antioxidant comprises sodium bisulfite and/or sodium meta bisulfite.

D.I. 1-1, '876 Patent, col. 28, ll. 1-14. The remaining asserted claims are dependent claims.[3]

         In claim construction, the parties agreed to the following claim construction: the word “about” should be given its ordinary meaning, which is “approximate.” D.I. 67, Joint Claim Construction Chart, Appendix A. A “pH raising agent” is a “component to raise the composition's pH, which may comprise a buffer system.” Id. A “buffer system” is a “component present in a composition or solution which may provide a resistance to significant change in pH caused by a strong acid or base; may comprise a single agent or more than one agent, such as a weak acid and its conjugate base.” Id. A pH lowering agent” is a “component to lower the composition's pH.” Id. A “transition metal complexing agent” is a “component to complex with transition metals, such as a chelating agent.” Id.

         The parties agree that Hospira's ANDA Product is a composition and is indicated for emergency treatment of allergic reactions (Type 1), including anaphylaxis. D.I. 192-1, Agreed Facts ¶ 6. Hospira's ANDA describes the composition of Hospira's ANDA Product, including the target amounts of each component and Hospira's stated function of each component. Id. at 4-5. The parties also agree that Hospira's ANDA Product contains: in the range of about 0.5 to 1.5 mg/mL of epinephrine and in the range of about 0.1 to 1.1 mg/mL of sodium metabisulfite. Id. at 5. Further, they agree that sodium metabisulfite is an antioxidant; sodium chloride is a tonicity regulating agent; citric acid and sodium citrate are a pH raising agent; citric acid and sodium citrate are a buffer system; hydrochloric acid is a pH lowering agent; and water for injection is a solvent. Id. Also, the parties agree that Hospira's ANDA Product contains a solvent comprising water and contains about 11% or less of ESA after 18 months of storage at 23° C to 32° C and 55% to 70% relative humidity and about 3% or less of D-Epinephrine after 18 months of storage at those temperature and humidity levels. Id. at 6.

         Par contends that Hospira's ANDA product contains amounts of the specified agents in the ranges that are claimed in at least one asserted claim in each of the patents at issue. Hospira contends that its ANDA product does not infringe Par's patents, arguing that Par and Hospira took fundamentally different approaches to remediating their former products.[4]

         There is no dispute that Hospira's ANDA product contains the active ingredient epinephrine and an antioxidant wherein the antioxidant comprises sodium bisulfite and/or sodium metabisulfite. D.I. 192-1, Agreed Facts ¶ 5, Table 13. There is also no dispute that Hospira's ANDA product meets the improved impurity profile that is specified in the claims. In support of its contention of noninfringement, Hospira points to different concentrations of 1) a tonicity regulating agent; 2) a pH raising agent and 3) absence of a transition metal complexing agent in its proposed product.

         At trial, Dr. Edmund Elder testified on behalf of Par (D.I. 223, Tr. at 59 to 149). He has a Ph.D. in Pharmaceutical Sciences, spent 16 years in the pharmaceutical industry, and is an expert in pharmaceutical formulations, including injectables. Id. at 63; JTX 113, Curriculum Vitae ("C.V."). He is director of the Zeeh Pharmaceutical Experiment Station in the School of Pharmacy, University of Wisconsin-Madison, where he oversees formulation development activities, including for injectable products. Id. at 60. Dr. Elder teaches drug development and formulation and sits on a committee that oversees the University's FDA-regulated research. Id. at 60-61. He also sits on the compounding expert committee of the United States Pharmacopeia and is an editor for peer-reviewed journals. Id. at 62-63.

         Dr. Elder reviewed Hospira's ANDA submission. D.I. 223, Tr. at 70-71; JTX 110, Hospira ANDA, overall summary; JTX 50, specification; and JTX 86, PTX 387, PTX 388, PTX 389, batch records. He testified that Hospira's ANDA product infringes claim 1 of the '876 Patent, both literally and under the doctrine of equivalents. Id. at 90-91. He first stated that Hospira's ANDA product contains 8.55 to 9 mg/mL of sodium chloride, which is a tonicity regulating agent. D.I. 223, Tr. at 73-74.

         The record shows that the target amount of sodium chloride in Hospira's ANDA Product is 9 mg/mL. JTX 110, Hospira ANDA at 18. The amount of sodium chloride in commercial batches of Hospira's ANDA Product will vary from the target concentration of 9 mg/mL. Id. at 72. The release specification for the first three exhibit batches was as low as 8.55 mg/mL. Id. at 75. The measured amount in the exhibit batches was between 8.91 and 9.27 mg/mL. Id. at 75; JTX 86 at 13, 19, 24; PTX 387 at 13, 19, 24; PTX 388 at 10, 17, 22. Dr. Elder expressed the opinion that the amount of sodium chloride in Hospira's ANDA product literally meets the claim limitation of “about 8 mg/mL.” Id. at 77-78.

         The patent specification describes the purpose of the tonicity regulating agent is to “maintain the tonicity of the composition in a physiologically acceptable range.” D.I. 223, Tr. at 77; JTX 1, '847 Patent at col. 8, ll. 46-53. “Physiologically acceptable” means that the product will not have a negative impact on the cells that are exposed to it-it will be in an isotonic range. D.I. 223, Tr. at 79; PTX 165 at 3, PTX 173 at 6. Dr. Elder stated that tonicity is osmotic pressure, explaining that when a blood cell is in an isotonic environment, the concentration of dissolved species in solution matches that inside the cell, creating an equilibrium of water exchange between the cell and the solution. Id. In a hypertonic solution, a higher concentration of dissolved particles in the surrounding solution causes water to flow out of the cell, resulting in cell shrinkage. Id. In a hypotonic solution, the fluid surrounding the cell has a lower concentration of dissolved particles, causing water to move into the cell, resulting in cell swelling and eventually bursting. Id. at 78-79. He also testified that a physiologically acceptable range of tonicity reported in the literature is between 225 and 350 milliosmoles per kilogram (mOsm/kg.) and formulations within that range are considered isotonic. Id. at 79.

         Hospira's ANDA similarly states that the purpose of the 9 mg/mL sodium chloride in Hospira's ANDA Product is to provide “isotonicity” to the composition. Id. at 80. That function is identical to the function for the claim limitation of “about 6 to 8 mg/mL of a tonicity regulating agent” in the patents in suit. Id. Also, Dr. Elder testified that the osmolality of Hospira's ANDA Product with 8.55 mg/mL sodium chloride would be slightly lower than the 323 or 324 mOsm/kg reported for the target of 9 mg/mL, which would also be well within the physiological acceptable range. Id. at 81-82. He concluded that Hospira's ANDA product, which contains 8.55 mg/mL to 9 mg/mL of sodium chloride as a tonicity regulating agent, meets the claimed limitation of about 6 to 8 milligrams per milliliter. Id. (emphasis added).

         Dr. Elder also testified that 8.55 to 9 mg/mL sodium chloride meets the limitation “about 8 mg/mL” in the '847 Patent under the doctrine of equivalents. Id.at 84. He evaluated the amount of sodium chloride in Hospira's ANDA Product under the function-way-result test and found it was equivalent: the function of the claimed range of tonicity regulating agent is to regulate tonicity; the way it does that is by providing dissolved particles; and the result is a physiologically acceptable tonicity. Id. at 83-85. He concluded that the sodium chloride concentration in the product is insubstantially different from the claimed range, because both provide a physiological acceptable tonicity. Id. at 83-84.

         Dr. Elder also noted that Hospira represented to FDA that the “calculated osmolality of 308 mOsm/kg for the reformulated Adrenalin is comparable to the measured values for the proposed product . . . the minor differences are not expected to affect safety and efficacy of epinephrine injection.” Id. at 81; JTX 49 at 16. Hospira's lead chemist on its ANDA project, Dr. Eric Zhang, confirmed Hospira's representations as to the osmolality of Hospira's ANDA product. D.I. 224, Tr. at 273, 299.

         The record also shows that during the development of its ANDA product, Hospira varied the sodium chloride concentration between 6 and 9 mg/mL without ever testing its impact. D.I. 224, Tr. at 262; Tr. at 82; (JTX 94, 2014 Hospira Product Technical Review at 18. Hospira never measured the osmolality of its formulations with 6 mg/mL sodium chloride and did not test for any difference between 6 and 9 mg/mL concentrations. D.I. 224, Tr. at 270. There was no suggestion or discussion within Hospira or Pfizer that such a variation would affect the safety of the drug product. Id. at 265.

         With respect to the limitations “a pH raising agent, ” “a pH lowering agent” and “a transition metals complexing agent, ” Hospira acknowledged to the FDA that Par's reformulated Adrenalin and Hospira's ANDA product have a difference in pH buffer, noting that the reformulated Adrenalin® includes a pH buffer formed by tartaric acid and sodium hydroxide, whereas the pH buffer in the Hospira's proposed drug contains sodium citrate and citric acid. JTX 49 at 15. Par argues that functionally Hospira's ANDA product meets the limitations of “about 2.8 to 3.8 mg/mL of a pH Raising Agent, ” and “about 0.001 to 0.010 mL/mL of a pH Lowering Agent” in Par's '876 Patent.

         Dr. Francisco Dean Toste testified on behalf of Par. D.I. 224, Tr. 319-423. He is the Gerald E. K. Branch Distinguished Professor at the University of California, Berkeley. Id. at 320. His research focuses on transition metal catalysts used in chemistry and pharmaceuticals. Id. at 320-21. Dr. Toste has consulted with pharmaceutical companies for 15 years. Id. at 321-22. Dr. Toste is a fellow of the American Academy of Arts and Sciences and the Royal Society of Canada. Id. at ...


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