Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 1 of 25
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE SOUTHERN DISTRICT OF FLORIDA
`
`AMGEN INC. and AMGEN
`MANUFACTURING LIMITED,
`
`
`Plaintiff,
`
`v.
`
`
`
`
`APOTEX INC. and APOTEX CORP.,
`
`
`Defendant.
`
`
`
`
`
`
`
`Case No. _____
`
`
`
`
`
`COMPLAINT FOR PATENT INFRINGEMENT
`
`Plaintiffs Amgen Inc. and Amgen Manufacturing Ltd. (together, “Amgen”) for its
`
`Complaint against Defendants Apotex Inc. and Apotex Corp. (together, “Apotex”) allege as
`
`follows:
`
`THE PARTIES
`
`1.
`
`Amgen Inc. is a corporation existing under the laws of the State of Delaware, with
`
`its principal place of business at One Amgen Center Drive, Thousand Oaks, California 91320.
`
`Amgen Inc. discovers, develops, manufactures, and sells innovative therapeutic products based
`
`on advances in molecular biology, recombinant DNA technology, and chemistry.
`
`2.
`
`Amgen Manufacturing Limited (“AML”) is a corporation existing under the laws
`
`of Bermuda with its principal place of business in Juncos, Puerto Rico. AML manufactures and
`
`sells biologic medicines for treating particular diseases in humans.
`
`3.
`
`Apotex Inc. is a corporation existing under the laws of Canada, with its principal
`
`place of business at 150 Signet Drive, Toronto, Ontario M9L 1T9, Canada. Upon information
`
`and belief, acting in concert with Defendant Apotex Corp., Apotex Inc. is in the business of
`
`developing, manufacturing, and marketing biopharmaceutical products that are distributed and
`
`
`
`
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 2 of 25
`
`
`
`
`sold throughout the United States and in the State of Florida. See Amgen Inc. & Amgen Mfg. Ltd.
`
`v. Apotex Inc. & Apotex Corp., No. 0:15-cv-61631-JIC (consolidated with No. 0:15-cv-62081-
`
`JIC), D.E. 47 at 2, 5 (S.D. Fla. Oct. 23, 2015).
`
`4.
`
`Apotex Corp. is a corporation existing under the laws of Delaware, with its
`
`principle place of business at 2400 North Commerce Parkway, Suite 400, Weston, Florida
`
`33326. Upon information and belief, acting in concert with Defendant Apotex Inc., Apotex
`
`Corp. is in the business of developing, manufacturing, and marketing biopharmaceutical products
`
`that are distributed and sold throughout the United States and in the State of Florida. Upon
`
`information and belief, Apotex Corp. is also the United States agent for Apotex Inc. for purposes
`
`including, but not limited to, filing regulatory submissions to and corresponding with the U.S.
`
`Food and Drug Administration (“FDA”). See No. 0:15-cv-61631-JIC, D.E. 47 at 2 (S.D. Fla.
`
`Oct. 23, 2015).
`
`5.
`
`Upon information and belief, Apotex Corp. is a wholly owned affiliate of Apotex
`
`Inc. Upon information and belief, Apotex Corp. acts at the direction of, under the control of, and
`
`for the direct benefit of Apotex Inc. and is controlled and/or dominated by Apotex Inc.
`
`NATURE OF THE ACTION
`
`6.
`
`This is an action for patent infringement involving United States Patent
`
`No. 9,856,287 (“the ’287 Patent”), attached hereto as Exhibit 1, arising under the patent laws of
`
`the United States, Title 35, United States Code, including 35 U.S.C. § 271(e)(2)(C)(i), which was
`
`enacted in 2010 as part of the Biologics Price Competition and Innovation Act of 2009 (“the
`
`BPCIA”), Pub. L. No. 111-148, §§ 7001-7003, 124 Stat. 119, 804-21 (2010) (amending, inter
`
`alia, 35 U.S.C. § 271 and 42 U.S.C. § 262).
`
`
`
`
`
`2
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 3 of 25
`
`
`
`
`
`
`
`A.
`
`7.
`
`BACKGROUND
`
`
`
`Amgen’s Innovative NEUPOGEN® and NEULASTA® Products
`
`Amgen is one of the world’s leading biopharmaceutical companies and is
`
`dedicated to using discoveries in human biology to invent, develop, manufacture, and sell new
`
`therapeutic products for the benefit of patients suffering from serious illnesses. Developing a
`
`new therapeutic product from scratch is extremely expensive: studies estimate the cost of
`
`obtaining FDA approval of a new biologic product at more than $2.5 billion. See DiMasi J.A. et
`
`al., Innovation in the pharmaceutical industry: New estimates of R&D costs, 47 J. Health Econ.
`
`20, 25-26 (2016), attached hereto as Exhibit 2. Toward that end, Amgen has invested billions of
`
`dollars into its research and development efforts.
`
`8.
`
`In 1991, after conducting extensive clinical trials and submitting the results of
`
`those trials to FDA to prove that NEUPOGEN® is safe, pure, and potent, Amgen first received
`
`FDA approval for NEUPOGEN® to decrease the incidence of infection, as manifested by febrile
`
`neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer
`
`drugs associated with a significant incidence of severe neutropenia with fever. The FDA later
`
`approved several additional indications for the therapeutic use of NEUPOGEN®, including the
`
`treatment of patients with severe chronic neutropenia, patients with acute myeloid leukemia
`
`receiving induction or consolidation chemotherapy, patients receiving bone marrow transplant,
`
`and patients undergoing peripheral blood progenitor cell collection and therapy.
`
`9.
`
`Neutropenia is a deficiency in neutrophils, a condition which makes the individual
`
`highly susceptible to infection. Neutrophils are the most abundant type of white blood cell and
`
`form a vital part of the human immune system. Neutropenia can result from a number of causes;
`
`it is a common side effect of chemotherapeutic drugs used to treat certain forms of cancer.
`
`3
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 4 of 25
`
`
`
`
`10.
`
`The active ingredient in NEUPOGEN® is filgrastim, a recombinantly expressed,
`
`175-amino acid form of a protein known as human granulocyte-colony stimulating factor or “G-
`
`CSF.” NEUPOGEN® is also known as recombinant methionyl human granulocyte-colony
`
`stimulating factor. NEUPOGEN® works by binding to specific receptors on the surface of
`
`certain types of cells to stimulate the production of neutrophils. NEUPOGEN® thus counteracts
`
`neutropenia.
`
`11.
`
`In 2002, Amgen received FDA approval for NEULASTA®. As it did for
`
`NEUPOGEN®, Amgen conducted extensive clinical trials and submitted the results of those
`
`trials to FDA to prove that NEULASTA® is safe, pure, and potent. NEULASTA® is also
`
`indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients
`
`with non-myeloid malignancies receiving myelosuppressive anticancer drugs associated with a
`
`significant incidence of severe neutropenia with fever.
`
`12.
`
`The active ingredient in NEULASTA® is pegfilgrastim, a form of the G-CSF
`
`protein conjugated to a 20 kD monomethoxypolyethylene glycol (“m-PEG” or simply, “PEG”).
`
`NEULASTA® counteracts neutropenia by the same mechanism of action as NEUPOGEN®.
`
`NEULASTA®, by virtue of the conjugated PEG moiety, has a longer serum half-life than
`
`NEUPOGEN® and therefore requires less frequent administration compared to NEUPOGEN®.
`
`13.
`
`NEUPOGEN® and NEULASTA® represent major advances in cancer treatment
`
`by protecting chemotherapy patients from the harmful effects of neutropenia and by thus
`
`facilitating more effective chemotherapy regimes.
`
`B.
`
`The BPCIA and the Prior Actions
`
`14.
`
`Under the traditional pathway for FDA approval, an innovator must demonstrate
`
`that its biologic drug is safe, pure, and potent through clinical trials. See 42 U.S.C. § 262(a).
`
`4
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 5 of 25
`
`
`
`
`The BPCIA created an abbreviated pathway for the approval of biosimilar versions of approved
`
`biologic drugs. 42 U.S.C. § 262(k). The abbreviated pathway (also known as “the subsection
`
`(k) pathway”) allows a biosimilar applicant (or “subsection (k) applicant”) to rely on the prior
`
`licensure and approval status of an innovative biological product (a “reference product”) that the
`
`biosimilar purports to copy. Under the subsection (k) pathway, the biosimilar applicant may rely
`
`on its reference product’s data rather than demonstrating that the biosimilar product is safe, pure,
`
`and potent, as the reference product sponsor (“RPS”) did when it filed its Biologics License
`
`Application (“BLA”) under the traditional 42 U.S.C. § 262(a) pathway.
`
`15.
`
`The BPCIA provides for the subsection (k) applicant and the RPS to engage in a
`
`series of information exchanges and good-faith negotiations between parties prior to the filing of
`
`a patent infringement lawsuit, as set forth in 42 U.S.C. § 262(l)(2)-(l)(5). This process
`
`culminates in an “immediate patent infringement action” pursuant to 42 U.S.C. § 262(l)(6).
`
`16.
`
`Additionally, under 42 U.S.C. § 262(l)(7), if a patent is issued to, or exclusively
`
`licensed by, the RPS after the date that the RPS provided the list to the subsection (k) applicant
`
`under 42 U.S.C. § 262(l)(3)(A), and the RPS reasonably believes that, due to the issuance of
`
`such a patent, a claim of patent infringement could reasonably be asserted by the RPS if a person
`
`not licensed by the RPS engaged in the making, using, offering to sell, selling, or importing into
`
`the United States of the biological product that is the subject of the subsection (k) application,
`
`not later than 30 days after such issuance or licensing, the RPS shall provide to the subsection (k)
`
`applicant a supplement to the list provided by the RPS under 42 U.S.C. § 262(l)(3)(A) that
`
`includes such patent. Not later than 30 days after such supplement is provided, the subsection
`
`(k) applicant shall provide a statement to the RPS in accordance with 42 U.S.C. § 262(l)(3)(B),
`
`and such patent shall be subject to 42 U.S.C. § 262(l)(8).
`
`5
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 6 of 25
`
`
`
`
`17.
`
`Under 42 U.S.C. § 262(l)(8)(A), a subsection (k) applicant must provide notice of
`
`commercial marketing to the RPS not later than 180 days before the date of the first commercial
`
`marketing of its biosimilar product.
`
`18.
`
`Here, Amgen is the sponsor of two reference products, NEUPOGEN® and
`
`NEULASTA® that are approved by FDA for decreasing the incidence of infection in patients
`
`receiving myelosuppressive anti-cancer drugs (among other indications in the case of
`
`NEUPOGEN®). See Amgen Inc. v. Apotex Inc., 712 F. App’x 985, 986 (Fed. Cir. 2017).
`
`19.
`
`Apotex, seeking the benefits of the subsection (k) pathway with Amgen as the
`
`RPS, submitted abbreviated Biologics License Application (“aBLA”) No. 761026 (“the Apotex
`
`Pegfilgrastim aBLA”), which FDA accepted on or about December 16, 2014. See Amgen, 712 F.
`
`App’x at 986; see also No. 0:15-cv-61631-JIC, D.E. 47 at 3, 10 (S.D. Fla. Oct. 23, 2015).
`
`Apotex filed the Apotex Pegfilgrastim aBLA under Section 351(k) of the Public Health Service
`
`Act to obtain approval to commercially manufacture, use, offer to sell, and sell, and import into
`
`the United States the Apotex Pegfilgrastim Product as a biosimilar version of Amgen’s
`
`NEULASTA®. See Amgen, 712 F. App’x at 986; see also No. 0:15-cv-61631-JIC, D.E. 47 at 10
`
`(S.D. Fla. Oct. 23, 2015). The Apotex Pegfilgrastim aBLA listed Amgen’s NEULASTA® as the
`
`reference product. See Amgen, 712 F. App’x at 986; see also No. 0:15-cv-61631-JIC, D.E. 47 at
`
`9 (S.D. Fla. Oct. 23, 2015).
`
`20.
`
`Apotex has represented to FDA that its Pegfilgrastim Product is biosimilar to
`
`Amgen’s NEULASTA®. As such, the Apotex Pegfilgrastim Product should work by the same
`
`mechanism of action as NEULASTA® for the conditions of use prescribed, recommended, or
`
`suggested in NEULASTA®’s approved label and the route of administration, the dosage form,
`
`and the strength of the Apotex Pegfilgrastim Product are the same as those of Amgen’s
`
`6
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 7 of 25
`
`
`
`
`NEULASTA®. See 42 U.S.C. § 262(k)(2)(A)(i); see also No. 0:15-cv-61631-JIC, D.E. 47 at 10
`
`(S.D. Fla. Oct. 23, 2015).
`
`21.
`
`In seeking approval for the Apotex Pegfilgrastim aBLA under the subsection (k)
`
`pathway, Apotex is able to rely on the clinical data that Amgen generated for NEULASTA®
`
`rather than independently demonstrating that the Apotex Pegfilgrastim Product is safe, pure, and
`
`potent, as Amgen was required to do to obtain FDA licensure of NEULASTA® under 42 U.S.C.
`
`§ 262(a). See 42 U.S.C. § 262(k); Sandoz Inc. v. Amgen Inc., 137 S. Ct. 1664, 1670 (2017).
`
`22.
`
`Apotex also submitted aBLA No. 761027 (“the Apotex Filgrastim aBLA”), which
`
`FDA accepted on or about February 13, 2015, seeking the benefits of the subsection (k) pathway
`
`with Amgen as the RPS. See Amgen, 712 F. App’x at 986; see also No. 0:15-cv-61631-JIC, D.E.
`
`64 at 3, 9–10 (S.D. Fla. Dec. 1, 2015). Apotex filed the Apotex Filgrastim aBLA under Section
`
`351(k) of the Public Health Service Act to obtain approval to commercially manufacture, use,
`
`offer to sell, and sell within the United States, and import into the United States the Apotex
`
`Filgrastim Product, which is a biosimilar of Amgen’s NEUPOGEN®. See Amgen, 712 F. App’x
`
`at 986; see also No. 0:15-cv-61631-JIC, D.E. 64 at 9-10 (S.D. Fla. Dec. 1, 2015). The Apotex
`
`Filgrastim aBLA listed Amgen’s NEUPOGEN® as the reference product. See Amgen, 712 F.
`
`App’x at 986; see also No. 0:15-cv-61631-JIC, D.E. 64 at 9 (S.D. Fla. Dec. 1, 2015).
`
`23.
`
`Apotex has represented to FDA that its Filgrastim Product is biosimilar to
`
`Amgen’s NEUPOGEN®. As such, the Apotex Filgrastim Product should work by the same
`
`mechanism of action as NEUPOGEN® for the conditions of use prescribed, recommended, or
`
`suggested in NEUPOGEN®’s approved label and the route of administration, the dosage form,
`
`and the strength of the Apotex Filgrastim Product are the same as those of Amgen’s
`
`7
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 8 of 25
`
`
`
`
`NEUPOGEN®. See 42 U.S.C. § 262(k)(2)(A)(i); see also No. 0:15-cv-61631-JIC, D.E. 64 at 9–
`
`10 (S.D. Fla. Dec. 1, 2015).
`
`24.
`
`In seeking approval for the Apotex Filgrastim aBLA under the subsection (k)
`
`pathway, Apotex is able to rely on the clinical data that Amgen generated for NEUPOGEN®
`
`rather than independently demonstrating that the Apotex Filgrastim Product is safe, pure, and
`
`potent, as Amgen was required to do to obtain FDA licensure of NEUPOGEN® under 42 U.S.C.
`
`§ 262(a). See 42 U.S.C. § 262(k); Sandoz Inc. v. Amgen Inc., 137 S. Ct. at 1670.
`
`25.
`
`After Apotex filed each of its aBLAs, Apotex and Amgen engaged in the
`
`information exchange described in the BPCIA. In particular, under 42 U.S.C. § 262(l)(3),
`
`“Amgen identified [United States Patent No. 8,952,138 (“the ’138 Patent”)] as a patent that the
`
`Apotex-proposed products would infringe, and Apotex replied by sending Amgen a detailed
`
`statement describing, claim by claim, the factual and legal basis for its opinion that it did not
`
`infringe. Amgen responded with its contrary, detailed view of infringement.” See Amgen, 712
`
`F. App’x at 986- 87.
`
`26.
`
`Following the information exchange, Amgen filed two immediate patent
`
`infringement suits against Apotex pursuant to 42 U.S.C. § 262(l)(6)—one for each of Apotex’s
`
`aBLAs—arising under 35 U.S.C. § 271(e)(2)(C)(i), (a),(b), (c), and/or (g) in this Court. See id.;
`
`see also No. 0:15-cv-61631-JIC, D.E. 1 (S.D. Fla. Aug. 6, 2015); Amgen Inc. & Amgen Mfg. Ltd.
`
`v. Apotex Inc. & Apotex Corp., No. 0:15-cv-62081-JIC, D.E. 1 (S.D. Fla. Oct. 2, 2015). Those
`
`lawsuits asserted the ’138 Patent. Amgen also identified and asserted U.S. Patent No. 6,162,427
`
`(“the ’427 Patent”) and U.S. Patent No. 5,824,784 (“the ’784 Patent”). See No. 0:15-cv-61631-
`
`JIC, D.E. 1 at 2 (S.D. Fla. Aug. 6, 2015); No. 0:15-cv-62081-JIC, D.E. 1 at 2 (S.D. Fla. Oct. 2,
`
`8
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 9 of 25
`
`
`
`
`2015). The Court later entered a Joint Stipulation of Dismissal of the ’427 Patent and the ’784
`
`Patent. See No. 0:15-cv-61631-JIC, D.E. 179 (S.D. Fla June 15, 2016).
`
`27.
`
`Amgen’s two immediate patent infringement suits against Apotex pursuant to 42
`
`U.S.C. § 262(l)(6) “were consolidated. [This Court] held a bench trial in July 2016, and it issued
`
`findings of fact and conclusions of law [and final judgment] on September 6, 2016. The [Court]
`
`found that Amgen had failed to prove that Apotex’s proposed commercial marketing of the two
`
`products, pursuant to [the Apotex aBLAs], would infringe the ’138 patent, either literally or
`
`under the doctrine of equivalents.” See Amgen, 712 F. App’x at 987; see also No. 0:15-cv-
`
`61631-JIC, D.E. 267 (S.D. Fla. Sep. 6, 2016); No. 0:15-cv-61631-JIC, D.E. 268 (S.D. Fla. Sep.
`
`6, 2016). Amgen appealed the Court’s judgment, and the Federal Circuit affirmed. See Amgen,
`
`712 F. App’x at 987. The Federal Circuit mandate for that case issued on December 12, 2017.
`
`See No. 0:15-cv-61631-JIC (S.D. Fla.), D.E. 292 (Mandate).
`
`C.
`
`This Action
`
`1.
`
`U.S Patent No. 9,856,287
`
`28.
`
`Following the issuance of the Federal Circuit mandate for the appeal from the
`
`prior patent infringement actions, the U.S. Patent and Trademark Office issued the ’287 Patent to
`
`Amgen on January 2, 2018. A true and correct copy of the ’287 Patent is attached as Exhibit 1.
`
`29.
`
`30.
`
`31.
`
`Amgen is the owner of all rights, title, and interest in the ’287 Patent.
`
`AML holds an exclusive license to the ’287 Patent.
`
`The ’287 Patent is titled “Refolding Proteins Using a Chemically Controlled
`
`Redox State.” The ’287 Patent was duly and legally issued on January 2, 2018 by the United
`
`States Patent and Trademark Office (“USPTO”). The inventors of the ’287 Patent are Joseph
`
`Edward Shultz, Roger Hart, and Ronald Nixon Keener III.
`
`9
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 10 of 25
`
`
`
`
`32.
`
`The ’287 Patent covers improved redox chemistry-based methodologies for
`
`efficiently refolding cysteine-containing proteins expressed in non-mammalian cells at high
`
`protein concentrations.
`
`33.
`
`34.
`
`Apotex infringes claims of the ’287 Patent, including for example, Claim 16.
`
`Claim 16 recites:
`
`A method of refolding proteins expressed in a nonmammalian expression system,
`the method comprising:
`preparing a solution comprising:
`the proteins;
`at least one ingredient selected from the group consisting of a
`denaturant, an aggregation suppressor and a protein stabilizer;
`an amount of oxidant; and
`an amount of reductant,
`wherein the amounts of the oxidant and the reductant are
`related through a thiol-pair ratio and a thiol-pair buffer
`strength,
`wherein the thiol-pair ratio is in the range of 0.001-100, and
`wherein the thiol-pair buffer strength maintains the
`solubility of the solution; and
`incubating the solution so that at least about 25% of the proteins
`are properly refolded.
`
`Claim 16 is infringed based at least on the information contained in the publicly available
`
`portions of the Apotex Pegfilgrastim aBLA and Apotex Filgrastim aBLA.
`
`35.
`
`As an initial matter, Apotex uses the same process to produce the same filgrastim
`
`used in its Filgrastim Product and Pegfilgrastim Product:
`
`Filgrastim is manufactured by IPL as a Drug Substance for the commercial
`product, Filgrastim Drug Product, as well as a Critical Intermediate, as an input
`for the pegylated Apo-Filgrastim DS. Both Filgrastim Critical Intermediate and
`Filgrastim Drug Substance are the same, however depending on the final fate of
`Filgrastim; these are identified as either Filgrastim Drug Substance (used to
`manufacture Filgrastim Drug Product) or Filgrastim Critical Intermediate (used as
`an input to manufacture by pegylation, pegylated Apo-Filgrastim DS)
`
`Amgen Inc. v. Apotex Inc., No. 2017-1010, Non-Confidential Joint Appendix Vol. III at
`
`Appx5556 n.1, D.E. 42-3 (Fed. Cir. Feb. 7, 2017) (“Non-Confidential Joint Appendix”).
`
`10
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 11 of 25
`
`
`
`
`36.
`
`Each of the elements in at least Claim 16 are satisfied in Apotex’s accused
`
`process. In Apotex’s accused process, Apotex expresses the filgrastim protein used in its
`
`Pegfilgrastim Product and Filgrastim Product in a nonmammalian expression system: E. coli
`
`(bacterial) cells:
`
`Apotex’s filgrastim critical intermediate is a “recombinant protein composed of
`the mature and unmodified form of human granulocyte colony stimulating factor
`(G-CSF). The recombinant protein is expressed by Escherichia coli (E.coli) as a
`single continuous polypeptide consisting of 175 amino acid residues.” The
`filgrastim critical intermediate is used as the starting material in the “Pegylated
`Apo-Filgrastim Drug Substance manufacturing process.”
`
`Id. at Appx7396 n.90 (internal citations omitted).
`
`37.
`
`In Apotex’s accused process, Apotex refolds the filgrastim contained in its
`
`Pegfilgrastim Product and Filgrastim Product using a refolding solution:
`
`
`
`See No. 2017-1010, Non-Confidential Apotex Responsive Brief at 8, D.E. 32, (Fed. Cir. Jan. 17,
`
`2017) (“Non-Confidential Apotex Brief”); Non-Confidential Joint Appendix at Appx5906.
`
`38.
`
`In Apotex’s accused process, Apotex’s refolding solution comprises:
`
`•
`
`•
`
`a protein: at least the filgrastim protein (see Non-Confidential Joint Appendix at
`Appx5904–5907, Appx7150, Appx7397, Appx7448; see also Non-Confidential
`Apotex Brief at 7–8 (Fed. Cir. 2017));
`
`at least one ingredient selected from the group consisting of a denaturant, an
`aggregation suppressor and a protein stabilizer: arginine and sorbitol (Non-
`
`11
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 12 of 25
`
`
`
`
`•
`
`•
`
`Confidential Joint Appendix at Appx5904–5907, Appx7150; ’287 Patent, 3:41-
`50);
`
`an amount of oxidant: cysteine (Non-Confidential Joint Appendix at Appx5904–
`5907, Appx7150, Appx7397, Appx7448; Non-Confidential Apotex Brief at 7–8;
`’287 Patent, 3:51-54);
`
`an amount of reductant: cystine (Non-Confidential Joint Appendix at Appx5904–
`5907, Appx7150, Appx7397, Appx7448; Non-Confidential Apotex Brief at 7–8;
`’287 Patent, 3:51-54).
`
`39.
`
`In Apotex’s accused process, the refolding solution that Apotex prepares, the
`
`amounts of oxidant (cysteine) and reductant (cystine) are related through a thiol-pair ratio and a
`
`thiol-pair buffer strength, wherein the thiol-pair ratio is in the range of 0.001-100 and the thiol-
`
`pair buffer strength maintains the solubility of the solution. See Non-Confidential Joint
`
`Appendix at Appx5904–5907.
`
`40.
`
`In Apotex’s accused process, Apotex incubates the refolding solution so that at
`
`least about 25% of the filgrastim protein it uses in its Pegfilgrastim Product and Filgrastim
`
`Product is properly refolded: the “Expected Range” of the “Refolding Step Yield” is “≥ 60%.”
`
`Id. at Appx7361.
`
`2.
`
`Apotex’s Submissions to FDA of its Pegfilgrastim aBLA
`and Filgrastim aBLA
`
`41.
`
`Apotex caused the submission of the Apotex Pegfilgrastim aBLA, which FDA
`
`accepted on or about December 16, 2014, for the purpose of obtaining FDA approval to engage
`
`in the commercial manufacture, use, or sale of the Apotex Pegfilgrastim Product. Apotex caused
`
`the submission of the Apotex Filgrastim aBLA, which FDA accepted on or about February 13,
`
`2015, for the purpose of obtaining FDA approval to engage in the commercial manufacture, use,
`
`or sale of the Apotex Filgrastim Product.
`
`42.
`
`This infringement action follows under 35 U.S.C. § 271(e)(2)(C)(i), which
`
`provides that “[i]t shall be an act of infringement to submit—with respect to a patent that is
`
`12
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 13 of 25
`
`
`
`
`identified in the list of patents” described in 42 U.S.C. § 262(l)(3)(A) “an application seeking
`
`approval of a biological product” for the purpose of obtaining FDA approval to engage in
`
`commercial manufacture, use, or sale. Under 42 U.S.C. § 262(l)(7), the RPS may supplement
`
`the 42 U.S.C. § 262(l)(3)(A) list with a patent issued to the RPS after the date the RPS provided
`
`the 42 U.S.C. § 262(l)(3)(A) list to the subsection (k) applicant.
`
`43.
`
`On January 31, 2018, Amgen supplemented each of the lists that Amgen provided
`
`to Apotex under 42 U.S.C. § 262(l)(3)(A) for the Apotex Pegfilgrastim aBLA and the Apotex
`
`Filgrastim aBLA to include the ’287 Patent; and Apotex provided Amgen with its statements
`
`under 42 U.S.C. § 262(l)(3)(B) on March 2, 2018 regarding the ’287 Patent. Accordingly,
`
`Apotex has committed an act of infringement under 35 U.S.C. § 271(e)(2)(C)(i) with respect to
`
`the ’287 Patent as to each of the Apotex Pegfilgrastim aBLA and Apotex Filgrastim aBLA
`
`submissions.
`
`44.
`
`Upon information and belief, Apotex is continuing its efforts to obtain FDA
`
`approval to engage in the commercial manufacture, use, or sale of each of the Apotex
`
`Pegfilgrastim Product and the Apotex Filgrastim Product. See Apobiologix, R&D Overview,
`
`http://www.apobiologix.com/rd/default.asp (last visited on Aug. 1, 2018) (indicating that the
`
`“Development Progress” of the Apotex Pegfilgrastim Product (Lapelga™) and the Apotex
`
`Filgrastim Product (“Grastofil™”) are currently “Filed” with “Marketed” as the next step in the
`
`United States). Upon information and belief, Apotex has committed further acts of infringement
`
`with respect to each of the Apotex Pegfilgrastim Product and the Apotex Filgrastim Product
`
`since the ’287 Patent issued.
`
`45.
`
`For an act of infringement under 35 U.S.C. § 271(e)(2), the Court may grant
`
`injunctive relief and damages or other monetary relief. 35 U.S.C. § 271(e)(4)(B)-(C).
`
`13
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 14 of 25
`
`
`
`
`46.
`
`Unless enjoined by this Court, upon information and belief, Apotex will infringe
`
`one or more claims of the ’287 Patent under 35 U.S.C. § 271(a), (b), (c), and/or (g) by making,
`
`using, offering to sell or selling within the United States, or importing into the United States the
`
`Apotex Pegfilgrastim Product, which Apotex makes by a process covered by the ’287 Patent,
`
`before the expiration of the ’287 Patent.
`
`47.
`
`Unless enjoined by this Court, upon information and belief, Apotex will infringe
`
`one or more claims of the ’287 Patent under 35 U.S.C. § 271(a), (b), (c), and/or (g) by making,
`
`using, offering to sell or selling within the United States, or importing into the United States the
`
`Apotex Filgrastim Product, which Apotex makes by a process covered by the ’287 Patent, before
`
`the expiration of the ’287 Patent.
`
`48.
`
`Apotex’s infringement of the ’287 Patent under 35 U.S.C. § 271(a), (b), (c),
`
`and/or (g) is a substantial controversy “of sufficient immediacy and reality to warrant the
`
`issuance of a declaratory judgment” under 28 U.S.C. § 2201. See Medimmune, Inc. v.
`
`Genentech, Inc., 549 U.S. 118, 127 (2007) (quoting Md. Cas. Co. v. Pac. Coal & Oil Co., 312
`
`U.S. 270, 273 (1941)). Upon information and belief, Apotex intends to launch each of its
`
`Pegfilgrastim Product and Filgrastim Product upon FDA approval. Apotex publicly states that
`
`the next step in the development process for its Pegfilgrastim Product and Filgrastim Product is
`
`to market it. See Apobiologix, R&D Overview, http://www.apobiologix.com/rd/default.asp (last
`
`visited on Aug. 1, 2018).
`
`JURISDICTION AND VENUE
`
`49.
`
`This action arises under the patent laws of the United States, Title 35 of the
`
`United States Code, and under the Declaratory Judgment Act of 1934 (28 U.S.C. §§ 2201-2202),
`
`Title 28 of the United States Code.
`
`14
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 15 of 25
`
`
`
`
`50.
`
`This Court has subject matter jurisdiction pursuant to 28 U.S.C. §§ 1331 and
`
`1338(a).
`
`51.
`
`Venue is proper in this Court pursuant to 28 U.S.C. §§ 1391(b) and (c), and 28
`
`U.S.C. § 1400(b).
`
`A.
`
`Apotex Inc.
`
`52.
`
`Apotex Inc. develops, manufactures, seeks regulatory approval for, markets,
`
`distributes, and sells biopharmaceuticals for sale and use throughout the United States, including
`
`in the State of Florida. See No. 0:15-cv-61631-JIC, D.E. 47 at 5 (S.D. Fla. Oct. 23, 2015); No.
`
`0:15-cv-61631-JIC, D.E. 64 at 4–5 (S.D. Fla. Dec. 1, 2015).
`
`53.
`
`This Court has personal specific jurisdiction over Apotex Inc. because Apotex
`
`Inc. has committed, or aided, abetted, contributed to and/or participated in the commission of,
`
`the tortious act of patent infringement that has led to foreseeable harm and injury to Amgen. In
`
`particular, Apotex Inc. collaborates with Apotex Corp. to develop, manufacture, seek approval
`
`for, and sell the disputed biosimilar products, which will cause tortious injury to Plaintiffs.
`
`54. Moreover, upon information and belief, Apotex Inc., following any FDA approval
`
`of the biosimilar product, will sell the Apotex Pegfilgrastim Product and the Apotex Filgrastim
`
`Product that is the subject of the patent infringement claims in this action in Florida and
`
`throughout the United States.
`
`55.
`
`This Court has personal general jurisdiction over Apotex Inc. by virtue of, inter
`
`alia, its having conducted business in this District, having availed itself of the rights and benefits
`
`of Florida law, and having engaged in substantial and continuing contacts with Florida. Upon
`
`information and belief, Apotex Inc. has regular and continuous commercial business dealings
`
`15
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 16 of 25
`
`
`
`
`with representatives, agents, distributors, and customers located in Florida and in this District,
`
`including with its subsidiary, Apotex Corp.
`
`56.
`
`Upon information and belief, Apotex Inc. exercises considerable control over
`
`Apotex Corp. with respect to biosimilar products and approves significant decisions of Apotex
`
`Corp., including designating Apotex Corp. as the agent for Apotex Inc. in connection with
`
`preparing and filing the Apotex aBLAs.
`
`57.
`
`Apotex Inc. submitted to the jurisdiction of this Court in the prior actions between
`
`Amgen and Apotex regarding the Apotex aBLAs. No. 0:15-cv-61631-JIC, D.E. 47 at 5–6 (S.D.
`
`Fla. Oct. 23, 2015); No. 0:15-cv-61631-JIC, D.E. 64 at 4–6 (S.D. Fla. Dec. 1, 2015).
`
`58.
`
`In addition, Apotex Inc. previously submitted to the jurisdiction of this Court and
`
`previously availed itself of this Court by filing suit in this jurisdiction and/or by asserting
`
`counterclaims in other civil actions initiated in this jurisdiction. See, e.g., Apotex, Inc. et al v.
`
`Mylan Pharmaceuticals, Inc., Case No. 12-cv-60704 (S.D. Fla. Apr. 20, 2012). Further, Apotex
`
`Inc.previously admitted that this Court has personal jurisdiction over both Apotex Corp. and
`
`Apotex Inc. See Alcon v. Apotex Inc. & Apotex Corp., C.A. No. 1:06-cv-01642, D.E. 23 at 7
`
`(S.D. Ind. Dec. 13, 2006) (“Plaintiffs could have brought this action in the S.D. Fla. because the
`
`S.D. Fla. has personal jurisdiction over both Defendants. Apotex Corp. has a principal place of
`
`business in Weston, Florida, while Apotex Inc. is a Canadian corporation that regularly conducts
`
`business in Florida. Thus, venue in the S.D. Fla. would also be proper.”).
`
`59.
`
`In the alternative, should Apotex Inc. contest jurisdiction in this forum, this Court
`
`has personal jurisdiction over Apotex Inc. under Fed. R. Civ. P. 4(k)(2) because, on information
`
`and belief, Apotex Inc. “is not subject to jurisdiction in any state’s courts of general jurisdiction,”
`
`and because “exercising jurisdiction is nevertheless consistent with the United States
`
`16
`
`

`

`Case 0:18-cv-61828-WPD Document 1 Entered on FLSD Docket 08/07/2018 Page 17 of 25
`
`
`
`
`Constitution and laws” given that Apotex Inc. has filed the Apotex aBLAs in the United States
`
`for a product that it intends to market in the United States.
`
`B.
`
`Apotex Corp.
`
`60.
`
`This Court has personal jurisdiction over Apotex Corp. by virtue of the fact that,
`
`inter alia, Apotex Corp. has a principle place of business within this judicial district, in Weston,
`
`Florida. See No. 0:15-cv-61631-JIC, D.E. 47 at 6 (S.D. Fla. Oct. 23, 2015); No. 0:15-cv-61631-
`
`JIC, D.E. 64 at 6 (S.D. Fla. Dec. 1, 2015).
`
`61.
`
`Apotex Corp. develops, manufactures, seeks regulatory approval for, markets,
`
`distributes, and sells biopharmaceuticals for sale and use throughout the United States, including
`
`in the State of Florida. See No. 0:15-cv-61631-JIC, D.E. 47 at 6 (S.D. Fla.