Patent Docs: Food and Drug Administration

Food and Drug Administration

November 11, 2024

Teva v. Amneal -- Amneal's Responsive Brief

The Federal Circuit has been petitioned by plaintiff Teva Branded Pharmaceutical Products R&D, Inc. to reverse a decision in favor of Defendant Amneal Pharmaceuticals, wherein the District Court entered an injunction ordering Teva to delist five Orange Book-listed patents, in Teva Pharms. Inc. v. Amneal Pharms. LLC. This post concerns Amneal's response to Teva's arguments in its Opening Brief.

To recap, the issues arose in litigation over Amneal's ANDA directed to its generic version of Teva's ProAir® HFA (albuterol sulfate) Inhalation Aerosol product. In this litigation, Teva asserted five Orange Book-listed patents: U.S. Patent Nos. 8,132,712 ("the '712 patent"), 9,463,289 ("the '289 patent"), 9,808,587 ("the '587 patent"), 10,561,808 ("the '808 patent"), and 11,395,889 ("the '889 patent") having these representative claims:

8,132,712:

1. A dose counter for a metered-dose inhaler, the counter comprising: an actuator; a rotary gear; a driver for driving the rotary gear in a step-wise fashion in response to displacement of the actuator, the rotary gear comprising a wheel mounted on a spindle which wheel having a plurality of ratchet teeth around its periphery; a pawl to prevent reverse rotation of the rotary gear; and a display coupled to the rotary gear, the display having a visible array of incrementing integers on a surface thereof indexable by a single integer in response to each step of the step-wise rotary motion of the rotary gear; wherein the pawl comprises at least two ratchet teeth each for engaging with the ratchet teeth of the wheel to prevent reverse rotation of the rotary gear, the at least two ratchet teeth being radially spaced such that one of the at least two ratchet teeth of the pawl engages with the ratchet teeth of the wheel following each step of the step-wise rotary motion of the rotary gear.

18. The use of a dose counter for preventing miscounting in a metered dose inhaler, the dose counter comprising: an actuator; a rotary gear; a driver for driving the rotary gear in a step-wise fashion in response to displacement of the actuator, the rotary gear comprising a wheel mounted on a spindle which wheel having a plurality of ratchet teeth around its periphery; a pawl to prevent reverse rotation of the rotary gear; and a display coupled to the rotary gear, the display having a visible array of incrementing integers on a surface thereof indexable by a single integer in response to each step of the step-wise rotary motion of the rotary gear; wherein the pawl comprises at least two ratchet teeth each for engaging with the ratchet teeth of the wheel to prevent reverse rotation of the rotary gear, the at least two ratchet teeth being radially spaced such that one of the at least two ratchet teeth of the pawl engages with the ratchet teeth of the wheel following each step of the step-wise rotary motion of the rotary gear.

9,463,289:

1. An inhaler for metered dose inhalation, the inhaler comprising:
    a main body having a canister housing,
    a medicament canister, which is moveable relative to the canister housing and retained in a central outlet port of the canister housing arranged to mate with a canister fire stem of the medicament canister, and
    a dose counter having an actuation member having at least a portion thereof located in the canister housing for operation by movement of the medicament canister,
    wherein the canister housing has an inner wall, and a first inner wall canister support formation extending inwardly from a main surface of the inner wall, and
    wherein the canister housing has a longitudinal axis X which passes through the center of the central outlet port,
    the inner wall canister support formation, the actuation member, and the central outlet port lying in a common plane coincident with the longitudinal axis X.

9,808,587:

1. An inhaler for metered dose inhalation, the inhaler comprising:
    a main body having a canister housing,
    a medicament canister, which is moveable relative to the canister housing and retained in a central outlet port of the canister housing arranged to mate with a canister fire stem of the medicament canister, and
    a dose counter having an actuation member having at least a portion thereof located in the canister housing for operation by movement of the medicament canister,
    wherein the canister housing has an inner wall, and a first inner wall canister support formation extending inwardly from a main surface of the inner wall,
    wherein the canister housing has a longitudinal axis X which passes through the center of the central outlet port, and
    wherein the first inner wall canister support formation, the actuation member, and the central outlet port lie in a common plane coincident with the longitudinal axis X such that the first inner wall canister support formation protects against unwanted actuation of the dose counter by reducing rocking of the medicament canister relative to the main body of the inhaler.

10,561,808:

1. A dose counter for an inhaler, the dose counter having a counter display arranged to indicate dosage information, a drive system arranged to move the counter display incrementally in a first direction from a first station to a second station in response to actuation input, wherein a regulator is provided which is arranged to act upon the counter display at the first station to regulate motion of the counter display at the first station to incremental movements.

11,395,889:

1. An incremental dose counter for a metered dose inhaler having a body arranged to retain a canister for movement of the canister relative thereto, the incremental dose counter having a main body, an actuator arranged to be driven and to drive an incremental output member in a count direction in response to canister motion, the actuator being configured to restrict motion of the output member in a direction opposite to the count direction, such that the actuator acts as an anti-back drive member when the actuator is in a non-depressed position, and wherein the incremental dose counter further comprises a second anti-back member configured to restrict motion of the output member in a direction opposite to the count direction when the actuator is disengaged from the output member by a bump surface.

The District Court granted Amneal's motion on the pleadings (asserted in its counterclaims as required by statute) that these patents were improperly listed in the Orange Book as not being directed to an FDA-approved drug nor method of using such a drug for treating a disease or disorder, and granted an injunction compelling Teva to delist these patents. Teva appealed, the Federal Circuit entering a stay on the order to delist during pendency of the appeal.

On appeal, Teva made two arguments: the first is based on a legal and technical definition of how the term "drug product" is defined in the statute, and the second is whether the District Court erred procedurally, including whether claim construction was required to properly determine the first question.

Amneal's Responsive Brief

In its responsive brief, Amneal (unsurprisingly) argues that the District Court made the right decision (and to be fair also has the easier argument, in view of the intrinsic tug of the argument that Orange Book-listed patents should, at a minimum, recite the drug product itself, in this case albuterol sulfate). In its argument, Amneal emphasizes (literally) that FDA's definition of a "drug product" recites "a finished dosage form…that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients," citing 21 C.F.R. § 314.3 (emphasis added) (in contrast to Teva, Amneal cites the FDA rules rather than the statutory language). Amneal contends that "the drug substance" is albuterol sulfate per se and not the combination of the drug and the inhaler that is the subject matter of the claims destined to be delisted if the District Court decision is affirmed. As Amneal states in its argument, "[i]t is undisputed, however, that the Asserted Patent claims do not recite, identify or refer to the drug substance—albuterol sulfate—as a part of the claimed inventions" (at least not expressly). Amneal argues that, to overcome these infirmities Teva and its amici (actually only two of seven amicus briefs filed) "seek in effect to rewrite the Listing Statute" by changing the plain meaning of the term "claims" therein to mean "reads on any part of" (which is an abbreviated but not entirely unfair characterization). Teva does indeed argue in its opening brief that the claims of its asserted patents read on its ProAir inhalation device, but that this is analogous to claims for excipients or generic claims that do not recite the species identified as the active pharmaceutical ingredient. Where Amneal identifies the principle distinction between the parties' positions is in the definition of the term "drug product," as will be set forth herein. Further, Amneal disputes the need for claim construction because "even if the claims were construed as Teva proposes, the Asserted Patents still would not qualify for listing in the Orange Book" as they do not recite albuterol sulfate as an affirmative limitation therein.

Amneal's brief identifies the legal issue in the appeal as being the proper construction of that portion of the statute that sets forth what must be disclosed in any patent listed in the Orange Book (21 U.S.C. § 355(b)(1)(A)(viii)):

(viii) the patent number and expiration date of each patent for which a claim of patent infringement could reasonably be asserted if a person not licensed by the owner of the patent engaged in the manufacture, use, or sale of the drug, and that—

(I) claims the drug for which the applicant submitted the application and is a drug substance (active ingredient) patent or a drug product (formulation or composition) patent; or

(II) claims a method of using such drug for which approval is sought or has been granted in the application.

Amneal's interpretation of this portion of the statute is that it requires any patent listed to be one wherein "there [would] be a reasonable basis to assert that the patent would be infringed by the unauthorized manufacture, use, or sale of the NDA drug" (emphasis added). The brief sets forth the history of this portion of the statute insofar as it was changed in 2021, purportedly due to an appreciation (evinced by a House committee report) of "the proliferation of device patents submitted under the auspices of the Listing Statute for drug device combination products, including, most commonly, inhalers," which delayed generic entry by an average of 3.4 years. Relevant to the issue before the Court, Amneal cites the definition of "drug product" in FDA regulations (but not the statute) to require the presence of the drug substance, citing 21 C.F.R. § 314.3: "Drug product is a finished dosage form, e.g., tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients (emphasis in brief)." The statute, on the other hand, defines the term "drug" broadly (according to Amneal) at 21 U.S.C. § 321(g)(1):

(A) articles recognized in [certain compendia]; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C).

and defines "device" at 21 U.S.C. § 321(h)(1) as:

[A]n instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including any component, part, or accessory, which is — (A) recognized in [certain compendia], (B) intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or (C) intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes.

As interpreted by the D.C. Circuit, "FDCA prohibits the FDA from treating a device as if it were a 'drug,'" citing Genus Medical Techs. LLC v. United States, 994 F.3d 631, 644 (D.C. Cir. 2021), "even though [Amneal concedes] the term 'drug' is so broadly defined that it linguistically could include a device." Amneal points out that the District Court held, consistent with the decision by the Second Circuit's decision in United Food v. Takeda Pharm. Co. Ltd., 11 F.4th 118, 134 (2d Cir. 2021), that "the Listing Statute required a drug product patent to claim not just any 'drug,' but specifically 'the drug for which the applicant submitted the application,'" nor did any of the asserted claims to inhaler devices qualify under the statute as a "finished dosage form."

Regarding the requirements for qualifying as a drug product Amneal's brief identifies three:

• "First, it must be a 'patent for which a claim of infringement could reasonably be asserted [against unauthorized] manufacture, use or sale' of the NDA product. 21 U.S.C. § 355(b)(1)(A)(viii). In other words, it must be infringed by the NDA product.

• "Second, the patent must be a 'drug product' patent, which simply means that it must claim a drug product. 21 U.S.C. § 355(b)(1)(A)(viii)(I) [although this seems to beg the question here].

• "Third, the patent must 'claim[] the drug for which the applicant submitted the application.""

Amneal argues that the second and third requirements act in tandem to require that the patents claim not just any drug product but the approved drug product itself. Under this interpretation, the Orange Book-listed claims must recite the drug product (here, albuterol sulfate) and as they undisputedly do not the Court should affirm the judgment of the District Court and lift the stay of the injunction compelling Teva to delist these patents.

Amneal argues that Teva's interpretation of these statutory provisions is erroneous, by being contrary to how the term "claims" is interpreted, inter alia, in Hoechst-Roussel Pharms., Inc. v. Lehman, 109 F.3d 756, 758-59 (Fed. Cir. 1997), and Graver Tank & Mfg. Co., Inc. v. Linde Air Prods. Co., 339 U.S. 605 (1950). Further, Amneal argues that this interpretation would render superfluous the requirement that the patent "claims the drug," contrary to statutory interpretation precedent citing Facebook, Inc. v. Windy City Innovations, LLC, 973 F.3d 1321, 1336 (Fed. Cir. 2020), and Arlington Cent. Sch. Dist. Bd. of Educ. v. Murphy, 548 U.S. 291, 299 n.1 (2006) in support for this argument. Also, Amneal argues, this overbroad reading of the statute would permit listing of patents for "any type of component, regardless of its nature." While conceding that "adjacent" provisions of the NDA statute permits "NDA applicants to submit information and samples of all components of the NDA drug" in Amneal's view what is permitted to be listed in the Orange Book is more narrow (it "does not broadly permit listing of any kind component patents" (emphasis in brief)). What is permitted is listing patents of only one kind, those that claim "a drug substance (active ingredient)" under 21 U.S.C. §355(b)(1)(A)(viii)(I), and Amneal argues that "this implies that patents on other kinds of drug components are not authorized," citing Syngenta Crop Protection, LLC v. Willowood, LLC, 944 F.3d 1344, 1361 (Fed. Cir. 2019) (emphasis added). Amneal objects to Teva's "plug[ging]" the "component" aspect of the definition of the term "drug" into the statute, due to the specificity of the statutory language for "the drug for which the applicant submitted the application." Citing Genus Medical Techs. again Amneal further argues that "the FDCA prohibits the FDA from treating a device as if it were a drug" and thus ("by extension") the statute should prohibit FDA from listing patents that claim only devices from being listed as if they claimed a drug.

Amneal argues that the plain meaning of the Listing Statute does not authorize listing of "any drug product" (emphasis in brief) but only if the patent "claims the [NDA] drug" under 21 U.S.C. § 355(b)(1)(A)(viii)(I) and further that this interpretation is supported by the legislative history (which indicates "congressional intent to curtail the listing of device component patents specifically"). This interpretation, Amneal argues, is also consistent with FDA's definition of a "drug product," the inclusion of which in the Listing Statute necessarily contains the NDA-approved drug product itself. (Amneal points out that in other contexts Teva itself argued that "drug product patents must require the presence of the active ingredient to qualify for listing in the Orange Book," citing Warner Chilcott (US), LLC v. Teva Pharms. USA, Inc., No. 18-1241 (Fed. Cir. 2018)). If a "drug product" requires the presence of an approved drug substance in the product, Amneal argues that a "drug product patent" must also do so (emphasis in brief), and if a drug product patent must also claim the FDA-approved drug, "at a minimum" such a patent "must . . . require the presence of the particular drug substance in the NDA product."

Taken together none of the asserted patents meet these requirements, Amneal asserts.

Turning to Teva's arguments, Amneal asserts they are "both erroneous and problematic" for four reasons: they "stray from controlling black letter patent law" under 35 U.S.C. § 112 and erroneously equating "claiming with being infringed"(emphasis in brief); the interpretation would make superfluous the "claiming the drug" requirement; Teva's arguments "ignore[] FDA's definition of 'drug product'"; and "would open up the Orange Book to patents on any aspect of the NDA product or any component that happens to be found in the NDA product." So doing would be contrary to the existence of the "powerful exclusionary rights bestowed on Orange Book patents" (naming an automatic preliminary injunction, i.e., the 30-month stay, and automatic permanent injunction for the prevailing NDA holder). Amneal also mentions that requiring Orange Book-listed patents to recite the approved drug product "provides a clear rule that will allow stakeholders to more confidently order their affairs when it comes to the listing of patents in the Orange Book" (elsewhere calling this a "commonsense notion").

Specifically, Amneal argues that the claims in an Orange Book-listed patent must recite the NDA-approved drug, not merely by infringed by the accused generic product as Teva contends, if only because Federal Circuit precedent, Hoechst-Roussel Pharms., Inc. v. Lehman, 109 F.3d 756, 758-59 (Fed. Cir. 1997), has acknowledged the statutory requirement that the patent "particularly pointing out and distinctly claiming the subject matter which the inventor . . . regards as the invention" under 35 U.S.C. § 112(b). Amneal makes a simple and straightforward argument, that because "the words of the claim do the claiming," citing Corning Glass Works v. Sumimoto Elec. U.S.A., Inc., 868 F.2d 1251, 1258 (Fed. Cir. 1989) (emphasis in brief), the absence of those words (specifically, of the NDA-approved drug substance, albuterol sulfate) precludes Teva from properly Orange Book listing the asserted claims. Once again, Amneal asserts the legislative history of amendments to the Listing Statute to illustrate Congress's concerns, including a direction to the General Accounting Office "to submit data on claims in listed patents 'that claim a device that is used for the delivery of the drug, but do not claim such device in combination with an active ingredient or formulation of a drug,'" Orange Book Transparency Act of 2020, Pub. L. No. 116-290, 134 Stat. 4889, 4892 (Jan. 5, 2021). This history, Amneal argues, also forms the basis for the Court to narrowly construe the Listing Statute, because it "demonstrates [that] these requirements were introduced expressly to preclude Orange Book listing of the very type of device patents at issue here." This "plain meaning" interpretative analysis is supported by the Takeda case from the Second Circuit and In re Lantus Direct Purchaser Antitrust Litig., 950 F.3d 1, 7-8 (1st Cir. 2020), relied upon by the District Court, Amneal argues. Amneal also cites a 1997 Guidance from FDA "explaining" that "a drug product patent must explicitly 'refer to' the NDA product," where Amneal contends "refer to" be interpreted to mean "recite in the claims" of such a patent. Teva's arguments that "being infringed" is equivalent to "claiming" is contrary to Federal Circuit precedent, Amneal argues, including Hoechst, and is not supported by the Apotex case, relied upon by Teva. In that case, Amneal argues, the Court merely held that infringement is a necessary, but not sufficient condition (emphasis in brief), and in any case Amneal contends, statements relied upon by Teva are merely dicta (because they were directed to whether the Federal Circuit had jurisdiction). Amneal similarly dismisses the relevance of Envirotech Corp. v. Al George, Inc., 730 F.2d 753, 759 (Fed. Cir. 1984), and Teva's proffered interpretation of Takeda.

Amneal further challenges Teva's construction of the Listing Statute as rendering the "claims the drug" requirement to be superfluous and that it is "far more expansive than afforded by a fair reading of the Listing Statute" so as to encompass "any component found in the [approved] NDA product" (emphasis in brief). Amneal challenges Teva's argument that requiring the "NDA drug substance" to be present would render the "drug substance" category superfluous, because the statute contains two categories of patents: "A drug substance patent requires only the drug substance per se, whereas a drug product patent requires both the drug substance and some further aspect(s) of the drug product." And the requirement is not merely for "a" drug but for "the" NDA-approved drug "for which the applicant submitted the application" under 21 U.S.C. § 355(b)(1)(A)(viii)(I), which is also the most unambiguous way of understanding the meaning of the term in the context of the Listing Statute, Amneal argues.

Amneal puts its greatest reliance in this regard on the Genus Medical Techs. LLC case, wherein the Court held that "the FDA is prohibited from regulating as a 'drug' anything that meets the statutory definition of a 'device,' even if that item also meets the definition of a 'drug'" because FDA is prohibited from Orange Book-listing patents that claim only a device, Amneal argues. ("Teva's interpretation cannot be correct, because it would permit precisely what the FDCA prohibits.") Devices are not drug formulation "ingredients" (which can be listed under the category as components of a "formulation" or "composition") in Amneal's view.

Amneal also addresses Teva's attempts to overcome ("decouple") the undisputed absence of any mention of the drug substance, albuterol sulfate, from the asserted claims of the Orange Book-listed patents at issue. Simply put, the proper consequence of this absence is for the Court to recognize that these patents to not "claim" the NDA drug product and thus should be delisted, according to Amneal.

Amneal further argues that its interpretation of the Listing Statute "best aligns" with Hatch-Waxman Act goals regarding the balance between exclusivity for brand drugmaker's NDA-approved drugs (and the "extraordinary" injunctive rights conferred by the statute) and opportunities for generic competition. Adopting Teva's interpretation of the Listing Statute, on the other hand, would permit "patents having nothing to do with the drug development efforts for a given product" to be listed in the Orange Book "as long as the claimed invention, no matter how inconsequential, was found in some part of the NDA product." And Teva (in addition to listing the asserted patents in this litigation in connection with 21 different products) retains the right to assert them against generic drugmakers under other subsections of 35 U.S.C.§ 271, albeit without the extraordinary advantages conferred by 35 U.S.C.§ 271(e)(2).

Finally, in this regard Amneal rebuts Teva's "baseless and hyperbolic" policy arguments (which will be discussed in future posts on the two amicus briefs submitted in support of Teva).

Amneal asserts in a separate section of the brief that the claims of any properly Orange Book-listed claims must recite the presence of the approved drug, albuterol substrate, and further that there is no need for claim construction because, on their face none of the listed patents asserted by Teva satisfy this requirement.

Teva's Reply to Amneal is discussed here.

Posted at 11:59 PM in Federal Circuit, Food and Drug Administration, Hatch-Waxman, Injunction | Permalink | Comments (0)

October 23, 2024

Teva v. Amneal -- Amneal's Responsive Brief & Teva's Reply Brief

By Kevin E. Noonan --

The Federal Circuit has been petitioned by plaintiff Teva Branded Pharmaceutical Products R&D, Inc. to reverse a decision in favor of Defendant Amneal Pharmaceuticals wherein the District Court entered an injunction ordering Teva to delist five Orange Book-listed patents, in Teva Pharms. Inc. v. Amneal Pharms. LLC. This post concerns Teva's Reply brief answering Amneal's Responsive brief to Teva's Opening Brief on appeal.

The District Court granted Amneal's motion on the pleadings (asserted in its counterclaims as required by statute) that these patents were improperly listed in the Orange Book as not being directed to an FDA-approved drug nor method of using such a drug for treating a disease or disorder and granted an injunction compelling Teva to delist these patents. Teva appealed, the Federal Circuit entering a stay on the order to delist during pendency of the appeal.

On appeal Teva made two arguments: the first is based on a legal and technical definition of how the term "drug product" is defined in the statute, and the second is whether the District Court erred procedurally, including whether claim construction was required to properly determine the first question.

Amneal's Responsive Brief

In its responsive brief, Amneal (unsurprisingly) argued that the District Court made the right decision (and to be fair has the easier argument, in view of the intrinsic tug of the argument that Orange Book-listed patents should, at a minimum, recite the drug product itself, in this case albuterol sulfate). In its argument, Amneal emphasized (literally) that FDA's definition of a "drug product" recites "a finished dosage form . . . that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients," citing 21 C.F.R. § 314.3 (emphasis added) (in contrast to Teva, Amneal cites the FDA rules rather than the statutory language). Amneal contended that "the drug substance" is albuterol sulfate per se and not the combination of the drug and the inhaler that is the subject matter of the claims destined to be delisted if the District Court decision is affirmed. As Amneal stated in its argument, "[i]t is undisputed, however, that the Asserted Patent claims do not recite, identify or refer to the drug substance—albuterol sulfate—as a part of the claimed inventions" (at least not expressly). Amneal argued that, to overcome these infirmities, Teva and its amici (actually only two of seven) "seek in effect to rewrite the Listing Statute" by changing the plain meaning of the term "claims" therein to mean "reads on any part of" (which is an abbreviated but not entirely unfair characterization). Where Amneal identified the principle distinction between the parties' positions was in the definition of the term "drug product." Further, Amneal disputed the need for claim construction because "even if the claims were construed as Teva proposes, the Asserted Patents still would not qualify for listing in the Orange Book" as they do not recite albuterol sulfate as an affirmative limitation therein.

Teva's Reply Brief

In Teva's Reply to Amneal initially the brief notes that FDA approved it ProAir HFA as a drug, that the inhaler component is the dosage form, and patents claiming dosage forms must be listed under 21 U.S.C. § 321(g)(1)(D). And this listing does precisely what the Hatch-Waxman regime intended: notifying generic drug applicants of the patents that can be asserted in ANDA litigation (i.e., it provides the intended statutory benefit to them). Teva continues by reasserting the consequences of affirming the District Court, including delisting "any genus patent, any patent that claims some but not all components of a drug product, and any patent that claims one but not all of the active ingredients in a drug product" (emphasis in brief).

Teva further reiterates its positions in its Opening Brief: that the statutory term "claim" should be interpreted to mean "read on" rather than "recite" (clearly a broader construction that resolves Teva's issue regarding the absence of the NDA-approved drug, albuterol sulfate, from the claims of the asserted patents); in this regard, Teva relies on the same precedent (and arguments) asserted in its Opening Brief. Teva rebuts Amneal's arguments regarding the definiteness requirement in the statute (35 U.S.C. § 112(b)) as not requiring express recitation of the NDA-approved drug but rather (citing the statutory language) that the claim "inform, with reasonable certainty, those skilled in the art about the scope of the invention," citing Nautilus, Inc. v. Biosig Instruments, Inc., 572 U.S. 898, 901 (2014). This requirement would not be necessary, Teva contends,"if the entire scope of a patent were explicitly recited in detail in the claims." Properly understood, what the statute entails is providing notice of the boundaries of the right to exclude and to define limits," Teva argues, citing Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1348 (Fed. Cir. 2010) (en banc).

As applied to the Listing Statute, Teva asserts Jazz Pharms., Inc. v. Avadel CNS Pharms., LLC, 60 F.4th 1373, 1379 (Fed. Cir. 2023), for the principle that claims must be construed based on "not just 'the words of the claims themselves'" but also "the remainder of the specification, the prosecution history, and extrinsic evidence concerning relevant scientific principles, the meaning of technical terms, and the state of the art," citing Phillips v. AWH Corp., 415 F.3d 1303, 1314 (Fed. Cir. 2005) (en banc) (citation omitted). Teva, in making this argument, seeks (it appears) to refute Amneal's more straightforward argument that the absence of any recitation of the NDA-approved drug in the asserted claims is dispositive. "'Claim language, standing alone' is not the correct standard of law and is contrary to uniform precedent" Teva asserts, quoting Nature Simulation Sys. Inc. v. Autodesk, Inc., 50 F.4th 1358, 1364 (Fed. Cir. 2022). "Claim language," Teva asserts, "is a boundary, not a laundry list" and "[a] genus claim unambiguously encompasses every species in the genus without mentioning any one of them." This is where Teva asserts Amneal errs in its responsive brief.

Teva first argues that its asserted patents "claim" a drug so long as it claims a component of the FDA-approved drug product. Citing Apotex, Teva argues that "[t]he listing decision thus requires what amounts to a finding of patent infringement [literal infringement, Teva specifies], except that the 'accused product' is the drug that is the subject of the NDA." Amneal doesn't address this, Teva asserts, and thus its attempts to "make something of the modest distinctions between the scope of a claim and the scope of infringement fall flat." This conclusion is supported, Teva asserts, by Teva Pharms. USA, Inc. v. Leavitt, 548 F.3d 103, 106 (D.C. Cir. 2008), and In re Actos End-Payor Antitrust Litig., 417 F. Supp. 3d 352, 369 (S.D.N.Y. Sept. 30, 2019). Teva rebuts Amneal's attempts to distinguish Apotex, construing the language of the statute to support its interpretation (and rebutting Amneal's dismissal of Apotex as dicta because that court's decision was directed to interpreting the Listing Statute to determine whether the case raised a substantial question of patent law for jurisdictional purposes). Teva also asserts the Jazz Pharma case as supporting its interpretation of the Apotex decision.

On somewhat less firm grounds, Teva argues that a patent that claims a component of an NDA drug claims "the drug" based on the express definition of the term "drug" under 21 U.S.C. § 321(g)(D). After distinguishing Amneal's (and the FTC's) analogy to construing claims to car brakes to encompass the car itself, Teva argues that "the term 'drug' is expressly defined to include its components" unlike the hypothetical car. Teva also addresses the distinctions raised by Amneal regarding statutory language to "drugs" and "drug substance" patents and conflicts between them (as well as Congress's amendments to the statute to include as listable drug substance as well as drug patents, citing Helsinn Healthcare S.A. v. Teva Pharms. USA, Inc., 586 U.S. 123, 131-32 (2019). (Indeed, Teva argues that some of these statutory changes were motivated by "a unique requirement to list patents claiming polymorphs" and, accordingly, "not all drug substance patents will also qualify as drug product patents." Teva states that (incorrectly) Amneal argues that "a patent on a component, including a drug substance, cannot be a 'drug product patent'" where according to Teva's interpretation of the statute "FDA recognizes that there is." Teva further argues that there is no "incongruity" between there being a broad definition of the term "drug" and the phrase "claims the drug for which the applicant submitted the application" in the statute because (in Teva's interpretation) this merely ensures that an applicant cannot list patents that claim "a" drug but claims the NDA-approved drug product. But this interpretation "does not rule out patents on the components that are submitted to FDA" which, Teva argues, is the situation here.

Teva also insists that FDA approved its ProAir HFA product as a drug, not a device. If Amneal (or its supportive amici) believe this is not the proper policy then this is an issue for Congress not the courts, Teva argues, because the statute mandates that FDA treat combination products as drugs "in their entirety" (under a single application whenever appropriate" under 21 U.S.C. § 353(g)(1)(B)). Contrary to Amneal's argument, Teva asserts that "FDA does not regulate 'the device part' of a combination product as a device on its own [but r]ather, a combination product in its entirety is regulated either as a drug or as a device, and the statutory scheme expressly contemplates that the device parts will sometimes be regulated as drug under 21 U.S.C. § 353(g)(1). (Indeed, Teva maintains that Congress amended the statute in 1990 to "remove the exclusion of devices and their counterparts to 'facilitate the regulation of combination products,' as drugs," citing Genus Medical Technologies LLC v. FDA, 994 F.3d 631, 644 (D.C. Cir. 2021), and the Safe Medical Devices Act of 1990, Pub. L. No. 101-629, § 16(b), 104 Stat. 4511, 4526 (Nov. 28, 1990).

Teva also disputes Amneal's arguments that its interpretation of the Listing Statute renders come provisions to be surplusage. With regard to the statutory phrase "claims the drug" Teva argues that FDA has excluded "[p]atents claiming packaging, patents claiming metabolites, and patents claiming intermediates." These patents may indeed raise infringement liability under the infringement clause of the Listing Statute but they cannot raise liability under the "claims the drug" clause, citing Hoechst-Roussel Pharms., Inc. v. Lehman, 109 F.3d 756, 759 & n.2 (Fed. Cir. 1997), for patents claiming metabolites, for example. Nor should the Court find persuasive Amneal's arguments regarding other changes in the statute under the Orange Book Transparency Act of 2020, Pub. L. No. 116-290, 134 Stat. 4889 (2021), codified at 21 C.F.R. § 314.53(b)(1) because, Teva argues, "both the text and the legislative history refute the notion that Congress sought to change listing practices in the significant way Amneal hypothesizes." Regarding Congress's motivations and directions to the GAO related to this statutory change, Teva disputes Amneal's implications that Congress intended to prevent device patents from being Orange Book listed. Instead, Teva contends Congress was trying to determine the number of patents claiming the device-drug combination and those claiming the device per se (a heavily nuanced argument that comes perilously close to mimicking Amneal's contentions). Nevertheless, "[c]urrent regulation and practice is to list precisely the types of patents Amneal complains are at issue here," Teva argues, and (turnabout being fair play) Teva notes that "[u]ntil recently, Amneal itself recognized as much with respect to its patents on epinephrine injection products—which likewise did not mention the active ingredient."

Teva devotes a separate section to its arguments that the asserted patents are properly drug product patents. This basis for affirming the District Court asserted by Amneal in its responsive brief was not part of the court's legal reasoning below, Teva states (terming it "an afterthought"). Regardless, Teva argues that the argument "cannot be reconciled with the text of either the Delisting Statute or the Listing Statute" (emphasis in brief), inter alia, because "Congress did not provide for delisting patents on the basis that it does not claim a drug product," citing 21 U.S.C. § 355(j)(5)(C)(ii)(I) (and Teva argues the patents ordered to be delisted did claim a drug product by virtue of being combination patents). (Teva takes the opportunity to disparage the lack of legal reasoning, in its view, the FTC mustered in supporting Amneal's arguments in this regard, explicated in a detailed footnote.) This portion of Teva's argument reaches the important difference between the parties (and amici): while agreeing that a "drug product" is a "finished dosage form, e.g., tablet, capsule, or solution, that contains a drug substance, generally, but not necessarily, in association with one or more other ingredients" under 21 C.F.R. § 314, does this definition include mechanical devices used to administer the drug? Teva's answer is expansive: a patent claims a drug product "if it reads on one or more components of a drug," in this case "whether albuterol sulfate, the propellant, the inhaler device, or the entire inhaler, with its constituent parts." Amneal contends that whatever else is claimed it must include the drug substance itself: "because a drug product contains a drug substance, it insists that every drug product patent must expressly recite a drug substance (i.e., active ingredient)." Teva's argument is bound up with the definitions and legal strictures of the relevant statutes ("the relevant regulation defines a 'drug product' as 'contain[ing] a drug substance, generally, but not necessarily, in association with one or more other ingredients," citing 21 C.F.R. § 314.3(b) (emphasis in brief)). In contrast, Amneal's position is a simple and straightforward one: how can a patent claim a drug product if the claims do not recite the drug substance itself?

Teva also disputes whether its asserted patents are "formulation or composition" patents. Teva claims they are, relying on FDA rules having "expressly recognized" that metered aerosols can be listed as "finished dosage forms." Teva cannot rely on FDA definitions for the term "composition" (Teva's brief concedes there isn't one) and falls back on patent law definitions of "compositions of matter" as "all compositions of two or more substances and all composite articles, whether they be the results of chemical union, or of mechanical mixture, or whether they be gases, fluids, powders, or solids," citing In re Nuijten, 500 F.3d 1346, 1357 (Fed. Cir. 2007), and Jazz Pharms. This language indicates that "composition patents" include patents on "composition articles" which easily (for Teva) includes "multiple physical components," citing, of all things, Ass'n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 591 (2013). Importantly here Teva argues that this use of the term is consistent with how the FDCA statute and FDA regulations use the term "component" with regard to drug products. And Teva points out that what Amneal (and the FTC) define as a composition (i.e., "a mixture of active and inactive ingredients") is more properly termed a formulation, citing HZNP Meds. LLC v. Actavis Lab'ys UT, Inc., 940 F.3d 680, 683 (Fed. Cir. 2019), for this distinction (supported in a footnote by reference to the Hatch-Waxman letter, cited by Amneal, to the effect that "a formulation patent as a subcategory of composition patents" at https://www.fda.gov/media/149035/download?attachment.)

The brief then addresses Teva's assertion that at a minimum claim construction is required, which the District Court pointedly did not perform. Teva maintains its position that "a patent can claim an active ingredient without naming it," citing genus claims as an example (emphasis in brief). Again here Teva takes the opportunity to denigrate the FTC's position (reminding the reader that it is "an agency with no specialized patent knowledge") that "limitations cannot be imported into the claims" (emphasis in brief), stating that claim construction is needed to ascertain properly whether the limitation is present in the claim in the first place.

Finally, Teva restates its contentions that following Amneal's arguments will "destabilize the Hatch-Waxman regime" because the line drawn to balance the rights of branded drugmakers and their generic counterparts is one for Congress, not the courts to set down, citing PDS Consultants, Inc. v. United States, 907 F.3d 1345, 1360 (Fed. Cir. 2018). Here, Congress had drawn the line, Teva argues, so that its patents are properly listed. The brief calls "deeply flawed" arguments by Amneal and certain amici that permitting patents like the ones at issue here to be Orange Book-listed "stifles generic competition." One reason is, Teva maintains, that "FDA typically takes more than 30 months to review an ANDA, meaning that the [statutory 30-month stay] does not actually delay approval" (although to be fair it cannot be said that the ANDA litigation process under §271(e)(2) accelerates approval, either). Teva argues that this case illustrates that the current situation does not prevent generic competition because "[m]ultiple generic versions of ProAir HFA are already on the market; the first [being] approved in 2020" and Teva itself is marketing an authorized generic version of its branded ProAir HFA inhaler. Teva extols the benefits of the Hatch-Waxman regime and its "highly ordered process" in contrast to "chaotic, hurried, and risky preliminary-injunction proceedings" arising from § 271(a) litigation proceedings. Lost will be the notice provisions provided by Orange Book listing Teva asserts, an outcome warned against by the Association for Accessible Medicines in a comment to FDA stating that "[i]nformation on those device-related patents that 'read on' the approved drug product and that is subsequently listed in the Orange Book would be beneficial to the generic drug industry by allowing the normal pre-approval patent resolution to take place . . . ."

The views of several amici will be discussed in future posts.

Posted at 09:44 PM in Federal Circuit, Food and Drug Administration, Hatch-Waxman, Injunction | Permalink | Comments (0)

October 17, 2024

Teva Pharms. Inc. v. Amneal Pharms. LLC (D.N.J. 2024)

By Kevin E. Noonan --

8,132,712:

9,463,289:

9,808,587:

1. An inhaler for metered dose inhalation, the inhaler comprising:
    a main body having a canister housing,
    a medicament canister, which is moveable relative to the canister housing and retained in a central outlet port of the canister housing arranged to mate with a canister fire stem of the medicament canister, and
    a dose counter having an actuation member having at least a portion thereof located in the canister housing for operation by movement of the medicament canister,
    wherein the canister housing has an inner wall, and a first inner wall canister support formation extending inwardly from a main surface of the inner wall,
    wherein the canister housing has a longitudinal axis X which passes through the center of the central outlet port, and
    wherein the first inner wall canister support formation, the actuation member, and the central outlet port lie in a common plane coincident with the longitudinal axis X such that the first inner wall canister support formation protects against unwanted actuation of the dose counter by reducing rocking of the medicament canister relative to the main body of the inhaler.

10,561,808:

11,395,889:

On appeal, Teva makes two arguments: the first is based on a legal and technical definition of how the term "drug product" is defined in the statute, and the second is whether the District Court erred procedurally, including whether claim construction was required to properly determine the first question. That first question is the more difficult one, to the extent to which Teva must convince the Court that the 1st Circuit erred in the Lantus decision and the District Court erred in interpreting the 2nd Circuit's decision in the Takeda case, both of which were decided consistently with the decision against Teva by the District Court.

With regard to its statutory construction argument, Teva maintains that not only did it comply with the listing statute but that it was compelled by the statute to do so. "A drug product patent must be listed in the Orange Book for a specific NDA (i.e., a brand-name product) if the patent 'claims the drug for which the applicant submitted the application'" under 21 U.S.C. § 355(b)(1)(A)(viii)(I) according to Teva's brief. This argument can only be persuasive should "the drug for which the applicant submitted the application" be interpreted to encompass per se the inhaler device (and related administration-related accoutrement and not need to include express recitation of the drug administered thereby). That interpretation further depends on the Federal Circuit being persuaded that the drug itself is impliedly contained in the claims to the "drug product," as interpreted by Teva, analogously to recitations of either genus claims to particular classes of drugs or more broadly to formulation claims reciting excipients and the like. Teva argues that accepting the arguments by Amneal (and their supportive amici) would greatly reduce the number of Orange Book-listed patents in ways that would harm the careful "balance'" struck under the Hatch-Waxman framework in disclosing to generic competitors (and the public) what patents could be asserted against ANDA-seeking drugmakers under 35 U.S.C. § 271(e)(2).

According to Teva, the District Court erred in what it means to claim a drug product, focusing not on that is recited in the claim but what generic drug product would be adjudged to be infringed. In the context of Orange Book listing, Teva argues that under the statute, that definition "includes not just an 'article' that treats an illness or affects the body's functioning, but also any 'component' of such an 'article'" under 21 U.S.C. § 321(g)(1)(B)-(D). This is because "FDA's rulemaking expressly contemplates that patents claiming a 'dosage form' will be listed in the Orange Book and identifies 'metered aerosols' like those at issue here as one example of a 'dosage form.'"

The brief relies on this definition of the term "drug" in the statute:

(A) articles recognized in the official United States Pharmacopoeia, official Homeopathic Pharmacopoeia of the United States, or official National Formulary, or any supplement to any of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals; and (C) articles (other than food) intended to affect the structure or any function of the body of man or other animals; and (D) articles intended for use as a component of any article specified in clause (A), (B), or (C).

21 U.S.C. § 321(g)(1) (italics emphasizing the portion of the statute expressly relied upon by Teva). This definition is both "express" and "expansive," Teva argues, and applies to the listing statute as well, according to the brief. Teva acknowledges that mere packaging cannot be listed but contends that its inhalers are part of the approved "finished dosage form" of the approved product and therefore the asserted patents to such inhalers et al. were properly listed. Inclusion of subsection (D) above "ensures that the term 'drug' will reach the entirety (any 'component') of any drug product (any 'article[]' used to treat disease)," Teva argues.

Relying on FDA regulations (68 Fed. Reg. 36,676, 36,680 (June 18, 2003)), the brief asserts that metered aerosols are "expressly categorized" as a dosage form, wherein 'drug delivery systems used and approved in combination with a drug'—a category that includes 'metered dose inhalers'—are distinguishable from the type of 'packaging and containers' that are not properly listed in the Orange Book," Teva citing Orange Book, Appendix C, at C- 1 (44th ed. 2024) in support for this argument. Moreover, Teva argues that "FDA classifies MDIs [metered dose inhalers] like ProAir as "single-entity combination products," meaning a drug and a device "combined or mixed and produced as a single entity," wherein "[c]ombination products 'constitute a combination of a drug, device, or biological product'" under 21 U.S.C. § 353(g)(1)(A)" that are "regulated either as a drug or a device" under 21 U.S.C. § 353(g)(1). Regarding MDIs, Teva argues that FDA has classified them as "drug-device combination products for which 'the primary mode of action . . . is attributable to the drug component,'" citing FDA guidance from 1993 (which states that "an aerosol delivery device will be considered a drug product . . . when the primary purpose of the device is delivering or aiding in the delivery of a drug and the device is distributed with the drug"). (This determination also applies to dose counters according to the brief.). In this way Teva contends the Court must treat the inhaler as it would an excipient or other component of a drug formulation covered under the statute and relevant FDA regulations because that is how FDA approved the combination.

The District Court, in Teva's telling, erred in ruling that the asserted claims must be delisted because none of those claims expressly recited the active ingredient of the drug product, albuterol sulfate, and did so without claim construction (despite the decision depending on whether the drug was claimed in any of the asserted claims). The brief also asserts that the District Court apparently vacillated "between stating that the claims must recite the active ingredient and stating that the claims must recite the full product itself," finally resting on the purported need for the claims to recite expressly albuterol sulfate. But Teva asserts another interpretation of the District Court's holding would require a properly Orange Book-listed patent would need to "recite every aspect of a drug (active ingredients, inactive ingredients, excipients, etc.)" which would permit listing only of "claim[s] with limitations explicitly directed to every part of the drug product [that] would satisfy the opinion," which would be "a dramatic narrowing of the scope of the Listing Statute and contrary to established law, citing in this regard Cadence Pharms. Inc. v. Exela PharmSci Inc., 780 F.3d 1364, 1369 (Fed. Cir. 2015), as an example.

Teva asserts that the statute requires that its claims must, under 21 U.S.C. § 355(b)(1)(A)(viii), claim "the drug for which the applicant submitted the application" and the test for whether this is the case is if the accused product would infringe the asserted claims ("The scope of what a patent 'claims' is effectively coterminous with the products that infringe a patent."). "Critically," the brief asserts (and this is the crux of whether Teva will be successful before the Federal Circuit), a "patent need not read on the entirety of a product to 'claim[]' the product," citing SunTiger, Inc. v. Sci Rsch. Funding Grp., 189 F.3d 1327, 1336 (Fed. Cir. 1999)("[i]f a claim reads merely on a part of an accused device, that is enough for infringement"), "[n]or, in the case of pharmaceuticals, must a patent recite the active ingredient by name in order to claim the drug" (basing this assertion on generic claims "whose active ingredient is one species within the genus," citing In re Omeprazole Patent Litig., 536 F.3d 1361, 1365-66 (Fed. Cir. 2008), and Indivior Inc. v. Dr. Reddy's Lab'ys, S.A., 930 F.3d 1325, 1349-50 (Fed. Cir. 2019)). Thus, Teva argues that the Federal Circuit has held that a patent that "'claims the drug for which the applicant submitted the application'—and therefore 'must be listed'— if it contains a product claim that reads on the drug that is the subject of the NDA,'" citing Apotex, Inc. v. Thompson, 347 F.3d 1335, 1343-44 (Fed. Cir. 2003). And under 21 U.S.C. § 321(g)(1)(D), that would include the claims Teva asserted before the District Court (because the term "drug" "covers the entirety of the drug product and any component thereof—not just the active ingredient"). This is because, Teva argues, the FDA-approved "drug product" is the ProAir HFA (the device in combination with albuterol sulfate) -- and "[t]he statutory scheme treats combination products like ProAir HFA as drug products where—as is the case with ProAir HFA—the product's 'primary mode of action' is that of a drug" under 21 U.S.C. § 353(g)(1)(D)(i).

The two "out-of-circuit" cases the District Court relied upon for its contrary determination -- United Food & Commercial Workers Local 1776 v. Takeda Pharmaceutical Co., 11 F.4th 118 (2d Cir. 2021), and In re Lantus Direct Purchaser Antitrust Litigation, 950 F.3d 1 (1st Cir. 2020) – either actually supported Teva's position (Takeda) or were wrongly decided (Lantus), the brief asserts. In the former case the court used an "infringement-type [judicial] analysis," which Teva argues was required but not performed by the district court. And the latter case (as did the District Court here) equated "claims" for a drug with "mention[ing]," the drug in the claims, which is Teva's basis for asserting error. The brief also notes that these were both antitrust cases, not patent cases, and as such did not address patent-specific issues important in this case. In Takeda, according to Teva, the Second Circuit adopted the approach Teva espoused, that "a patent claims any product that falls within the bounds of the claim—a determination that must be made through an infringement-type analysis." And that case was directed to a combination product, with the Second Circuit holding that a patent on only one component of the combination did not "read on" the approved drug comprising the combination. Regarding Lantus, which held that "if a patent 'do[es] not mention the drug for which the sNDA was submitted, the patent does not "claim the drug" under the Listing Statute,'" the District Court also did not perform claim construction. Moreover, Teva's brief contends "Lantus's reasoning is inapplicable by its own terms to Teva's claims directed to the entire inhaler product [because the] patent at issue in Lantus did 'not include a claim for an injector pen more broadly,' but rather 'mention[ed] that the drive mechanism is intended for use in a "drug delivery device"'" and in that case the listed claim, despite claiming "a device intended for use as an injector pen [did] not claim any injector pen" (rather it claimed merely a component part of the injector pen). In this case, "three of the Asserted Patents plainly claim the entire inhaler . . . and thus claim the equivalent of the injector pen—precisely what the court in Lantus thought was missing."

At a minimum, Teva argues, the District Court's decision was error because it was decided on the pleadings and not properly supported by claim construction, because the listing question is one of patent law needing "ordinary claim construction principles" to be applied in making a determination whether an accused infringing product infringes (and there is more to this analysis than "whether a claim name-checks the active ingredient or the drug" according to the brief). The brief cites several Federal Circuit decisions and those from other circuit courts, including Jazz Pharms., Inc. v. Avadel CNS Pharms., LLC, 60 F.4th 1373 (Fed. Cir. 2023); Biogen Int'l GmbH v. Mylan Pharms. Inc., 18 F.4th 1333, 1336 (Fed. Cir. 2021); Teva Pharmaceuticals USA, Inc. v. Leavitt, 548 F.3d 103 (D.C. Cir. 2008); Am. Bioscience, Inc. v. Thompson, 269 F.3d 1077, 1080 (D.C. Cir. 2001), for the primacy of this principle. Teva argues that the asserted claims in fact contain terms that encompass the active drug -- albuterol sulfate -- including "[a]n inhaler for metered dose inhalation" recited in the '289 and '587 patents; "medicament canister" recited in the '289, 587, and '712 patents; "an inhaler" recited in the '808 patent; "a metered dose inhaler" recited in the '889 and '712 patents; and "cannister" recited in the '889 patent.

These errors by the District Court require the Federal Circuit to vacate the judgment and remand for further consideration, Teva argues. Further Teva asserts that this would pose no burden on the District Court, which is construing claims in these patents during the litigation that has proceeded on other grounds not affected by the order to delist. And doing so would help clarify circumstances like this under the Hatch-Waxman framework, Teva argues, which is beneficial because it "facilitate[s] a scheme that allows the parties to obtain patent certainty before the launch of a drug, thereby supporting the development of both brand and generic medicines" (emphasis in brief); without doing so the consequence of the District Court's decision will result in "significant uncertainty and risk" because "many more infringement disputes would be resolved only after launch of a generic product, including preliminary injunction proceedings, a post-launch jury trial, and an award of money damages."

Teva concludes these arguments by imploring the Federal Circuit not to "disrupt" the balance struck by Congress that "[a]ll drug product patents must be listed in the Orange Book for every drug they claim, for as long as a claim of infringement can reasonably be made under those patents," and that "[t]raditional Paragraph IV invalidity and noninfringement challenges to those listed patents provide an expeditious pathway toward patent certainty." It must be said that the highest burden towards that end will be the ineluctable lure of the more simple-minded concept that claims not reciting the drug product should not be Orange Book listed, regardless of the nuances found in Teva's explication of the statute and FDA ruled implementing its provisions. The arguments against such statutory interpretations, by Amneal and almost all the amici, will be set forth in later posts.

Posted at 11:59 PM in District Court, Food and Drug Administration, Hatch-Waxman, Injunction | Permalink | Comments (0)

August 07, 2024

Amarin Pharma, Inc. v. Hikma Pharmaceuticals USA Inc. (Fed. Cir. 2024)

By Kevin E. Noonan --

The Federal Circuit once again had an opportunity to opine on the extent of behavior by a generic drugmaker who opts to accept a "section viii carve-out" in its FDA approval (resulting in a so-called "skinny label) on liability for inducing infringement in Amarin Pharma, Inc. v. Hikma Pharmaceuticals USA Inc.

The case arose over Amarin's Vascepa® (icosapent ethyl) drug product, an omega-3 fatty acid from fish oil, for treatment of severe hypertriglyceridemia (blood triglyceride levels at least 500 mg/dL; normal range is less than 150 mg/dL) (the "SH indication"). Amarin also later received approval for a second indication, reducing cardiovascular disease risk (wherein the second approval removed a Limitation of Use in this regard on the original label) (the "CV indication"). Hikma filed its ANDA against the first approved Vascepa® product; upon Amarin receiving its second FDA approval Hikma filed a section viii statement to carve-out the CV indication under 21 U.S.C. § 355(j)(2)(A)(viii) (the so-called "skinny label"). FDA approved Hikma's skinny label ANDA in 2020 not containing the CV Limitation of Use on the label.

Thereafter, in a series of press releases, Hikma asserted its product as a "generic version of Amarin's Vascepa®." In a particular press release, Hikma claimed its two-month U.S. sales to be $1.1 billion, a figure for all uses of its product, with up to 75% of these sales being for the putatively carved-out CV (off-label) indication (albeit there being other press releases emphasizing the limitation of FDA approval to the SH indication). And on Hikma's website, while asserting an AB rating for its product (generic approval for all indications on the label), the website also said "Hikma's generic version is indicated for fewer than all approved indications of the Reference Listed Drug."

In the ensuing litigation (this case), Amarin sued Hikma for inducement of infringement under 35 U.S.C. § 271(b) of Orange Book listed U.S. Patent Nos. 9,700,537 and 10,568,861 (for claim 1 of the '527 patent and claim 1 and 2 of the '861 patent):

'537 patent:

1. A method of reducing occurrence of a cardiovascular event in a hypercholesterolemia patient consisting of:
    identifying a patient having triglycerides (TG) of at least 150 mg/DL and HDL-C of less than 40 mg/dL in a blood sample taken from the patient as a risk factor of a cardiovascular event, wherein the patient has not previously had a cardiovascular event, and administering ethyl icosapentate in combination with a 3-hydroxy3-methylglutaryl coenzyme A reductase inhibitor,
    wherein said 3-hydroxyl-3-methylglutaryl coenzyme A reductase inhibitor is administered to the patient at least one of before, during and after administering the ethyl icosapentate; and wherein the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor is selected from the group consisting of pravastatin, lovastatin, simvastatin, fluvastatin, atorvastatin, pitavastatin, rosuvastatin, and salts thereof, and
    wherein daily dose of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor are 5 to 60 mg for pravastatin, 2.5 to 60 mg for simvastatin, 10 to 180 mg for fluvastatin sodium, 5 to 120 mg for atorvastatin calcium hydrate, 0.5 to 12 mg for pitavastatin calcium, 1.25 to 60 mg for rosuvastatin calcium, 5 to 160 mg for lovastatin, and 0.075 to 0.9 mg for cerivastatin sodium.

'861 patent:

1. A method of reducing risk of cardiovascular death in a subject with established cardiovascular disease, the method comprising administering to said subject about 4 g of ethyl icosapentate per day for a period effective to reduce risk of cardiovascular death in the subject.

2. The method of claim 1, wherein the subject has a fasting baseline triglyceride level of about 135 mg/dL to about 500 mg/dL and a fasting baseline LDL-C level of about 40 mg/dL to about 100 mg/dL.

In its complaint, Amarin asserted Hikma's press releases, website content, and product label as evidence of "specific intent to actively encourage physicians to directly infringe the asserted patents by prescribing its generic icosapent ethyl product for the off-label CV indication, an indication for which Hikma did not get FDA approval."

The District Court granted Hikma's motion to dismiss under Fed. R. Civ. Pro. 12(b)(6) for failure to state a claim in Amarin's complaint alleging inducement of infringement, based on its determination that the complaint failed to allege facts that Hikma had taken "affirmative steps" to induce infringement (a decision contrary to the recommendation of the magistrate judge to whom the district court judge referred the motion). The District Court judge cited the cautionary language in Hikma's label regarding side effects as "hardly instruction or encouragement" for the alleged off-label use and that removal of the CV Limitation of Use from Hikma's label would not have been persuasive that its product had been "shown to reduce cardiovascular risk" and thus to have "encourage[d] its use for that purpose." The distinction relied upon by the District Court was that "'merely describing an infringing [treatment] mode is not the same as recommending, encouraging, or promoting an infringing use,'" quoting, with alterations, Takeda Pharms. U.S.A., Inc. v. W.-Ward Pharm. Corp., 785 F.3d 625, 631 (Fed Cir. 2015). With regard to Hikma's press releases and other public statements, the District Court considered that while they "may be relevant to Hikma's intent to induce infringement" (emphasis in opinion), they were not evidence of "an inducing act" constituting a separate element for inducement under § 271(b). The website evidence was deemed insufficient because it did not "rise to the level of encouraging, recommending, or promoting taking Hikma's generic for the reduction of CV risk," comparing GlaxoSmithKline LLC v. Teva Pharms. USA, Inc., 7 F.4th 1320, 1336 (Fed. Cir. 2021) (per curiam) ("GSK"), with Grunenthal GmbH v. Alkem Lab'ys Ltd., 919 F.3d 1333, 1339 (Fed. Cir. 2019).

The Federal Circuit reversed in an opinion by Judge Lourie, joined by Chief Judge Moore and District Court Judge Albright (W.D. Tx), sitting by designation. The opinion begins by emphasizing that the matter below was not an ANDA case under 35 U.S.C. § 271(e)(2)(A), wherein the alleged infringement does not involve an infringing act other than filing the ANDA (what the opinion denotes as a "hypothetical" act of infringement, based on what would arise if the ANDA applicant received FDA approval and marketed the allegedly infringing generic drug). The panel also asserted that this is not a typical "skinny label" case under section viii wherein the plaintiff asserts the generic label isn't "skinny enough" and wherein "the label alone induces infringement," relying on H. Lundbeck A/S v. Lupin Ltd., 87 F.4th 1361, 1370 (Fed. Cir. 2023), and HZNP Meds. LLC v. Actavis Lab'ys UT, Inc., 940 F.3d 680, 699 (Fed. Cir. 2019). The basis for Amarin's assertions, in the Federal Circuit's view, is the combination of the skinny label and Hikma's "public statements and marketing" of its approved generic product (which the opinion states makes this "nothing more than a run-of-the-mill induced infringement case," a characterization perhaps motivated by the contretemps arising in its decisions in GSK, see "GlaxoSmithKline LLC v. Teva Pharmaceuticals USA (Fed Cir. 2020)" and "GlaxoSmithKline LLC v. Teva Pharmaceuticals USA (Fed. Cir. 2022)", and Hikma's assertions of the consequences that would arise if the Federal Circuit reversed, see below). In such a case, the standard the Court applied was "whether the totality of the allegations, taken as true, plausibly plead that Hikma induced infringement" (emphasis in opinion) that would provide "substantial evidence to support a jury verdict of induced infringement."

The panel noted that the case has come before them in a "nascent" stage, without the benefit of discovery or as an appeal of denial of a preliminary injunction motion or an appeal of a summary judgment motion or post-trial motion (citing several of the Court's earlier precedent on skinny label cases having those attributes). As a consequence, the Court stated it is responsible here for "reviewing allegations, not findings, for plausibility, not probability" under Bell Atl. Corp. v. Twombly, 550 U.S. 544, 556 (2007)(emphasis in opinion).

Turning to the evidence relied upon by the District Court in granting Hikma's motion, the opinion states as being "undisputed" that there has been direct infringement by doctors and other healthcare providers in prescribing Hikma's alleged infringing product for off-label use (the CV indication) and that Hikma had "the requisite intent and knowledge to induce that infringement" as found by the District Court. This leads the Court to determining whether Hikma "actively" induced healthcare providers' direct infringement. At least due to the analytical basis for reviewing motions to dismiss ("[a]ccepting all well-pleaded facts as true and drawing all reasonable inferences in Amarin's favor"), the opinion finds that it did. However, the panel discarded any implication that Hikma's label (the "Indications & Usage" section) provides "implied or express instruction to prescribe the drug for the CV indication."

The panel instead turned to the parties' contentions. First, Amarin's complaint alleged that other portions of Hikma's label (specifically, "the clinical studies section, which describes statin-treated patients with the same cardiovascular event history and lipid levels covered by the asserted patents") would teach physicians that the product could be prescribed for treating cardiovascular risk (because, inter alia, the patient populations for the SH and CV indications overlap). Moreover Amarin contended that while FDA approved removal of the CV Limitation of Use regarding CV indications from their label it did not do so for Hikma's label. Hikma's removal of the CV Limitation of Use regarding CV indications as well as including warnings of potential cardiovascular side effects from its drug, Amarin contended, communicated to physicians that its generic drug could be used off-label for the CV indication.

Hikma for its part argued that Amarin was asserting a requirement (and infringement liability for the absence thereof) for language discouraging infringement contrary to law, relying on Takeda Pharms. U.S.A., Inc. v. W.-Ward Pharm. Corp., 785 F.3d 625, 631 (Fed Cir. 2015). Hikma attempted to take refuge (as has arisen in other skinny label disputes) on FDA's requirement that the label for generic copies of branded approved drugs be "the same as the labeling approved for the listed drug" under 21 U.S.C. § 355(j)(2)(A)(v). Also, Hikma argued that its silence regarding its product's effects on risk of cardiovascular complications "cannot plausibly instruct infringement." Finally, Hikma argued that it is "implausible" and "borderline frivolous" to contend (as Amarin does) that information related to clinical studies and attendant warnings about side effects would encourage a physician to prescribe their drug.

The Federal Circuit conceded that Hikma's label does not "recommend[], encourag[e], or promot[e] an infringing use" as a matter of law as found by the District Court. But (agreeing with the magistrate judge) the Court (and Amarin) did not rely on the label alone. Rather, it is the combination (emphasis in opinion) of the label and Hikma's "public statements and marketing materials" that render the District Court's grant of Hikma's motion to dismiss to be in error. Specifically, the Court considered that while the "AB rating" description on Hikma's website may be broad enough to encompass both infringing and non-infringing uses (and thus not support a finding of inducement liability) their press releases consistently characterized their drug as being a "generic equivalent to Vascepa®" and cite the SH indication limitation as being only a part of their approved indication. These implications were supported by reports on sales figures resulting in large (75%) part from off-label use for CV indications. "Those allegations, taken together with those relating to Hikma's label, at least plausibly state a claim for induced infringement," the Court held.

Importantly, these allegations by Amarin regarding Hikma's inducement liability are, according to the opinion, "question[s] of fact—not law" and therefore are "not proper for resolution on a motion to dismiss." The panel asserted they "[we]re unpersuaded" by Hikma's arguments that, because these facts are not in dispute the District Court was correct in deciding to grant Hikma's motion to dismiss on legal grounds. And the opinion distinguishes earlier cases where inducement was decided as a matter of law on the procedural posture of one such case, wherein HZNP was decided ("critically") on summary judgment and was solely based on the contents of the label; the parties access to discovery placing this case (motion to dismiss) on a different footing, insofar as Amarin was entitled to having all factual considerations and inferences in its favor (finding Amarin's contentions on how Hikma's statements and representations could "plausibly" suggest to a physician that its drug was effective the CV indications). The panel also refused to interpret Hikma's representations regarding its AB rating for the drug as being sufficient to insulate it from inducing infringement liability.

The opinion also rejects Hikma's assertions that reversing the district court would be contrary to the Court's decision in GSK, distinguishing that decision on the basis of procedural differences (a motion to dismiss here with a post-trial judgment as a matter of law there) as well as substantive distinctions (there, the label itself taught an infringing use and hence "it was reasonable for the jury to find that the generic manufacturer's marketing of its product as an "AB rated generic equivalent" encouraged physicians to prescribe the drug for the infringing use instructed by the label"), which is not the case here. Here, Amarin was entitled to have all its allegations accepted as true in the context of a motion to dismiss, including their allegations that "Hikma did much more than call its product a 'generic version' of Vascepa" in the face of evidence of Hikma's other activities.

The opinion disdainfully rejects Hikma's "inflated characterizations" regarding the dire consequences for section viii carve-outs should the Court rule (as it does) against them. The opinion states its decision is "limited to the allegations before us" and "guided by the standard of review appropriate for this stage of proceedings," while pledging fealty to the "careful balance struck by the Hatch-Waxman Act regarding section viii carve-outs." The Court cautioned generic drugmakers that "clarity and consistency in a generic manufacturer's communications regarding a drug marketed under a skinny label may be essential in avoiding liability for induced infringement," which was not found here.

This case is remanded to the District Court where, absent settlement (unlikely in view of Hikma's $1 billion + annual sales) the Federal Circuit will likely have the opportunity to rule on the substantive questions regarding skinny label inducement raised by these circumstances.

Amarin Pharma, Inc. v. Hikma Pharmaceuticals USA Inc. (Fed. Cir. 2024)
Panel: Chief Judge Moore, Circuit Judge Lourie, and District Judge Albright (sitting by designation)
Opinion by Circuit Judge Lourie

Posted at 10:16 PM in Federal Circuit, Food and Drug Administration, Infringement - Contributory or Induced | Permalink | Comments (0)

March 07, 2024

FDA Approves Three Interchangeable Biosimilar Drugs in 2024

By Kevin E. Noonan --

After taking most of a decade to approve its first interchangeable biosimilar (Semglee (insulin glargine-yfgn), the U.S. Food and Drug Administration has approved three interchangeable biosimilars since the beginning of this year.

The first of these is simlandi (adalimumab-ryvk), approved on February 24th, made by Alvotech and Teva Pharmaceuticals, and interchangeable with Humira). The biosimilar, a TNF alpha inhibitor, was approved to be provided as a single-dose autoinjector delivering 40 mg/0.4 mL, for treating plaque psoriasis, Crohn's disease, ulcerative colitis, rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, hidradenitis suppurativa, and uveitis.

The FDA also approved on March 5th two interchangeable biosimilars from Sandoz for a pair of Amgen biologic drugs: Jubbonti (denosumab-bbdz), interchangeable for Prolia (denosumab), and Wyost (denosumab-bbdz), interchangeable for Xgeva (denosumb). Jubbonti was approved for increasing bone mass in men and women (inter alia due to chemotherapeutic treatment for prostate cancer (men) and breast cancer (women), for osteoporosis (induced by glucocorticoid treatment or otherwise) in men and women, and for preventing fracture in post-menopausal women with osteoporosis. Wyost was approved for treating patients with multiple myeloma and solid tumor bone metastases, giant cell bone tumors, and treatment of hypercalcemia of malignancy refractory to bisphosphonate therapy.

Both Prolia and Jubbonti have a boxed warning for increased risk of severe hypocalcemia (low blood calcium levels) in patients with advanced chronic kidney disease taking osteoporosis medicine.

With these approvals, there are a total of 48 biosimilars (and 10 interchangeable biosimilars) approved by the FDA since Zarxio was approved in March 2015.

Posted at 09:42 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (0)

January 28, 2024

FDA Approves Yet Another Interchangeable Biosimilar and Another Biosimilar

By Kevin E. Noonan --

On October 3, 2023, the U.S. Food and Drug Administration (FDA) announced approval of Biogen's Byooviz (ranibizumab-nuna) as an interchangeable biosimilar to Genentech's Lucentis (ranibizumab injection). The drug was approved for intravitreal injection for the following indications:

• Neovascular (Wet) Age-Related Macular Degeneration (AMD),
• Macular Edema Following Retinal Vein Occlusion (RVO), and
• Myopic Choroidal Neovascularization (mCNV).

Byooviz and Lucentis share administration route, dose (0.5 mg), and formulation (10 mg/mL). Byooviz had been previously approved as a biosimilar on September 20, 2021.

On December 6, 2023, the FDA approved Bio-Thera Solution's Avzivi (bevacizumab-tnjn) as a biosimilar to Genentech's Avastin (bevacizumab). This drug was approved for treatment of colorectal cancer, non-small cell lung cancer, glioblastoma, renal cell carcinoma, cervical cancer, and epithelial ovarian, fallopian tube, or primary peritoneal cancer. The biosimilar is available as 100 mg/4 mL (25 mg/mL) or 400 mg/16 mL (25 mg/mL) injections in a single-dose vial.

These approvals bring to 45 the number of approved biosimilar products of which seven are interchangeable.

Posted at 11:07 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (0)

December 27, 2023

FDA Approves Another Interchangeable Biosimilar

By Kevin E. Noonan --

Earlier this year, the U.S. Food and Drug Administration announced approval of Amgen's Wezlana (ustekinumab-auub) as an interchangeable biosimilar to Janssen Biotech's Stelara (ustekinumab). The drug was approved for multiple inflammatory disorders:

Adult patients with:

• moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy;
• active psoriatic arthritis;
• moderately to severely active Crohn's disease; and
• moderately to severely active ulcerative colitis.

Pediatric patients 6 years of age and older with:

• moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy; and
• active psoriatic arthritis.

Wezlana shares with Stelara a risk of increased infection, and has as side effects "nasopharyngitis, upper respiratory tract infection, headache, fatigue, nausea, vomiting, injection site erythema, vulvovaginal candidiasis/mycotic infection, bronchitis, pruritus, urinary tract infection, sinusitis, abdominal pain, influenza, fever and diarrhea." The biosmilar showed "no clinically meaningful differences from" Stelara and satisfied the requirements for interchangeable status under § 351(k)(2)(B) of the Public Health Service Act (codified in 42 U.S.C. § 262(k)(2)(B)).

This approval brings to 45 the number of approved biosimilar products of which five are interchangeable.

* Approved as interchangeable biosimilar

Posted at 11:48 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (2)

November 02, 2023

FDA Signals Willingness to Approve CRISPR-Based Treatment for Sickle Cell Anemia

By Kevin E. Noonan --

Ever since Watson and Crick ended their seminal Nature paper in 1953 by saying that: "It has not escaped our notice that the specific pairing we have postulated immediately suggests a possible copying mechanism for the genetic material," James Watson & Francis Crick, "Molecular Structure of Nucleic Acids; A Structure for Deoxyribose Nucleic Acid," Nature 171: 737-38 (April 25, 1953), it has been envisioned that identification of genetic mutations causing disease would someday provide a way to repair them to achieve a cure. Those hopes have only increased over the years since then, particularly in light of the ever-increasing genetic information that arose from cloning specific human genes in the late 1970's and the 1980's and even more so with the crowning achievement of the Human Genome Project at the turn of the century. Unfortunately, these hopes have not been fulfilled, in large part due to failures in successful introduction of unmutated genes into appropriate cells in patients suffering from genetic diseases. The causes for these failures are many, ranging from delivery of intact genetic constructs into these cells to stable insertion of the genes into the genome at a chromosomal location capable of efficient transcription under circumstances that did not result in inappropriate or disease-causing) expression of endogenous genes.

On October 31st, the U.S. Food and Drug Administration's Cellular, Tissue, and Gene Therapies Advisory Committee announced its recommendation that exagamglogene autotemcel (exa-cel) is safe for clinical use. This drug is the subject of biologics license application (BLA) 125787 from Vertex Pharmaceuticals, Inc. in collaboration with CRISPR Therapeutics (Zug, Switzerland) and provides for the first time gene therapy for sickle cell anemia. Sickle cell anemia was the first known human disease associated with a genetic polymorphism (an A→T single nucleotide polymorphism, or SNP), resulting in the substitution of a valine residue (encoded by a GTG codon) for a glutamic acid residue (encoded by a GAG codon) in the beta chain of human hemoglobin.* The Advisory Committee's announcement followed the FDA's earlier announcement on October 27th that exagamglogene autotemcel is effective, having 29 of 30 patients stay pain-free for 18 months.

The CRISPR-mediated effect on sickle cell disease from exa-cel is mediated by targeting the binding site of an inhibitor (BCL11a) of the gamma-globulin gene, which results in fetal globin expression that alleviates the symptoms of the disease. While there remains the possibility in some patients for "off-target" effects (some of which have been predicted by scanning human genomic DNA for such targets), the expected frequencies are low (1.6% according to David Altshuler MD, Vertex's Chief Science Officer). Scot Wolfe, PhD (UMass Chan Medical School), a member of the FDA advisory committee, voiced the sentiment that:

We don't want to let perfect be the enemy of the good. At some point we have to try things out in patients. There is a huge unmet need for sickle cell disease. It's important to advance therapies. I certainly think that this is one of them.

The FDA is scheduled to decide whether to approve the drug at a meeting scheduled for December 8th.

* The work, by Linus Pauling and colleagues at Cal Tech was published in the November 25, 1949 issue of the journal Science, about three and a half years before Watson and Crick deciphered the structure of DNA.

Posted at 10:32 PM in Food and Drug Administration | Permalink | Comments (0)

August 24, 2023

FDA Approves Sandoz Biosimilar for Tysabri®

By Kevin E. Noonan --

It was not so long ago that many, including members of Congress, were bemoaning the slow approval and introduction into the marketplace of biosimilar alternatives to (generally expensive) biologic drugs. See "Trump Administration Considering Reduction in Biologics Exclusivity Period"; "A Solution in Search of a Problem"; "FDA Issues Plan for Further Facilitating Biosimilar Development"; "Senators Ask FTC to Investigate Biosimilar Litigation Settlement Agreement"; "Biosimilars Action Plan: Balancing Innovation and Competition"; "Congress Jumps on Bandwagon to Reduce Biologic Drug Exclusivity Term". These sentiments were largely from outcome-oriented groups with little understanding or regard for process or an appreciation of what has been required of the U.S. Food and Drug Administration and biosimilar applicants to bring safe and effective biosimilar drugs to market (and to be sure the same chorus would be vocally critical should a biosimilar fail to be safe, effective, and cheaper than the reference biologic drug product). These calls have only intensified in the wake of the COVID pandemic (see, e.g., S6: The Biosimilar Red Tape Elimination Act, introduced on November 17, 2022; "Interchangeable Biosimilars: In a Battle of Safety vs. Cost, Where Does Sen. Lee Stand?").

Things have been looking up with a half dozen biosimilar drugs having been allowed in the past year (see Table). The most recent is Tyruko (natalizumab-sztn) from Sandoz, whose approval was announced by the FDA and is a biosimilar for Biogen's Tysabri (natalizumab) approved for the treatment of relapsing forms of multiple sclerosis (MS), specifically clinically recognized forms of the disease that includes clinically isolated MS, relapsing-remitting MS (West Wing viewers will recognize this as the form President Bartlet suffered from), and active secondary progressive MS.

According to the announcement, in addition to MS the drug is approved for "inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn’s Disease (CD) with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α (tumor necrosis factor)."

The announcement contains a caution, that use of Tyruko, like Tysabri, is associated with an increased risk of progressive multifocal leukoencephalopathy (PML), "a viral infection of the brain that usually leads to death or severe disability." For this reason availability of the drug is limited by a risk evaluation and mitigation strategy (REMS).

This approval brings to 42 the number of approved biosimilar products.

* Approved as interchangeable biosimilar

Posted at 09:28 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (0)

May 15, 2023

Solicitor General Files Brief Advocating Certiorari Grant in Teva Pharmaceuticals v. GlaxoSmithKline; Court Declines Invitation

By Kevin E. Noonan --

Today, the Supreme Court again disregarded the views of the Federal government regarding whether to grant certiorari, here in Teva Pharmaceuticals USA v. GlaxoSmithKline LLC, and in some ways the only positive outcome is that the Court has shown it is willing to refuse to take action is cases other than subject matter eligibility (although Justice Kavanaugh indicated he would have granted the petition). Perhaps the Justices felt that the Federal Circuit's backtracking in its second panel decision on the breadth of infringement inducement set forth in its first decision, in light of then Chief Judge Prost's strong dissent and the firestorm of protest (public and through amicus briefing regarding Teva's petition for rehearing), was enough to cabin the decision to the somewhat unique facts in this case. Nevertheless, consideration of the Solicitor General's arguments is sufficiently important to review them here despite the Court's decision not to do so.

The Federal Circuit's decisions, rendered separately (see "GlaxoSmithKline LLC v. Teva Pharmaceuticals USA, Inc. (Fed. Cir. 2020)" and "GlaxoSmithKline LLC v. Teva Pharmaceuticals USA (Fed. Cir. 2021)") over strong dissents by former Chief Judge Prost in both instances, regarding whether a generic applicant filing a "skinny label" ANDA could properly be found liable for inducing infringement under 35 U.S.C. § 271(b) led, not surprisingly, to a petition to the Supreme Court for certiorari. The Court issued an Order to the Solicitor General soliciting the government's views and that brief was filed in March, advocating that the Court grant cert.

The matter arose in litigation over GSK's Coreg^® product (carvedilol) for treatment of hypertension (the initial approved indication; U.S. Patent No. 4,503,067), congestive heart failure (CHF) (the subject of U.S. Patent No. 5,760,069), and left ventricular dysfunction following myocardial infarction (LVD-MI). The '069 patent recites a method of treating CHF with a combination of carvedilol and "one or more of an angiotensin-converting enzyme ("ACE") inhibitor, a diuretic, and digoxin."

Teva's ANDA was filed with a Paragraph III certification over the '067 patent and a Paragraph IV certification over the '069 patent. The FDA tentatively approved Teva's generic product for "treatment of hypertension and heart failure" which Teva launched on expiration of the '067 patent. Teva's label indicated that the product was approved for treatment of LVD-MI and hypertension and announced that the FDA had given its product an "AB rating" (which the opinion explained "allow[s] users to determine quickly whether the Agency has evaluated a particular approved product as therapeutically equivalent to other pharmaceutically equivalent products"). Thereafter, the FDA required Teva to amend its label to be identical to the GSK label for Coreg®, which introduced treatment of heart failure into the approved treatments recited in Teva's label.

GSK filed for reissue of the '069 patent which was duly granted by the U.S. Patent and Trademark Office as Reissue Patent No. RE40,000; claim 1 is representative of the invention as claimed in the '000 reissue patent:

1. A method of decreasing mortality caused by congestive heart failure in a patient in need thereof which comprises administering a therapeutically acceptable amount of carvedilol in conjunction with one or more other therapeutic agents, said agents being selected from the group consisting of an angiotensin converting enzyme inhibitor (ACE), a diuretic, and digoxin,
wherein the administering comprises administering to said patient daily maintenance dosages for a maintenance period to decrease a risk of mortality caused by congestive heart failure, and said maintenance period is greater than six months.

(where the italicized portion of the claim represents the modifications introduced in prosecution of the reissue application.)

GSK filed suit against Teva for inducement of infringement in light of the Teva label, based on direct infringement by physicians prescribing the drug for the label indications. Teva argued that it had "carved out" the indication for CHF pursuant to 21 U.S.C. § 355(j)(2)(A)(viii), resulting in a "skinny label" with regard to this indication. Thereafter, the FDA compelled Teva to amend its label to include that indication. In addition, Teva argued that it could be liable for inducement only if GSK could show that Teva had "directly communicated with the direct infringers and 'caused' them to directly infringe the method in the '000 patent." In an instruction, the District Court informed the jury that circumstantial evidence could be used to satisfy this burden.

The jury found that Teva induced infringement of the '000 reissue patent both before and after the label amendment (albeit infringing several claims after but not before that change). The District Court granted Teva's motion for judgment as a matter of law (JMOL) on the basis that GSK had not "caused" physicians to prescribe their product for the infringing uses. Because proof of such causation was required, according to the District Court, its absence precluded the jury from having substantial evidence in support of its decision. The Court relied on the "many sources of information available to prescribing physicians" other than Teva's label (including paradoxically GSK's label and promotion of its Coreg® product) in finding this evidentiary deficiency. Also, the Court based its decision on physician testimony that their prescribing behavior relied on "guidelines and research, as well as their own experience" and not Teva's label. "In sum," the Court said, "substantial evidence [did] not support the jury's finding on causation, and therefore [did] not support its verdict that Teva is liable for induced infringement, during both the skinny and full label periods."

In a first appeal, the Federal Circuit reversed, in an opinion by Judge Newman joined by Judge Moore; Chief Judge Prost provided a lengthy, comprehensive dissent. The panel majority relied on the Supreme Court's decision in Global-Tech Appliances, Inc. v. SEB S.A., 563 U.S. 754 (2011), that copying is evidence of inducement, and also found compelling evidence from Teva's website regarding its product's AB rating with GSK's Coreg® product and other promotional content, as well as testimony from GSK's witnesses regarding physician reliance on information from generic drug makers.

The panel majority opined that the District Court erred in applying the incorrect legal standard, stating that "precedent makes clear that when the provider of an identical product knows of and markets the same product for intended direct infringing activity, the criteria of induced infringement are met." Considering this precedent, the majority held that "[t]here was ample record evidence of promotional materials, press releases, product catalogs, the FDA labels, and testimony of witnesses from both sides, to support the jury verdict of inducement to infringe the designated claims for the period of the '000 reissue patent."

Then-Chief Judge Prost dissented based on her objections to the quanta of evidence adduced and policy consequences should the majority's position be sustained. In the then-Chief's view, the majority's decision undermined the policy goals, embodied in the provisions of the law regarding skinny labels, for balance between the incentives patents provide for pharmaceutical innovation and the public's need for access to that innovation once the patent term has expired. In her view, the majority's decision undermined these policy goals by finding Teva induced infringement by marketing its generic drug produce for unpatented uses (emphasis in dissent) using its skinny label. The dissent not only disagreed with the majority's decision, but apprehended it to "nullify[y] Congress's statutory provision for skinny labels—creating liability for inducement where there should be none," contrary to Congressional intent and "slowing, rather than speeding, the introduction of low-cost generics."

The original majority opinion occasioned an outpouring of outrage from industry groups (particularly generic ones) who latched onto the then-Chief Judge's rhetoric in her dissent to the effect that the opinion eviscerated the congressional sanctioning of skinny labels. The Court granted panel rehearing that resulted in the second opinion (that was later the subject of the Court's denial of en banc review).

The outcome did not change in the second opinion, which recited with approval behavioral distinctions underpinning the majority's decision based on the law with regard to skinny labels:

Generics could be held liable for actively inducing infringement if they marketed a drug with a label describing a patented therapeutic use or if they took active steps to encourage doctors or patients to use the drug in an infringing manner. But generics could not be held liable for merely marketing and selling under a 'skinny' label omitting all patented indications, or for merely noting (without mentioning any infringing uses) that FDA had rated a product as therapeutically equivalent to a brand-name drug [emphasis in original].

Stating that the panel (or at least the majority) agreed to rehear arguments "to make clear how the facts of this case place it clearly outside the boundaries of the concerns expressed by amici," the opinion stated that the basis for their decision that the jury correctly found Teva liable for inducing infringement was "by marketing a drug with a label encouraging a patented therapeutic use" (emphasis in opinion). The opinion also stated more precisely the procedural basis for their opinion: "[t]his is a case in which substantial evidence supports a jury finding that the patented use was on the generic label at all relevant times and that, therefore, Teva failed to carve out all patented indications." The majority also emphasized that their decision was a "narrow, case-specific review of substantial evidence [that] does not upset the careful balance struck by the Hatch-Waxman Act regarding section viii carve-outs." The remainder of the majority opinion set forth (extensively) the evidentiary basis for their opinion that there was sufficient evidence (including expert testimony and marketing efforts occurring both before and after FDA-mandated changes to Teva's label) to satisfy the substantiality standard, and that the District Court erred in granting Teva JMOL to the contrary (inter alia including specific errors in treating factual questions as legal ones that the majority state were "not this court or the district court, to resolve").

Former Chief Judge Prost remained unconvinced, in large part because this outcome (in her view) undermined the congressionally sanctioned skinny label regime (if only by rendering it much more case- and fact-specific than she perceived Congress intended). The skinny label regime was Congress's solution to a "problem" it "saw coming" in Judge Prost's view, specifically that "[b]ecause the FDA cannot authorize a generic version of a drug that would infringe a patent, this one remaining patented use could have prevented a less-expensive, generic carvedilol from coming to market altogether—even though the drug itself and other uses of it were unpatented." The majority's decision thwarted this intent, according to Judge Prost, based on evidence of inducement that was "thin to nonexistent." The District Court had properly exercised its supervisory role in remedying a situation where a jury came to the wrong conclusion, Judge Prost concluded, based on her evaluation of the evidence before it. The Judge set forth her motivation for writing (once again) in dissent (and that the majority's attempt to provide a comforting standard falls short in her opinion):

I write in this case because far from being a disagreement among reasonable minds about the individual facts, this case signals that our law on this issue has gone awry. I am particularly concerned with three aspects of the majority's analysis. First, even setting aside the majority's willingness to glean intentional encouragement from a label specifically designed to avoid encouragement, the majority further weakens the intentional-encouragement prong of inducement by effectively eliminating the demarcation between describing an infringing use and encouraging that use in a label. Second, the majority defies basic tort law by eviscerating the causation prong of inducement. The upshot of these two moves is that a plaintiff now has to show very little for a jury to speculate as to the rest. Third, the majority creates confusion for generics, leaving them in the dark about what might expose them to liability. These missteps throw a wrench into Congress's design for enabling quick public access to generic versions of unpatented drugs with unpatented uses.

The decision by the full Court not to rehear the case en banc was announced in a simple Order to that effect, and was accompanied by three written dissents: one by Judge Prost, joined by Judges Dyk and Reyna; another by Judge Dyk writing alone, and the third by Judge Reyna.

The Solicitor General's brief recites most of this history as an introduction to the government's views on whether the Court should grant cert on this Question Presented:

Whether the court of appeals erred in holding that the FDA-approved labeling for petitioner's generic drug could provide evidence of intent to induce infringement of respondents' method-of-use patent, where that labeling carved out the portions of the brand-name reference drug's labeling that the brand-name manufacturer and FDA had identified as corresponding to the patented method.

The Solicitor General recognizes and extends the concerns and arguments raised by former Chief Judge Prost in her dissents below. According to the brief,

[A] jury may conclude that a generic manufacturer's engagement in the precise conduct that the Hatch-Waxman Amendments contemplate—namely, marketing an FDA-approved generic version of a brand-name drug with labeling that carves out those indications that the brand-name manufacturer has identified to FDA as claimed by a method-of-use patent—is itself evidence of intent to induce infringement of the patented method.

Under these circumstances, the government argues that uncertainty produced by the majority's decision below is "likely to deter generic manufacturers from invoking that mechanism, thereby threatening the availability of lower-cost generic drugs, in contravention of the statutory design." The brief frankly asserts that the decision below is "incorrect" because "[n]o reasonable jury could have concluded that the carved-out labeling for petitioner's generic carvedilol from 2007-2011 was itself evidence of intent to induce infringement." Reciting the requirement of intent embedded in assessment of inducement under § 271(b), the Solicitor General contends that submission of a skinny label carveout as here cannot satisfy this intent requirement in the face of Congress's intent that "one patented use will not foreclose marketing a generic drug for other unpatented ones." Any other interpretation of the statute will "substantially deter[]" use of Section viii of the statute, the brief asserts. The Solicitor General reserves from this avoidance of inducement liability situations where a generic manufacturer "actively promotes direct infringement of a brand-name manufacturer's method-of-use patent through communications other than the carved-out labeling" or when a brand name manufacturer "timely objects to the generic drug's labeling as failing to carve out a still patented method of use and puts the generic manufacturer on notice that the labeling teaches the method." In the Solicitor General's view, a generic manufacturer submitting a Section viii carveout is better understood to be evidence of an intent "not to encourage infringement" (emphasis in brief).

The brief argues that the inference of an intent to induce infringement by the Federal Circuit was erroneous inter alia because the carveout "was driven by FDA regulatory requirements and GSK's own identification of the indication that should be excised." While the brief hypothesizes that there could be circumstances where a generic manufacturer could take advantage of a branded drugmaker's failure to "identify all the language in its labeling that corresponds to a patented method of use," that was not the case here.

Like former Chief Judge Prost, the Solicitor General appreciates that the Federal Circuit's decisions below "subverts the balance struck by Congress, creates significant uncertainty for FDA and generic manufacturers, and invites gamesmanship by brand-name manufacturers" (and the FDA does not have the expertise or responsibility for reviewing patent claims to address these concerns). The structure of how the FDA has implemented this Congressional intent (by producing use codes obtained from the branded drugmakers) is ministerial, providing the needed information regarding use codes entered in the Orange Book and not independently vetting them. But in this role it is the brand-name drug manufacturers that submit the use codes, and the Solicitor General exhorts the Court that "[t]he section viii pathway cannot function as designed unless FDA and generic manufacturers can rely on brand-name manufacturers' representations to the agency" regarding, inter alia, what parts of the brand-name indications are omitted in the carveout. The continuing responsibility resides in the brand-name drugmaker to ensure that the indications in its label accurately reflect those protected by Orange Book-listed patents and any inaccuracies found in the label can be corrected by the NDA holder (none of which GSK did in this case, the Solicitor General reminds the Court).

The Solicitor General's brief also sets forth its apprehension of the harm to "competition and consumers" that could be occasioned by deigning not to grant certiorari. These include that the Section viii carveout procedural pathway is "an integral component of a complex statutory scheme designed to encourage market entry by generic-drug manufacturers 'as soon as patents allow,'" citing Caraco Pharm. Labs., Ltd. v. Novo Nordisk A/S, 566 U.S. 399, 405 (2012). The brief also cites economic statistics, including savings of more than $50 million during the first 12 months of generic sales (at over 75% price reductions) and that "first generic" approvals "often" have carved-out labels. Another aspect is time -- the brief notes that Section viii carve-outs have "permitted generic drugs to be approved for sale an average of three years before the relevant method-of-use patents expired." The Federal Circuit's decisions below threaten to reduce such benefits, the Solicitor General argues in this brief.

Finally, the government asserts that this case is a "suitable vehicle" for the Court to consider the proper relationship between the skinny label pathway, generic drug maker behavior, and inducement of infringement liability. The Solicitor General contends that the "interlocutory" nature of the decision below, being on remand to consider whether equitable estoppel provides a defense, will not diminish the broader harm to competition posed by the Federal Circuit's decisions. And the government disagrees with Respondent GlaxoSmithKline that changes to the statute have made the Court's review unwarranted because those "clarifying revisions" did not "fundamentally alter the regulatory scheme, which has always placed the onus on the brand-name manufacturer—not FDA or generic competitors—to identify accurately any methods of use claimed by a patent." Finally, the relatively specific factual bases for the Federal Circuit's decisions below should not alter the fundamental issue, the government asserts, that "the potential for inducement liability in these circumstances may significantly deter use of the section viii pathway, even if such liability is rarely imposed" (emphasis in brief). Agreeing again with former Chief Judge Prost, in future "[i]f petitioner's carved-out labeling supports a finding of intent to induce infringement [in this case], the section viii pathway will be seriously jeopardized."

Posted at 10:13 AM in Food and Drug Administration, Infringement - Contributory or Induced, Supreme Court | Permalink | Comments (2)

November 28, 2022

FDA Approves Lantus® Interchangeable Biosimilar

By Kevin E. Noonan --

On November 18th, the U.S. Food and Drug Administration (FDA) announced its approval of Eli Lilly's Rezvoglar (insulin glargine-aglr) product as an interchangeable biosimilar to Sanofi's Lantus (insulin glargine). Both the reference product and the interchangeable biosimilar are "long-acting human insulin analog[s] indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus" according to FDA's press release. Rezvoglar had been approved on December 17, 2021 as a biosimilar, and with this approval joins Semglee (insulin glargine-yfgn), which was the first approved Lantus-interchangeable biosimilar. The Rezvoglar product will be marketed as 3 mL prefilled injectable pens.

This approval brings to four the number of approved interchangeable biosimilar products; in addition to Semglee, these include Cyltezo (adalimumab-adbm), an interchangeable biosimilar to AbbVie's Humira (adalimumab) and Cimerli™ (ranibizumab-eqrn), an interchangeable biosimilar to Genentech/Roche's Lucentis® (ranibizumab).

Posted at 11:07 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (0)

July 24, 2022

FDA Releases Draft Guidance on Evaluation of Therapeutic Equivalence of Small Molecule Drugs

By Kevin E. Noonan --

On July 20th, the FDA released draft Guidance regarding its standards on therapeutic equivalence (TE) between different versions of small molecule drugs. The definition of "therapeutic equivalence" in the Guidance is:

[A]pproved drug products that FDA has determined are pharmaceutical equivalents for which bioequivalence has been demonstrated, and that can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling.

The purported purpose of the Guidance and the standards set forth therein is to provide states, formularies, pharmacies, and the like in situations where there are multiple sources of the same drug (e.g., branded and generic). The asserted policy goal of the Guidance is to give the public easier access to more inexpensive drugs. However, the Guidance emphasizes that economics is to be a beneficial consequence and not the determinant of TE, by stating that "[t]herapeutic equivalence evaluations are a scientific judgment based upon evidence" (as opposed to "social and economic policies"). Interestingly, in the context of this Guidance the word should means "suggested or recommended, but not required," which is certainly a departure from how words of command are interpreted.

The Guidance sets forth three types of equivalence: pharmaceutical, bioequivalence, and the state of having the "same clinical effect and safety profile" for conditions of use set forth on the drug label. TE is limited to drugs having multiple sources because there needs to be a comparator (such as a drug approved under an NDA). The Guidance also set as a goal that drugs deemed to have TE can be substituted "with the full expectation that the substituted product will produce the same clinical effect and safety profile as the prescribed product when administered to patients under the conditions specified in the labeling."

The Guidance then sets forth the standards for each of the equivalency requirements. Pharmaceutical equivalence, defined at 21 C.F.R. § 314.3(b), has four criteria:

• in identical dosage form and route(s) of administration;

• contain identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the same therapeutic moiety, or, in the case of modified-release dosage forms that require a reservoir or overage or such forms as prefilled syringes where residual volume may vary, that deliver identical amounts of the active drug ingredient over the identical dosing period;

• do not necessarily contain the same inactive ingredients; and

• meet the identical compendial or other applicable standard of identity, strength, quality, and purity, including potency and, where applicable, content uniformity, disintegration times, and/or dissolution rates.

The requirements for bioequivalence, defined as:

[T]he absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.

As set forth in FDA Regulations at 21 C.F.R. § 314.94(a)(7) and 21 C.F.R. part 320, supplemented by further Guidances, the Guidance makes a distinction for drugs not intended to be absorbed into bloodstream, wherein bioequivalence is determined at the site of action.

For the requirement of having the "same clinical effect and safety profile" the Guidance states that labeling is a critical criteria: "pharmaceutically equivalent products with differences in labeling may not be considered therapeutically equivalent to one another." This determination is (particularly) product-specific.

Regarding coverage and applicability, the Guidance asserts that only certain drug products evaluated for TE. FDA does not evaluate TE for NDA-approved drugs because they are not pharmaceutically equivalent (and thus not TE) to any other drug. With regard to drugs filed under § 505(b)(1) and approved under 505(c), the FDA will not accept filing for a drug that is a duplicate of one eligible under § 505(j) (ANDA), wherein while duplicate is defined as a "drug product that has the same active ingredient(s), dosage form, strength, route of administration, and conditions of use as a listed drug," it doesn't mean "identical in all aspects." TE for drugs approved under § 505(b)(2) can be obtained by Citizen's Petition. Drugs approved under an ANDA (§ 505(j) approval pathway) satisfy the TE requirements "generally" so there's no need for an applicant to request a TE determination by the agency. "Petitioned" ANDAs on the other hand differ from the reference product in some way ("dosage form, route of administration, strength, or active ingredient (in a product with more than one active ingredient)") and approval can be obtained on petition under § 505(j)(2)(C).

The Orange Book reflects these TE determinations using a multi-letter coding system. The Guidance sets forth the following specific code types:

• first letter A codes, which indicate FDA considers the drug to be TE to "other pharmaceutically equivalent products";

• first letter B codes, which indicate whether there were any bioequivalence problems upon filing and how they have been resolved.

• three-letter codes for instances e.g. where there are "more than one RLD of the same strength has been designated under the same product heading (i.e., same active ingredient(s), dosage form, route(s) of administration, and strength)."

These codes can be revised by the FDA as deemed warranted by evidence.

The Guidance also contains a set of FAQs in the Guidance, including an assertion that so-called "skinny label" ANDAs can be eligible for TE determinations and that differences in inactive ingredients generally don't negatively affect TE determinations for ANDA products, among other questions.

As with all draft Guidances, this one contains prominently set out in a black-lined box the qualification that that:

This draft guidance, when finalized, will represent the current thinking of the Food and Drug Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible for this guidance as listed on the title page.

Posted at 11:42 PM in Food and Drug Administration | Permalink | Comments (1)

February 03, 2022

FDA Approves Generic Restasis

By Kevin E. Noonan --

On Wednesday, the U.S. Food and Drug Administration announced approval to Mylan Pharmaceuticals for a generic form of Allergan's RESTASIS® (Cyclosporine Ophthalmic Emulsion 0.05%) product for treatment of chronic dry eye. RESTASIS® is "a calcineurin inhibitor immunosuppressant indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca." The FDA issued a press release that stated:

"Restasis has been approved for use in the US for nearly 20 years, but until today, there was no approved generic product of this drug that can help the millions of Americans who suffer from dry eyes," said Sally Choe, PhD, director of the Office of Generic Drugs in FDA's Center for Drug Evaluation and Research. "Today's approval reflects the FDA's continued commitment to advancing patient access to lower-cost, high-quality generic drug products that are as safe and effective as their brand name counterparts."

As a reminder, a little more than four years ago, innovator pharmaceutical company Allergan caused a stir by entering into an assignment agreement with the St. Regis Mohawk Tribe over Patent Nos. 8,629,111; 8,633,162; 8,642,556; 8,648,048; 8,685,930; and 9,248,191,that protected its Restasis® product (see "Allergan Avails Itself of Sovereign Immunity"). These patents had been challenged by Mylan in inter partes review proceedings and St. Regis moved for the Patent Trial and Appeal Board (PTAB) to dismiss these IPRs on sovereign immunity grounds (see "Mohawk Nation Exercises Sovereign Immunity in Inter Partes Review"). The PTAB denied the motion (see "PTAB Denies St. Regis Mohawk Tribe's Motion to Terminate IPRs based on Sovereign Immunity") and the Federal Circuit affirmed (see "Saint Regis Mohawk Tribe v. Mylan Pharmaceuticals Inc."). In parallel ANDA proceedings, the District Court (Federal Circuit Judge William Bryson, sitting by designation) granted the St. Regis Tribe's motion to be named as a party (see "District Court Allows Mohawk Tribe to Join ANDA Litigation, Finds Patents at Issue Invalid") but, as the post title indicates, found the patent-in-suit to be invalid for obviousness.

The value of the RESTASIS® product provides ample motivation for trying to protect the RESTASIS® franchise and while that profitability will surely be reduced in the face of generic competition between now and 2025, it is countered by the lack of generic competition between 2017 and now. More significantly, the Board's decision and the Federal Circuit's affirmance of that decision (followed by Federal Circuit decisions in Regents of the University of Minnesota v. LSI Corp. and Board of Regents of the University of Texas System v. Baylor College of Medicine and PTAB decisions in Ericsson Inc. and Telefonaktiebolaget LM Ericsson v. Regents of the University of Minnesota) effectively ended sovereign immunity as a basis for an assignee sovereign to avoid validity challenged by IPR (and thus eliminated any motivation or impetus for patentees to use assignment as a tool for protecting their patents from IPR challenges).

Posted at 10:57 PM in Biosimilars, Food and Drug Administration | Permalink | Comments (0)

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