Rituximab - Netherlands

On Feb 21, 2018, District Court the Hague handed down its decision in Rituximab case & revoked Dutch part of EP 2055313 patent for lack of inventive step.

Biogen holds EP 2055313 patent that relates to a ‘Treatment of hematologic malignancies associated with circulating tumor cells using chimeric anti-CD20 antibody’.  Previously by a judgment of May 12, 2017, the preliminary relief judge rejected Biogen’s infringement claim because, according to his provisional judgment, there is a serious, not negligible chance exists that the patent is destroyed in a bottom procedure or becomes opposition revoked due to added matter.

Celltrion then initiated invalidity proceedings based on lack of inventive step which was the central issue here. Celltrion stated that EP’313 patent lacks inventive step based on McLaughlin which is the closest prior art along with other prior arts. Biogen said that McLaughlin does not see the treatment of CLL. McLaughlin deals with the treatment of lymphomas such as SLL and patients with CLL are explicitly excluded from research in McLaughlin. Court held that as explained the morphology, the immunophenotype and the molecular properties of tumor cells at CLL and SLL are the same (for this case is in the particularly relevant the equality of the CD20 proteins on the surface of the cells) In view of this, it cannot be said that McLaughlin is not real the starting point.

The difference measures of claims 1 and 3 of the EP’313 assistance request compared to McLaughlin are therefore 1) the application of rituximab for treatment of CLL and 2) the higher dose of 500-1,500 mg / m2. The technical effect of the different measures is an effective treatment of CLL patients with rituximab so that the objective technical problem can be formulated to provide effective treatment for CLL.

Court further said that McLaughlin first teaches the practitioner that the antigen CD20 occurs on more than one 90% of the surface of B cells in both lymphomas and chronic lymphatic leukemia (CLL) and that it is 'appealing for targeted therapy'. Expert testified that the finding of McLaughlin would prompt practitioner to try rituximab also in the treatment of CLL. Due to the higher amount of circulating B-cells, it would be logical to try higher doses, as also suggested by McLaughlin. Therefore practitioner would have felt comfortable to try higher doses on subsequent infusions due to the reported safety profile, which is very favorable.

Berinstein  et al is also an extra incentive for the skilled person to apply higher dosages to suit the treatment of SLL and therefore, as explained above, also CLL. The Biogen's defense that hinting at higher doses in Berinstein only applies to enlarged tum ears in the lymph ('bulky disease') fails. Because the practitioner would starts to use higher doses in more places general, and not exclusively in connection with 'bulky disease'. In the second place the doctor would recognize that the mechanism of action of rituximab at SLL and CLL would be the same and would certainly apply incentives in the context of SLL in the treatment of patients with CLL.

Court further held that Biogen has not stated that there would be other 'pointers-away' that would keep the practitioner from examining the use of rituximab in CLL patients at a higher dose than 375 mg / m2.

The conclusion is that the Dutch part of EP’313 will be destroyed, as advanced. This means that the other arguments that Celltrion has put forward, such as the claim that there is added matter, need no further discussion.

Rituximab - USA

IPR decision (Feb. 21, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Status
IPR2016-01614	08/15/2016	Celltrion, Inc.	Apotex Inc.	US 7,820,161	claims 1–12 are patentable

On US’161 patent, Celltrion previously filed IPR (IPR2015-01744) which was denied.  Boehringer Ingelheim filed IPR (IPR2015-00415) which was terminated (Oct 2015) as BI filed “Request for Adverse Judgment”. Pfizer also filed IPR (IPR2017-01115) on 03/24/2017 which was instituted on 07/18/2017.

US 7,820,161 (Genentech / Biogen; Exp: May 04, 2020)

1. A method of treating rheumatoid arthritis in a human comprising: (a) administering to the human more than one intravenous dose of a therapeutically effective amount of rituximab; and (b) administering to the human methotrexate.

5. A method of treating rheumatoid arthritis in a human comprising: (a) administering to the human more than one intravenous dose of a therapeutically effective amount of an antibody that binds to the CD20 antigen on human B lymphocytes; and (b) administering to the human methotrexate; wherein the CD20 antibody administration consists of intravenous administration of the CD20 antibody, and the CD20 antibody is rituximab.

9. A method of treating rheumatoid arthritis in a human comprising: (a) administering to the human more than one intravenous dose of a therapeutically effective amount of an antibody that binds to the CD20 antigen on human B lymphocytes; and (b) administering to the human methotrexate; wherein the therapeutically effective amount of the CD20 antibody is administered intravenously, and the CD20 antibody is rituximab.

Cinacalcet - USA

On Feb. 17, 2018, U.S. District Judge Randolph D. Moss of District of Columbia granted FDA’s renewed motion & denied pediatric exclusivity to Amgen’s Sensipar drug.

Amgen brought this action to challenge the decision of the Food and Drug Administration (“FDA”) denying Amgen pediatric exclusivity for its drug, Sensipar (cinacalcet hydrochloride). In an earlier opinion and order, the Court granted the FDA summary judgment on all but one of Amgen’s claims: its claim that the agency’s denial of pediatric exclusivity for Sensipar was inconsistent with its decision to grant pediatric exclusivity for Johnson & Johnson’s drug Ortho Tri-Cyclen [Amgen Inc. v. Hargan, --- F. Supp. 3d ---, 2018 WL 581006 (D.D.C. Jan. 26, 2018)]. As to that claim, the Court concluded that the FDA had failed to offer a “reasoned explanation” for why it reached a “disparate outcome” with respect to Ortho TriCyclen. On remand, the FDA reaffirmed its Sensipar decision and explained why, in its view, this result was consistent with its decision on Ortho Tri-Cyclen. The FDA issued an addendum to its Remand Decision, again concluding that its Sensipar and Ortho Tri-Cyclen decisions were not inconsistent. Amgen has now renewed its motion for summary judgment on the grounds that the FDA’s latest explanation is inadequate and that its denial of pediatric exclusivity for Sensipar thus remains arbitrary and capricious.

The FDA denied Amgen’s request for pediatric exclusivity for Sensipar because Amgen’s studies did not, in the agency’s view, “fairly respond” to the written request. According to the FDA, Amgen’s studies did not fully comply with the requirements of the written request: for one of the studies, the written request required a minimum of fifteen patients ages 28 days to < 6 years, but only four patients completed the study and in the FDA’s view, Amgen’s data did not yield “clinically meaningful” information on cinacalcet’s safety in that age group—a key objective of the written request. FDA granted exclusivity for Ortho Tri-Cyclen because the agency “decided” that the Ortho Tri-Cyclen studies, unlike the Sensipar studies, “met the enrollment criteria in the [written request] at the time of the [exclusivity] decision.”

Court held that in the FDA’s scientific judgment at the time of the relevant decisions, the Ortho Tri-Cyclen studies met the terms of the written request, and the Sensipar studies did not. Whether the FDA was, in fact, correct in determining that the Ortho Tri-Cyclen study subjects met the DSM-IV criteria is not the relevant question. All that matters for present purposes is whether the FDA applied an interpretation of “fairly respond” to Amgen that differed from the standard it applied to Johnson & Johnson, and the agency has reasonably explained that it did not do so. Court further held that Amgen has not met its burden of demonstrating that the FDA applied different standards. The Court, accordingly, satisfied that the FDA has offered a reasoned—and reasonable—basis for distinguishing the Ortho Tri-Cyclen precedent.

Applying these principles here, the Court concluded that the FDA has offered a reasoned explanation for why it reached different outcomes in response to the Ortho Tri-Cyclen and Sensipar applications for pediatric exclusivity. Thus For the reasons stated above, the Court DENIED Amgen’s renewed motion for summary judgment and GRANTED the FDA’s renewed motion for summary judgment.

Sofosbuvir - USA

On Feb 16, 2018, Judge Stark of District of Delaware held that Idenix’s patent is invalid for lack of enablement & thus granted Gilead's renewed motion for judgment as a matter of law.

In this patent infringement case involving groundbreaking work by both parties in the field of treatments for the Hepatitis C virus ("HCV") infection, Plaintiffs Idenix Pharmaceuticals LLC and Universita Degli Studi di Cagliari (together, "Idenix") sued Defendant Gilead Sciences, Inc. ("Gilead"). Prior to trial, Gilead stipulated that, under the Court's claim construction, its accused products, Harvoni and Sovaldi, infringe the asserted claims of ldenix's patent, U.S. Patent No. 7,608,597 ("'597 patent"). After a two week-trial in December 2016, a jury found that Gilead failed to prove that the asserted claims are invalid and awarded Idenix $2.54 billion in damages. Gilead now renews its motion for judgment as a matter of law ("JMOL"). In its JMOL motion, Gilead urges the Court to set aside the jury's verdict on the basis that Idenix's asserted patent claims are invalid for failure to meet 35 U.S.C. § 112's written description and enablement requirements. Gilead alternatively asks the Court to reduce the jury's damages award as unsupported by the evidence.

Background:

In 2000, Idenix discovered an important modification to HCV compounds and filed a provisional patent application at the United States Patent and Trademark Office ("PTO"). Idenix's work addressed the placement of a methyl group (CH3) at the nucleoside's 2' (pronounced "two prime") up position. The application eventually led to, among others, U.S. Patent Nos. 6,914,054 ('"054 patent") and the '597 patent. Around the same time, a company called Pharmasset was pursuing similar research. Pharmasset was eventually acquired by Gilead. It worked on modified nucleosides that, like Idenix's, included a methyl group at the 2' up position. Pharmassets work also involved placing a fluorine atom at the 2' down position. This compound - 2'-methyl up 2'-fluoro down - led to the groundbreaking "miracle" treatment that has cured HCV for millions and has produced billions of dollars in revenue for Gilead. Gilead named its drug containing 2' methyl up 2' fluoro down-which acts on HCV's NSSB polymerase - sofosbuvir, which Gilead markets under the trade name Sovaldi. Gilead also markets a combination of sofosbuvir and ledipasvir, which also inhibits the virus's NS5A protein activity, under the trade name Harvoni.

The instant suit began in 2013, when Idenix sued Gilead for infringement of the '054 and '597 patents in the United States District Court for the District of Massachusetts. The case was later transferred to Delaware court. As the parties prepared for trial, Gilead stipulated to infringement of the '597 patent based on the Court's claim constructions, and Idenix dropped the '054 patent from the case. The parties proceeded to trial on willfulness, damages, and invalidity with respect to several claims of the '597 patent. The jury then returned a verdict finding that Gilead's infringement was willful, that Gilead had failed to prove the patent claims are invalid, and that Idenix is entitled to $2.54 billion in damages. On September 22, 2017, the Court issued its Opinion on Idenix's motion, denying Idenix's request to enhance damages for willful infringement as well as its request to declare this case exceptional and award Idenix attorney fees. The Court granted Idenix's request that the pre-judgment interest it was being awarded be compounded at 3.25 - 3.75 % (prime rate) instead of 0.10 - 0.14 % (T-bill rate).

Current issue:

The Court then turned to the issues raised in Gilead's motion. With respect to damages, Gilead requests judgment as a matter of law, remittitur of the jury's damage award-to an amount not to exceed $380 million. Gilead contends that Idenix' s damages presentation was fatally deficient in two respects. First, Idenix's damages expert, Andrew Carter, failed to establish that the patent license agreements on which he relied were sufficiently comparable. Second, Carter and Idenix's damages case violated the Entire Market Value Rule ("EMVR"). The Court disagrees with Gilead.

Gilead's motion next asked the Court to conclude that Idenix's '597 patent is invalid due to its failure to comply with the requirements of 35 U.S.C. § 112. Gilead challenges the jury's finding that the '597 patent sufficiently described and enabled its claimed subject matter. With respect to written description, which is a factual issue, the Court found that there was substantial evidence to support the jury's conclusion that clear and convincing evidence does not support a finding of lack of written description. Hence, the Court denied this portion of Gilead's motion.

With respect to enablement, which presents a question of law, the Court concluded, as a matter of law, that no reasonable fact finder could find anything other than that the '597 patent is not enabled. Gilead argued that the term "B-D-2'-methyl-ribofuranosyl nucleoside" encompasses any B-D-nucleoside that includes "a five member sugar ring with a methyl group in the 2' up position and non-hydrogen substituents at the 2' down and 3' down positions. Second, at Idenix' s urging, the Court construed the claims to contain a functional limitation, through claim 1 's preamble ("A method for the treatment of a hepatitis C virus infection") and its "effective amount" term. Combining these two limitations, the claims cover all those nucleosides, but only all those nucleosides, that meet the Structural Limitations - including a methyl group at the 2'-up position - and the Functional Limitations of exhibiting effective anti-HCV activity. Thus, as further explained below, the claims as construed combine Structural Limitations that are satisfied by an enormous number of compounds with Functional Limitations that are satisfied by an unknown, but far smaller, number of undisclosed compounds.

Court held that POSA would ask the crucial question: which of the compounds meeting the Refined Structural Limitations also satisfy the Functional Limitations? A reasonable fact finder could only conclude that the patent fails to provide this necessary information. The accused embodiment - 2' methyl up 2' fluoro down - which, undisputedly, comes within the scope of the claims as construed is not expressly disclosed in the '597 patent. While fluorine is disclosed as a candidate for the 2' up position, it is not disclosed as a candidate for the 2' down position. Even the inventor of the '597 patent, Dr. Michael Somadossi, testified that there is no disclosure of the 2' methyl up 2' fluoro down nucleoside in either the May 2000 provisional patent application or the May 2001 patent application.

This conclusion further compelled by application of the Wands factors to the record. First, with respect to "the quantity of experimentation necessary," significant work is necessary to synthesize and screen the full scope of the compounds that fall within the claims, or even to synthesize and screen any particular compound coming within the scope of the claims. The next factors -the disclosure in the patent of "specific working examples" and the "amount of guidance presented in the patent" - also favor a finding of non-enablement. While the patent discloses working embodiments, routes for making the claimed nucleosides, and assays for screening candidates, the claims' Structural Limitations are enormously broad, the Refined Structural Limitations are also quite broad, and the patent's examples disclose a significant number of possible arrangements.

Because the Structural Limitations are satisfied by such a large number of compounds, and because of the other Wands factors as applied here, the amount of experimentation to refine this broad set of compounds to those that also satisfy the Functional Limitations, given the limited teachings on this point in the patent and the state of the prior art, is an "undue" amount. Thus, the only conclusion that can be reached based on the trial record is that the asserted claims of the '597 patent are invalid for lack of enablement.

For the reasons given above, the Court found that, while judgment as a matter of law is improper on damages and written description, the '597 patent is invalid for lack of enablement. Accordingly, the Court granted in part and denied in part Gilead’s motion.

Filgrastim & Pegfilgrastim - USA

IPR decision (Feb. 15, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Status
IPR2016-01542	08/05/2016	02/17/2017	Apotex Inc.	US 8,952,138	(Claims 1–17, 19–24 are unpatentable AND claim 18 is patentable)

US 8,952,138 (Amgen; Jul 29, 2031)

1. A method of refolding a protein expressed in a non-mammalian expression system and present in a volume at a concentration of 2.0 g/L or greater comprising: (a) contacting the protein with a refold buffer comprising a redox component comprising a final thiol-pair ratio having a range of 0.001 to 100 and a redox buffer strength of 2 mM or greater and one or more of: (i) a denaturant; (ii) an aggregation suppressor; and (iii) a protein stabilizer; to form a refold mixture; (b) incubating the refold mixture; and (c) isolating the protein from the refold mixture.

Meloxicam - USA

On Feb 01, 2018, Judge Marvin J. Garbis of District of Maryland granted Lupin's Motion for Summary Judgment in VIVLODEX® (meloxicam) Hatch-Waxman litigation.

In 2015, Co-Plaintiff Iroko Pharmaceuticals, LLC ("Iroko") gained approval from USFDA for its New Drug Application ("NDA") for 5 milligram ("mg") and 10 mg formulations of the drug meloxicam which it markets under the VIVLODEX®. The NDA lists United States Patent Nos. 9,526,734 ("the '734 patent") and 9,649,318 ("the '318 patent") in Orange Book. The alleged invention in patents pertains to formulations of meloxicam (5 mg and 10 mg formulations) that are milled to meet a specified nanoparticulate size distribution profile. The Patents-in-Suit are owned by the Co-Plaintiff iCeutica Pty Ltd. ("iCeutica") which exclusively licenses the patents to Iroko (Iroko and iCeutica collectively referred to as "Plaintiffs").

On August 4, 2016, Defendant Lupin filed an Abbreviated New Drug Application ("ANDA") with P-IV certification seeking FDA approval for a generic version of VIVLODEX®. Plaintiffs filed suit & contended that Lupin's product directly infringes on all claims of the '734 and '318 patent—either literally or through the doctrine of equivalents—and that the prosecution history does not estop it from arguing doctrine of equivalents. In its ANDA application, Lupin specifies that the generic products it intends to market will have a D(0.9) of less than 800 nm.

Independent Claim 1 of '734 patent:

1. A capsule form of a pharmaceutical composition comprising 5 mg of meloxicam having a median particle size, on a volume basis, between 100 nm and 500 nm and a D(0.9) that is between 1200 nm and 3000 nm, wherein a single capsule, upon oral administration to a population of healthy adults in the fasted state, provides a mean plasma AUC (0-∞) of 7500-20000 h*ng/ml and a mean plasma Cmax of 350-950 ng/ml, wherein the dissolution rate is such that, when the capsule is tested using USP Apparatus 1 (baskets) set to rotation speed of 100 RPM in 500 mL of pH 6.1 phosphate buffer with 0.1% sodium lauryl sulfate (SLS) at 37° C.+0.5° C., at least 80% of the meloxicam dissolves in 10 minutes or less, wherein a single capsule is effective for treating osteoarthritis pain.

Independent Claim 1 of '318 patent:

1. A capsule form of a pharmaceutical composition comprising 5 mg of meloxicam having a median particle size, on a volume basis, between 100nm and 1000 nm, wherein a single dose, upon oral administration to a population of healthy adults in the fasted state, provides a mean plasma AUC (0-∞) of 7500-20000 h*ng/ml and a mean plasma Cmax of 350-950 ng/ml, wherein the D(0.9) of the particles of meloxicam is less than 4000 nm and greater than 1200 nm, and wherein the dissolution rate is such that, when tested using USP Apparatus 1 (baskets) set to rotation speed of 100 RPM in 500 mL of pH 6.1 phosphate buffer with 0.1% sodium laurel sulfate (SLS) at 37° C.±0.5° C., at least 80% of the meloxicam dissolves in 10 minutes or less.

Plaintiffs contended that Lupin infringes on the '734 and '318 patents through the doctrine of equivalents (for particle size limitations) and literally (for all other limitations). In its Motion for Summary Judgment, Lupin contended that its ANDA products do not literally infringe on Plaintiffs' patents, that Plaintiffs are estopped from arguing the doctrine of equivalents in light of the prosecution history, and that it is entitled to summary judgment as a matter of law.

On literal infringement, Court held that Lupin's ANDA products would not literally infringe on the '734 and '318 claims because the product's particle size distribution would not fall within the claimed ranges. The '734 patent claims a D(0.5) of 100-500 nm and a D(0.9) of 1200-3000 nm. The '318 patent claims a D(0.5) of 100-1000 nm and a D(0.9) of 1200-4000 nm. Lupin's ANDA product needs a D(0.9) of less than 800 nm for FDA approval. Any D(0.9) value below 800 nm will fall outside of the minimum claimed value of 1200 nm. Because the D(0.9) of Lupin's products does not fall within the claimed range of 1200-3000 nm (or 1200-4000 nm), the Court holds that a reasonable fact finder could not find that Lupin's products will contain every limitation in the '734 and '318 patent claims.

With respect to Doctrine of Equivalents, Court held that that Plaintiffs are estopped from arguing that Lupin's ANDA products would infringe on the '734 and '318 patent claims through the doctrine of equivalents because the applicant surrendered any particle size distributions with a D(0.9) below 1200 nm during prosecution through both amendment-based and argument-based estoppel.

The prosecution history shows that the '734 patent claimed a D(0.9) value of "less than 3000 nm" in the original application, indicating a range of 0-3000 nm. In a Response to the Examiner’s rejection, the applicant amended the D(0.5) to 100-3000 nm and the D(0.9) to 900-3000 nm. The Examiner still upheld the rejection over Cooper in a second Non-Final Office Action. Finally, the claims were further amended to a D(0.5) of 100-500 nm and a D(0.9) of 1200-3000 nm. In an Examiner Interview Summary, the Examiner noted that the amended ranges would "still adequately describe a broader particle size distribution, wherein the D(0.9) is distinct from the median particle size, which was not taught or contemplated by the prior art teachings of Cooper" and would be "commensurate in scope with the data provided in the specification."

The '318 patent underwent a similar prosecution as the '734 patent. However, the examiner allowed the claims with a D(0.5) of 100-1000 nm and a D(0.9) of 1200-4000 nm. The upper bounds for the D(0.5) and D(0.9) are higher than those of the '734 patent. The prosecution history does not reveal a reason for why the upper bounds of the D(0.5) were allowed to remain at 1000 nm (as opposed to 500 nm as amended in the '734 patent).

Court further held that the Plaintiffs clearly narrowed its D(0.5) and D(0.9) values through amendments during prosecution. These amendments were made to overcome a § 103 rejection over Cooper. Therefore, a presumption is raised that bars a DOE argument for any product with a D(0.5) greater than 500 nm and a D(0.9) below 1200 nm. The equivalent in question (Lupin's ANDA product) would have a D(0.5) of roughly 200 nm and a D(0.9) of less than 800 nm, falling below the claimed 1200 nm threshold. The Court also concluded that Plaintiffs have not rebutted the presumption (through the tangential relation exception) that Plaintiffs have surrendered D(0.9) values of less than 1200 nm, and Plaintiffs are thus barred from arguing that Lupin's products will infringe through doctrine of equivalents for the '734 patent. Finally Court held that because the Plaintiffs cannot prove literal infringement of the '734 and '318 patents and are barred from proving infringement through the doctrine of equivalents, the Court found that there are no remaining genuine issues of material fact, and Lupin is entitled to judgment as a matter of law.

Prepopik - USA

On Feb 13, 2018, Judge Rudolph Contreras of District of Columbia denied Ferring’s Motion to Enforce Judgment in PREPOPIK new chemical entity (NCE) exclusivity case.

Prepopik, a fixed-combination drug product used to cleanse the colon prior to colonoscopies, contains three active ingredients: sodium picosulfate, magnesium oxide, and anhydrous citric acid. While magnesium oxide and anhydrous citric acid had already been approved in previous New Drug Applications (“NDA”) when Ferring submitted its NDA for Prepopik, sodium picosulfate had not been. Therefore, when it submitted its NDA for Prepopik, Ferring also sought five years of exclusivity for the drug as a New Chemical Entity (“NCE”). The FDA approved Ferring’s NDA for Prepopik on Jul 16, 2012. However, the agency refused to grant Ferring five years of exclusivity for Prepopik because two of the active ingredients in the drug (magnesium oxide and anhydrous citric acid) existed in drugs previously approved by the FDA. Instead, it granted Ferring three years of exclusivity for new clinical investigation.

Ferring submitted a Citizen Petition requesting that the FDA change its exclusivity determination for Prepopik. A year later, the FDA issued a response to this Citizen Petition and Citizen Petitions filed by two other pharmaceutical companies & stated that it believed that its then-current interpretation of the relevant statute and regulations—that fixed-combination drugs that contain at least one previously approved active moiety cannot be granted exclusivity, even if the drug also contains at least one new active moiety—was “permissible.” After filing a Petition for Reconsideration and Petition for Stay, which the FDA denied, Ferring filed this action in federal court & sought “a declaratory judgment declaring that the FDA’s determination of the exclusivity period for Prepopik violates the [APA]” and “injunctive relief ordering the FDA to grant the full five years of exclusivity for Prepopik.” On first review, the Court denied Ferring all of the relief it requested [Ferring Pharm. Inc. v. Burwell (“Ferring I”), 169 F. Supp. 3d 199 (D.D.C. 2016)]. Following the Court’s grant of summary judgment to the FDA, Ferring moved for reconsideration on the grounds that it could identify several examples of a single-entity drug substance being denied five-year exclusivity due to the order in which the NDAs for drugs that include that substance were approved. The Court granted the motion for reconsideration, entered summary judgment for Ferring, and “remand[ed] th[e] action to FDA for further proceedings not inconsistent with [its] opinion.” Ferring Pharm., Inc. v. Burwell (“Ferring II”), No. 15-802, 2016 WL 4734333, at *11 (D.D.C. Sept. 9, 2016).

Throughout the NDA process, the NCE exclusivity Citizen Petition process, and this litigation, the FDA has consistently agreed with Ferring that the active moiety in sodium picosulfate is picosulfate. For example, when Ferring submitted its NDA for Prepopik, the FDA classified the NDA as a “Type 1 – New Molecular Entity” submission. Eight months after the Court remanded this matter back to the FDA for further proceedings consistent with its arbitrary and capriciousness finding, the FDA changed its mind regarding the identity of the active moiety in sodium picosulfate. It now believes, upon “further review,” that the active moiety in sodium picosulfate is not picosulfate, but rather bis-(p-hydroxyphenyl)-pyridyl-2-methane (BPHM), an active moiety that is also found in other previously approved drug products. As such, it concluded that Prepopik was not entitled to five-year NCE exclusivity. The agency’s change in position is based in its new chemical analysis of picosulfate.  Now the FDA explains that, following the Court’s remand, it has taken a closer look at the chemical properties of sodium picosulfate and “determined that sodium picosulfate is the disodium salt of a di-sulfate derivative of [BPHM],” because “[a]fter excluding the salt and ester portions of sodium picosulfate, as FDA’s regulations require, what remains is BPHM. After performing a “virtual hydrolysis to cleave all ester bonds,” and “[e]xamin[ing] the alcohol and acid components” to “determine which are ‘responsible for the physiological or pharmacological action of the drug substance,’” the FDA determined that the active moiety in sodium picosulfate is BPHM. It therefore concluded that “[d]espite [its] prior statements that sodium picosulfate was an NME and an NCE, it is now evident that those statements were incorrect because this drug substance contained a previously approved active moiety when it was approved in Prepopik.”

Ferring did not accept this conclusion, claiming that it resulted from a mid-adjudication change in the interpretation of the term “ester” to include “covalently bound sulfur-based appendages.” It argued that if the agency wanted to change its interpretation of the term “ester,” it should have followed the appropriate administrative procedures.  According to Ferring, the FDA’s “sudden reversal is not just an unreasonable break with past practice,” but also “an end-run around this Court’s” grant of summary judgment and remand order. Therefore, it has filed a motion to enforce the Court’s prior judgment, requesting that the Court “order FDA to award NCE exclusivity to Prepopik instead of ordering another remand.” Ferring argued that the FDA’s change in position regarding sodium picosulfate’s prior approval status violates the law of the case; that the agency is judicially estopped from changing its position in this manner; that the agency’s eleventh hour chemical analysis of sodium picosulfate impermissibly retroactively applies a new interpretation of the term “ester” and violates due process; and that the agency’s actions are arbitrary and capricious.

Ferring’s first argument was that the FDA’s change in position regarding the active moiety in sodium picosulfate violates the law of the case doctrine because the FDA’s actions on remand “undermine the clear thrust of this Court’s order instructing FDA to take further proceedings. The FDA counters that “[t]he doctrine of law of the case is inapplicable here because the factual issue of whether sodium picosulfate contains a new active moiety was never raised as a disputed issue to be decided during the litigation and FDA’s actions on remand were fully within the scope of the Court’s mandate.” Court sided with FDA & said that the FDA is correct that its determination regarding the active moiety in sodium picosulfate cannot be bound by the law of the case doctrine, though not, as it suggests, because the parties never disputed the issue. Court further held that at a basic level, Ferring’s argument that the law of the case applies here must fail because the Court never actually found that the active moiety in sodium picosulfate is picosulfate, either explicitly or by necessary implication.

Ferring’s second argument was that the FDA’s switch in position regarding the active moiety in sodium picosulfate is barred by judicial estoppel, which “prevents parties from abusing the legal system by taking a position in one legal proceeding that is inconsistent with a position taken in a later proceeding. The FDA responds that judicial estoppel does not apply because the agency did not intentionally change its position regarding the active moiety in sodium picosulfate in order to gain a tactical advantage in this suit, and because it never “succeeded in persuading [the Court] to accept [its] earlier position” regarding the active moiety in sodium picosulfate. Court held that the FDA is correct on both counts, and accordingly, the Court will not grant Ferring the relief it seeks on this ground either.

Court said that there is no doubt that Ferring is inconvenienced by the FDA’s new position that the active moiety in sodium picosulfate can be found in other, previously approved active ingredients. Indeed, had Ferring known that the FDA would argue that the active moiety in sodium picosulfate was BPHM rather than picosulfate, it may have decided not to pursue this litigation in the first place. At the very least, this revelation is a setback. However, this change in position certainly did not give the FDA an unfair advantage throughout the course of this litigation. Indeed, had the FDA staked out this position at the outset, it may have avoided litigating two dispositive motions regarding its prior interpretation of the NCE statutory and regulatory provisions, depending on how Ferring had chosen to respond. Because the FDA’s actions do not meet the three criteria set forth in Maine, and because it appears that the FDA’s late change in position may have been due to inadvertence or mistake, the Court does not find that the FDA is judicially estopped from determining that the active moiety in sodium picosulfate is BPHM, thereby denying Prepopik five years of exclusivity. Accordingly, the Court cannot grant Ferring the relief it seeks on this basis either.

Therefore for the reasons set forth above, the Court found that the FDA’s actions on remand do not violate the law of the case and that the FDA is not judicially estopped from asserting its change in position concerning sodium picosulfate’s prior approval status. The Court also found that Ferring’s arguments regarding retroactivity, due process, and arbitrary and capriciousness are not suitable for consideration within the context of a motion to enforce judgment. Thus Ferring’s Motion to Enforce Judgment is DENIED.

Mometasone furoate – USA

On Feb 9, 2018, Federal Circuit affirmed a district court’s finding that Amneal doesn’t infringe a patent belonging to Merck in Nasonex® ANDA case.

Merck Sharp & Dohme Corp. (“Merck”) owns U.S. Patent No. 6,127,353, which claims mometasone furoate monohydrate (MFM), the active ingredient in Merck’s Nasonex® nasal product. Amneal Pharmaceuticals LLC (“Amneal”) submitted an Abbreviated New Drug Application (“ANDA”) to the U.S. Food & Drug Administration (“FDA”) seeking approval to market a generic mometasone furoate nasal spray comprising mometasone furoate anhydrous (MFA) as the active ingredient. Merck filed an infringement suit in the District of Delaware alleging that Amneal’s proposed ANDA product would infringe the ’353 patent if approved by the FDA. Specifically Merck alleged that although Amneal’s ANDA product contained MFA, its ANDA product would convert to the infringing MFM form over time. Following a bench trial, the district court found that Merck failed to prove by preponderant evidence that Amneal’s ANDA product will infringe the ’353 patent. On appeal, Merck argued that the district court abused its discretion by not compelling Amneal to produce additional samples of its ANDA product for testing before trial. Merck also argued that the district court’s noninfringement finding must be reversed because it was not based on Amneal’s final commercial product. Merck also challenged the district court’s fact-finding that a Raman spectroscopy three-peak analysis was required to confirm the infringing form of mometasone furoate in Amneal’s  product.

Amneal’s ANDA specification allowed for a maximum bulk suspension hold of up to four days, therefore the FDA required Amneal to complete a bulk-hold study. On February 29, 2016, Amneal responded to the FDA, providing data on samples from the Day 1 and Day 4 Batches from the requested bulk-hold study. Amneal did not provide the FDA data on samples from the A Batch. On May 9 and 13, 2016—six weeks before trial—Merck sought emergency relief from the district court, arguing that Amneal should have produced samples from the Day 4 and A Batches. Merck argued that because the Day 4 and A Batches underwent additional mixing, which can promote conversion of MFA to the infringing MFM form, Amneal should have produced samples from those batches for testing. Amneal argued that additional samples would have been cumulative of the Day 1 Batch samples already produced and maintained its representation that the Day 1 Batch samples were representative of its ANDA product.

Following two discovery hearings on the issue, the district court became aware of Amneal’s discovery violation and acknowledged that ideally Amneal should have produced samples of the Day 4 and A Batches. The district court determined, however, that it did not have enough information at the time to determine whether the Day 4 and A Batch samples were materially different from the Day 1 Batch samples. The district court concluded that it was “not persuaded sitting right here that mixing [] makes a substantive difference, and if it doesn’t, then it doesn’t matter that Amneal didn’t give [Merck] a sample of both [the Day 4 and A Batches] . . . [and] only gave [Merck the Day 1 Batch].” The district court did not compel Amneal to produce the additional samples. Nor did the court postpone trial. Instead, the district court gave Merck the opportunity to prove at trial that the Day 4 and A Batch samples were substantively different than the Day 1 Batch samples.

At trial, Merck’s expert, Dr. Matzger did not identify any MFM crystals in Exhibit Batches samples. But Dr. Matzger also tested samples from the Day 1 Batch and testified that he identified a single Raman peak at 1709 cm-1, which is characteristic of MFM. Dr. Matzger testified that although he tested the Exhibit and Day 1 Batch samples, he would have preferred to test samples of Amneal’s Day 4 and A Batches because they underwent additional mixing and thus were more representative of the final ANDA product. Amneal’s expert, Dr. Marquardt, testified that Dr. Matzger misinterpreted the data as identifying MFM in Amneal’s Day 1 Batch samples and opined that MFM was not present in Amneal’s final ANDA product. Dr. Marquardt further opined that three Raman peaks were required to confirm the presence of MFM rather than a single Raman peak. Amneal’s other expert, Dr. Rogers, opined that the likelihood of conversion of MFA to MFM was merely theoretical and unlikely due to the high energy required to convert between forms.

On the evidence presented, the court concluded that Merck has not demonstrated that the additional samples would yield different results. Consequently, the court denies Merck’s alternative request for the production of [the Day 4 and A Batch] samples and a new trial. Regarding infringement, the district court credited Amneal’s expert that three Raman peaks were required to identify MFM in Amneal’s ANDA product.  As a result, the district court “assigned little weight to Dr. Matzger’s identification of MFM based on a single peak. The district court concluded that based on the “lack of MFM in the Exhibit Batches and opposing conclusions on the same testing of the [Day 1 Batch],” Merck failed to carry its burden of proving by a preponderance of the evidence that MFM is present in Amneal’s ANDA product. Merck appealed.

Federal circuit upon appeal held that district court did not abuse its discretion in choosing this particular approach as opposed to ordering additional discovery and delaying trial. The district court took adequate steps to ensure that proceeding with trial would not prejudice Merck. Also the court allowed Merck the opportunity to prove at trial that the Day 4 and A Batch samples were different than the Day 1 Batch samples for purposes of infringement. Therefore it cannot be said that Merck was prejudiced by the district court’s decision to proceed to trial. And in fact at trial, Merck attempted to prove that mixing promotes conversion of MFA to MFM such that the additional mixing of Amneal’s Day 4 and A Batches would likely convert the MFA to MFM.  In light of the competing evidence in the record, CAFC discerned no clear error in the district court’s finding that the trial evidence failed to demonstrate that the MFA in Amneal’s product would have converted to MFM based on Amneal’s additional mixing. As the district court found, Merck presented little more than theoretical evidence to show that the Day 4 and A Batch samples would be more likely to undergo conversion than the Day 1 Batch samples. Federal circuit also rejected Merck’s argument that it could not prove conversion without testing the Day 4 and A Batch samples. Merck had samples of Amneal’s Exhibit and Day 1 Batches, but made no attempt to experiment with Amneal’s ANDA product to demonstrate conversion by additional mixing and passage of time alone, let alone by matching the mixing, in both speed and duration, that Amneal carried out to arrive at the Day 4 and A Batch samples.

Having concluded that the district court did not abuse its discretion in denying discovery of the Day 4 and A Batch samples, CAFC next turned to Merck’s argument that the district court erred in relying on Amneal’s Day 1 Batch samples to find that Amneal will not infringe the ’353 patent. Merck argued that the district court’s finding of noninfringement must be reversed as a matter of law because the district court improperly based its noninfringement finding on Amneal’s intermediate product (the Day 1 Batch samples) rather than its final, commercial-sized product (the A Batch samples). Federal circuit said that Merck was allowed an opportunity to prove at trial that samples of the Day 4 and A Batches would have materially differed from the Day 1 Batch samples. But Merck failed to do so. Based on the lack of conclusive evidence that Amneal’s additional mixing would have caused conversion in the Day 4 and A Batches, we cannot say that the district court erred in finding that Amneal’s Day 1 Batch samples were adequate to represent Amneal’s final ANDA product for purposes of determining infringement.

Federal circuit also discerned no clear error in the district court’s fact-finding of noninfringement. Although Dr. Matzger testified that he identified a single Raman peak characteristic of MFM in Amneal’s Day 1 Batch samples, his testimony was rebutted. Amneal’s expert, Dr. Marquardt, opined that Dr. Matzger misinterpreted his data and testified that MFM was not present in the Day 1 Batch samples. Dr. Marquardt also disagreed that a single Raman peak was sufficient to distinguish between MFA and MFM. Because its noninfringement finding is supported by the record, CAFC concluded that the district court did not clearly err in its noninfringement finding. Specifically because the district court’s finding that three Raman peaks were required to identify MFM is supported by Dr. Marquardt’s testimony, CAFC concluded that the district court did not clearly err in so finding. 

Methotrexate (RASUVO) - USA

IPR decision (February 7, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Status
IPR2016-01370	July 20, 2016	Feb 8, 2017	Koios Pharmaceuticals LLC	US 8,664,231	Final Written Decision (claims 1–22 are patentable)

On US’231 patent, Antares & Frontier Therapeutic previously filed IPRs (IPR2014-01091 & IPR2016-00649) which were terminated by PTAB.

US 8,664,231 (Medac; 06/01/2029) – OB listed

1. A method for the treatment of inflammatory autoimmune diseases in a patient in need thereof, comprising subcutaneously administering to said patient a medicament comprising methotrexate in a pharmaceutically acceptable solvent at a concentration of more than 30 mg/ml.

Bivalirudin – USA

On Feb 6, 2018, Federal Circuit affirmed a district court’s finding that Hospira doesn’t infringe two blood thinner patents belonging to The Medicines Co., but remanded the question of whether The Medicines Co.'s distribution agreement with another company would render the patents invalid under the so-called on-sale bar.

The Medicines Company owns U.S. Patent Nos. 7,582,727 and 7,598,343. The patents cover an improved process for manufacturing a drug product of bivalirudin, a synthetic peptide used as an anti-coagulant. The Medicines Company’s original manufacturing process occasionally produced batches of Angiomax with unacceptably high levels of the impurity Asp9-bivalirudin. To solve this problem, The Medicines Company developed a new mixing method, which it incorporated in the master batch record on October 25, 2006. The Medicines Company’s contract manufacturer, Ben Venue Laboratories, used this patented mixing method for all Angiomax batches manufactured since October 31, 2006. By using this process, Ben Venue consistently manufactures Angiomax batches with a maximum Asp9-bivalirudin impurity level of 0.6%.

On Feb 27, 2007, The Medicines Company entered into a “Distribution Agreement” with Integrated Commercialization Solutions, Inc. (ICS). That agreement stated that The Medicines Company “now desire[d] to sell the Product” to ICS and ICS “desire[d] to purchase and distribute the Product.” Accordingly, title passed to ICS “upon receipt of Product at the distribution center.” The Distribution Agreement included a “Commercial Price List” dictating the price of the product, and required ICS to place weekly orders “for such quantities of Product as are necessary to maintain an appropriate level of inventory based on customers’ historical purchase volumes.” ICS first received batches of Angiomax produced by the improved process in August 2007.

Seeking to market a generic version of Angiomax, Hospira submitted an Abbreviated New Drug Application (ANDA) to the Food and Drug Administration. In Hospira’s mixing process, the pH-adjusting solution is added to the bivalirudin solution in three equivalent portions. The first two portions are “added rapidly with about 2-minute mixing time,” and the third portion is “added gradually over a period of approximately 10 minutes.” The Medicines Company filed suit in the District of Delaware alleging infringement of the ’727 and ’343 patents under 35 U.S.C. § 271(e)(2). In response, Hospira asserted that the patents are invalid. After a bench trial, the district court concluded that the patents were neither infringed nor invalid. The district court found that the invention was ready for patenting but was not sold or offered for sale before the critical date of July 27, 2008.  Both parties appealed. This case is on remand from Medicines Co. v. Hospira, Inc. (Medicines I), 827 F.3d 1363 (Fed. Cir. 2016) (en banc).

Federal circuit analyzed claims of the ’727 and ’343 patents & determined that both patents require “efficient mixing” as defined by Example 5 of the specification. Therefore, Hospira clearly does not infringe the patented method because it does not perform “efficient mixing.” Hospira adds the pH-adjusting solution in three portions, rather than at a controlled rate. Hospira also uses a single paddle mixer at 560 rpm, but the claimed method requires using a paddle mixer in conjunction with a homogenizer. Because Hospira’s mixing process does not satisfy the “efficient mixing” limitation, federal circuit affirmed the district court’s finding of non-infringement.

With respect to invalidity a patent is invalid under the on-sale bar if, before the critical date, 1) the product is the subject of a commercial offer for sale, and 2) the invention is ready for patenting. Federal circuit said that under the standards established by Medicines I, the terms of the Distribution Agreement make clear that the Medicines Company and ICS entered into an agreement to sell and purchase the product. Those relevant terms include: a statement that The Medicines Company “now desire[d] to sell the Product” to ICS and ICS “desire[d] to purchase and distribute the Product,” the price of the product, the purchase schedule, and the passage of title from The Medicines Company to ICS. Here, the terms of the Distribution Agreement clearly demonstrate the “commercial character” of the transaction. Therefore, the Distribution Agreement was a commercial offer for sale. Of course, the question remains whether the Distribution Agreement covered the patented product. For the on sale bar to apply, the invention, as defined by the patent’s claims, must be on sale. Because the district court incorrectly concluded that the Distribution Agreement was not a commercial offer for sale, it did not reach the question of whether the Distribution Agreement covered the Angiomax created by the new, patented process. Therefore federal circuit left this question for the district court to consider on remand.

With respect to second prong, the district court found that the invention was ready for patenting before the critical date because the master batch record “disclose[d] how to use the process according to the invention.” Federal circuit agreed & held that Ben Venue used the master batch record to produce batches of Angiomax using the patented process. Furthermore, Ben Venue reduced the invention to practice by following the master batch record. Thus the district court correctly determined that the invention was ready for patenting before the critical date.