Bendamustine - USA

On Apr 27, 2020, Delaware court found Eagle pharmaceuticals patents valid & infringed by ANDA filers.

Plaintiffs (Teva, Cephalon and Eagle Pharmaceuticals) sued Defendants (Apotex, Fresenius Kabi, Mylan, and Slayback Pharma) as they sought to bring to market generic versions of Plaintiffs' Bendeka®, a drug indicated for the treatment of chronic lymphocytic leukemia (CLL) and indolent B-cell nonHodgkin lymphoma (NHL). Plaintiffs alleged infringement of U.S. Patent Nos. 9,265,831, 9,572,797 (formulation patents) and  9,144,568, 9,597,399, 9,572,887 (administration patents). Defendants mostly stipulated to infringement of the asserted claims (except two) and argued that all asserted claims are invalid.

Obviousness:

      1.   Formulation patents:

The main components of the asserted formulation are: a non-aqueous liquid composition that contains (1) bendamustine (or a pharmaceutically acceptable salt thereof); (2) about 5% to about 10% by volume of the solvent propylene glycol (PG); (3) the solvent polyethylene glycol (PEG); (4) one of the following ratios of PEG to PG: about 95:5, about 90:10, about 85:15, about 80:20, and about 75:25; and (5) a stabilizing amount of an antioxidant. Two claims also specify components and quantities: (1) claim 11 of the #797 patent requires that "the antioxidant is thioglycerol or monothioglycerol," and (2) claim 5 of the #831 patent requires that "the bendamustine concentration is from about 25 mg/mL to about 50 mg/mL." Certain claims also recite stability limitations such as "less than or equal to 0.11 % PG esters at about 1 month of storage at about 5°C.

Bendamustine is prone to degradation because of two functional groups (a nitrogen mustard group and a carboxylic acid group). Because water causes bendamustine to degrade at its nitrogen mustard group, the prior art bendamustine formulations used a lyophilized (freeze-dried) form of bendamustine that required a human operator to reconstitute it using water shortly before administering it to a patient. But this reconstitution by human manipulation had two known disadvantages: it increased the risk of contamination and, because bendamustine is a cytotoxic compound, it posed a potential danger to the operator. Inventor of the asserted patents overcame this problem by providing stable non-aqueous bendamustine composition which contains appropriate quantities of PG & PEG solvents.

Defendants argued that five prior art references would have motivated a POSITA to arrive at the asserted formulation claims with a reasonable expectation of success: Olthoff, Drager, Alam, Rowe, and Boylan.

Olthoff (1983) – discloses non-aqueous, ready to use bendamustine formulation (25 and 100 mg/mL) in polyols such as PG & PEG. Olthoff's examples did not use an antioxidant.

Drager (2008) – discloses stable liquid pharmaceutical formulations comprising bendamustine.But Drager determined that the "results described in [Olthoff] were not reproducible." Drager' s data showed that bendamustine in 99% PG degraded almost completely after eight weeks at 25°C and more than 20% at 5°C after one year.  The reason for that degradation, according to Drager, was that (1) PG causes bendamustine to degrade at the nitrogen mustard group and (2) PG's OH groups cause bendamustine to degrade at the carboxylic acid group through esterification. As a solution to the degradation problem, Drager disclosed the use of aprotic solvents (DMA). Drager also taught that protic solvents-i.e., solvents, including PEG and PG, that have OH groups-are acceptable to use with bendamustine but only when combined with aprotic solvents.

Alam (1989) - disclosed stable liquid formulations of cyclophosphamide, a compound that, like bendamustine, has a nitrogen mustard group & tested its stability in 3 polyols (PG, PEG & glycerols). Alam disclosed using PG at a ratio of from about 10% to about 90% and PEG at a ratio of from about 90% to about 10%.

Rowe -  Rowe's Handbook of Pharmaceutical Excipients disclosed that PEG is susceptible to oxidation and that one can use an antioxidant to prevent such oxidation.

Boylan - Boylan disclosed a list of "some of the most commonly used antioxidants in pharmaceutical injectable formulations" including monothioglycerol.

Defendants argued that Olthoff, Drager, and Alam would have motivated a POSITA to use PEG and PG with bendamustine. Court, however, said that Drager teaches away from Olthoffs teaching of using polyols. Specifically, Drager determined that the results described in [Olthoff] were not reproducible & bendamustine degrades completely in PG after 8 weeks. Drager, therefore, suggested use of aprotic solvent as major component. Drager specifically showed that a formulation containing 66% DMA and 34% PG is stable. Drager, thus, teaches away from the use of only protic solvents (PG & PEG). Therefore, Drager would not have motivated a POSA to replace DMA with a low-OH protic solvent. POSA would have given more weightage to Dragger over Olthoff because data is more reliable in Dragger since it used HPLC & Olthoff used TLC method. Moreover, in the decades between Olthoffs publication in 1983 and the priority date in 2010, Olthoffs formulations were never used, suggesting that POSA generally did not rely on Olthoff. Third reference, Alam is related to cyclophosphamide & the structural differences between bendamustine & cyclophosphamide would have discouraged POSA because degradation pathway would be different. Therefore, POS A would not have viewed cyclophosphamide as a relevant comparator for bendamustine reactions, and would not have considered Alam in formulating a stable bendamustine formulation. In sum, Defendants have not proven by clear and convincing evidence that Olthoff, Drager, and Alam would have motivated a POSITA to use PEG and PG to create a non-aqueous liquid bendamustine formulation.

Since, POSA would not have motivated to use PG & PEG, the other claimed limitations such as PEG:PG ratio, use of antioxidant, bendamustine concentration, stability limitations would not have been obvious. With respect to only argued secondary consideration - “commercial success”,  court said that the evidence of $2 billion sales of Bendeka  does not support a finding of nonobviousness. First, Bendeka® sells at a lower price than the prior art lyophilized Treanda® product. Second, Plaintiffs' cluster of exclusivities has blocked others from entering the market. Court finally held that although the evidence of commercial success does not support a finding of nonobviousness, Defendants have not shown by clear and convincing evidence that the prior art they cited would have motivated a POSIT A to reach the claimed formulations.

      2.  Administration patents:

The asserted administration claims recite methods of treating CLL or NHL with a liquid bendamustine composition. Certain claims require administering the bendamustine composition on days one and two of a 21-day cycle for NHL, or on days one and two of a 28-day cycle for CLL. One claim requires a bendamustine dose of"about 25 mg/m2 to about 120 mg/m2”. The asserted administration claims also specify administration times, the longest time being "about 15 minutes or less”.They also specify administration volumes that are all 100 mL or less. Finally, certain claims specify post dilution bendamustine concentrations ranging from 0.05 mg/mL to 12.5 mg/mL.

Defendants argued that eight prior art references would have motivated a POSIT A to combine the elements of the claimed administration with a reasonable expectation of success: Palepu 2011 (Formulation patents as discussed above), the Treanda® Label, Preiss 1985 (PK study with 3 minutes of administration of bendamustine with 280 to 375 mg dose), Preiss 1998 (MTD study with 3 to 10 minutes of administration of bendamustine with 54 to 226 mg/m2 dose), Schoffski 2000a (administration of bendamustine over 30 minutes and compared its results to the three-to-ten-minute infusions disclosed in Preiss 1998), Schoffski 2000b (Schoffski 2000b administered 60 to 80 mg/m2 of bendamustine in 30 minutes), Barth (suggested administering bendamustine in a solvent volume of 100 to 250 mL), and Glimelius (disclosed the administration of 5-Fluorouracil to treat colorectal cancer as an infusion lasting ten to 20 minutes using a 50 to 100 mL mini-bag).

Court said that prior arts would have motivated a POSA to reach the claimed formulation, dose, and dosing schedule. But, the prior arts would not have motivated a POSA to reach the remaining claim limitations (Administration Times, Volumes, and Post-Dilution Concentrations), and thus the claims as a whole are not obvious. All asserted claims require administering bendamustine in 15 minutes or less, with some requiring ten minutes or less. All asserted claims also require administering bendamustine in a volume of 100 mL or less, with some claims requiring about 50 mL. Finally, all but one of the asserted administration claims require post-dilution bendamustine concentrations ranging from 0.05 to 12.5 mg/mL. Defendants argued that the Preiss studies support a finding that the claimed administration times, volumes, and concentrations are obvious. Court, however,found that Preiss studies would not have motivated a POSA to reach the claimed administration times, volumes, or concentrations because (1) a POSA would not have relied on the Preiss studies to determine a safe and effective infusion time, volume, or concentration for bendamustine because those studies were not designed to evaluate safety, (2) subsequent prior art taught away from Preiss's three-to-ten-minute infusions, instead, it would have considered later prior art references that used 30 to 60 minute infusions and a 500 mL volume and (3) Defendants only hypothesize that the Preiss studies used volumes and concentrations similar to those in the claimed administrations, such speculations about Preiss's infusion rate and volume, however, are only based on "conclusory and unsupported expert testimony" and they do not support a finding of obviousness by clear and convincing evidence.

With respect to secondary consideration, Plaintiffs offered at trial evidence of four secondary considerations that bear on the administration claims: skepticism, long-felt need, commercial success, and industry praise. Court, however, did not find this evidence to be probative indicia of nonobviousness.

Indefiniteness:

Defendants argued that the asserted formulation claims are invalid because they each require "a stabilizing amount of antioxidant"-a requirement Defendants contend is indefinite. Specifically, Defendants argued that the term is indefinite because "[t]he specification does not explain how to determine whether stability has been 'increased' or 'enhanced.’ Court, however, disagreed  & said that the patents provide a POSA with a method for measuring stability: using HPLC to compare the amount of overall bendamustine degradation with and without the antioxidant. Example 3 demonstrates that a POSA would compare the amount of bendamustine remaining in the same formulation, stored under the same conditions, with and without the antioxidant. In addition to providing exemplary test methods, the specification also lists "suitable antioxidant amounts" and "antioxidants," and provides examples of "stabilizing" amounts. Court, thus found that the term "stabilizing amount of antioxidant" is not indefinite and court construed it as: any amount of an antioxidant that decreases the amount of bendamustine degradation after any time period and at any temperature.

Enablement:

Defendants asserted that the asserted formulation claims are invalid for lack of enablement because the formulation patents disclosed neither the use of sodium hydroxide (NaOH) or of "other undisclosed variables." Specifically, Defendants argued that the asserted formulation claims are not enabled because the claims do not contain NaOH and "a pH adjuster like NaOH is necessary to obtain the PG ester levels claimed in the [a]sserted [f]ormulation claims. Court said that evidence that some claimed formulations did not result in the PG ester limitations, does not establish that the claims are not enabled. Defendants have not presented any evidence to show that a POSA would have had to undertake undue experimentation to alter the formulation to obtain the PG ester limitations. That some formulations with the claimed ingredients do not satisfy the PG ester limitations does not support non-enablement unless the number of such formulations is significant enough to have required a POSA to experiment unduly. [Atlas Powder, 750 F.2d at 1576-77….Even if some of the claimed combinations were inoperative, the claims are not necessarily invalid ....)]. Accordingly, Defendants failed to establish by clear and convincing evidence that the asserted claims are invalid for lack of enablement.

Lack of written description:

Apotex argued that claim 9 of the #797 patent is invalid for lack of written description. It asserted that "the absence of any mention of a pH adjuster like NaOH in the [#]797 patent demonstrates that the inventors did not have possession of it at that time, as confirmed by their later filing of another patent application that discloses and claims it." Court said that "written description is about whether the skilled reader of the patent disclosure can recognize that what was claimed corresponds to what was described .... ["Alcon Research Ltd. v. Barr Labs., Inc., 745 F.3d 1180, 1191 (Fed. Cir. 2014)]. And Apotex never citeed the intrinsic record to show that the asserted formulation patents claim something that they do not describe in their written descriptions. Instead, Apotex improperly cited extrinsic evidence-the later-filed Eagle patent application. Apotex has thus failed to establish that claim 9 is invalid for lack of written description.

Infringement:

Defendants stipulated to infringement of the asserted claims with two exceptions. Apotex, Fresenius Kabi, and Mylan argued that (1) they do not infringe the asserted formulation claims because their ANDA products do not contain "a stabilizing amount of an antioxidant" as the asserted formulation claims require, and (2) they do not directly infringe or induce infringement of claim 9 of the #797 patent, which requires that the "bendamustine-containing composition ha[ve] less than or equal to 0.43 % total PG esters at about 3 months of storage at a temperature of about 25°C," because their proposed labeling does not direct physicians to store their ANDA products for about 3 months at about 25°C.

With respect to first point, court said that it has construed the term as any amount of an antioxidant that decreases the amount of bendamustine degradation after any time period and at any temperature. Defendants' ANDA products each contain 5 mg/mL of the antioxidant monothioglycerol and the formulation patents' written description shows that 5 mg/mL of monothioglycerol is a stabilizing amount. The written description identifies "5 mg/mL to about 20 mg/mL" as a "preferable" stabilizing amount of antioxidant. Moreover, Example 3 demonstrates that adding "5 mg/m[L] of lipoic acid ... as a stabilizing antioxidant" to 20 mg/mL of bendamustine in PEG decreased the amount of bendamustine degradation after 15 days at 25°C and 40°C as compared to the same formulation without an antioxidant. Moreover, Fresenius Kabi and Mylan represented to the FDA that 5 mg/mL monothioglycerol was sufficient to ensure that the amount of bendamustine in their ANDA products did not fall below specification limits.

With respect to second point,  Defendants stipulated that their ANDA Products have "less than or equal to 0.43% total PG esters at about 3 months of storage at a temperature of about 25° C," but contend that they do not directly infringe or induce infringement of claim 9 because their proposed labeling does not recommend storing their ANDA Products for "about 3 months" at "a temperature of about 25° C." Court, however, said that even though Defendants' labeling does not mention storage, Defendants' ANDA products directly and indirectly infringe claim 9 because the PG ester limitation does not require the user to store the products for three months at 25°C. Claim 9's PG ester limitation describes a characteristic of the claimed formula; it is not a method step and thus, does not require action to infringe. The claim does not recite testing for the PG ester limitation; it just describes a composition that would have less than 0.43% PG esters if one were to test for them after storing the composition for three months at 25°C. Therefore, Defendants infringe and induce infringement of each of the asserted claims.

Rituximab – USA

On Apr. 27, 2020, Federal Circuit dismissed Pfizer’s appeal for lack of standing as it failed to establish that it was suffering a cognizable injury at all stages of appeals.

Chugai Pharmaceutical Co., Ltd., owns US 7,332,289 and US 7,927,815 patents. In two inter partes review proceedings, Pfizer Inc. petitioned the Patent Trial and Appeal Board to invalidate most of the claims of the ’289 and ’815 patents. In each IPR, the Board held that Pfizer did not prove that any of the challenged claims were unpatentable.

Pfizer appealed.

During appeal, Federal Circuit said that to establish Article III standing, an appellant must show that it has “(1) suffered an injury in fact, (2) that is fairly traceable to the challenged conduct of the defendant, and (3) that is likely to be redressed by a favorable judicial decision.” “To qualify as a case fit for federal-court adjudication, ‘an actual controversy must be extant at all stages of review . . . .’” [Arizonans for Official English v. Arizona, 520 U.S. 43, 67 (1997)]. Pfizer filed its notice of appeal on January 30, 2019. Evidence of standing that Pfizer provided to the court occurred much later in 2019. Specifically, Pfizer submitted evidence that the FDA approved its rituximab biosimilar in July 2019 and that Pfizer announced at the end of October 2019 that it would begin selling the biosimilar in the USA in January 2020 as result of settlement between Pfizer & Genentech (Roche group). F. Hoffmann-La Roche Ltd is the majority owner of appellee, Chugai. But, Chugai was not a party to that settlement agreement, and Pfizer did not get a license from Chugai for the patents at issue in this appeal. Moreover, Pfizer did not cite any evidence regarding its activities or plans relating to its rituximab biosimilar before July 2019. Pfizer thus failed to supply any evidence that it was suffering from an injury in fact when this appeal began. Nor has Pfizer offered evidence that would allow court to evaluate whether it practices or intends to practice the patented methods in the course of making its biosimilar product.

Court also rejected Pfizer’s “self-evident” theory that there was “a product at issue” when the appeal began. Specifically, Pfizer listed “rituximabIPR@win-ston.com” in its petitions as its service email address for the IPR proceedings. Court said that Pfizer’s service email address and Chugai’s response do not tell the court anything useful about Pfizer’s plans for its biosimilar, Ruxience®, as of the beginning of 2019, when this appeal began. Nor does that evidence establish with sufficient likelihood that the processes used to prepare Pfizer’s product would infringe Chugai’s patents. The court therefore did not find standing based on that evidence and dismissed the appeal.

Fosaprepitant - USA

IPR decision: Apr. 20, 2020

AIA Review #	Filing Date	Institution Date	Petitioner	Patent	Respondent	Status
IPR2019-01446	08/01/2019	01/31/2020	Nevakar, Inc.	9,913,853	Cipla	Terminated-Dismissed

US 9,913,853 (Cipla Ltd.; Exp: 11/3/2036)

1. A liquid composition comprising fosaprepitant or a salt thereof and at least one liquid excipient, wherein after storage at 2-8.degree. C. for at least 1 month, aprepitant is present in an amount concentration of no more than 10%, wherein the composition is ready-to-use or ready-to-dilute.

17. A liquid pharmaceutical composition comprising: a) fosaprepitant dimeglumine in an amount from 50-250 mg; b) at least one salt of ethylenediaminetetraacetic acid in an amount from 10-100 mg; c) albumin in an amount from 250 mg-100 g; and d) water in an amount from 3-300 ml.

20. A liquid pharmaceutical composition comprising: a) fosaprepitant dimeglumine in an amount from 50-250 mg; and b) at least one solubilizer in an amount from 1-5 ml.

Fingolimod – USA

On Apr. 23, 2020, Federal Circuit dismissed Argentum’s appeal for lack of standing without reaching merit of the case.

Petitioners such as Apotex, Sun pharma, Teva/Actavis & Argentum filed IPRs on US 9,187,405 patent with PTAB. On July 11, 2018, the Board concluded that Apotex, Sun, Teva, Actavis, and Argentum had not demonstrated unpatentability of the claims. Petitioners appealed the Board’s findings. During the appeal process, all Petitioners other than Argentum settled their respective appeal with Novartis. On August 29, 2018, before opening briefs had been filed, Novartis filed a motion to dismiss Argentum’s appeal for lack of standing.

Court said that to prove standing, Argentum bears the burden of showing that it has “(1) suffered an injury in fact, (2) that is fairly traceable to the challenged conduct of the defendant, and (3) that is likely to be redressed by a favorable judicial decision.” Argentum argued that it demonstrated at least three concrete injuries in fact.

First, Argentum argued that without an opportunity to seek this Court’s redress, it faces a real and imminent threat of litigation as it jointly pursues, along with its partner KVK-Tech, Inc., a generic version of Novartis’ Gilenya® product for which they are in the process of filing an ANDA. It  further argued that given that Novartis already sued multiple generic companies to protect Gilenya®, “it is virtually certain that Novartis will sue Argentum and KVK,” which is “far from conjectural” and “constitutes an imminent injury for purposes of standing.” Novartis responded that any ANDA to be filed for a generic version of Gilenya® “will be filed by KVK, Argentum’s manufacturing and marketing partner”, and thus KVK, not Argentum is at risk of being sued. And even if the litigation were personal to Argentum, it would not confer standing because it is merely conjectural. Citing decision in “Altaire Pharmaceuticals, Inc. v. Paragon Bioteck, Inc.”, Argentum responded that “showing a concrete injury-in-fact does not necessitate an already-filed ANDA.” Court said that in Altaire, Altaire was the company which intended to file an ANDA and would be at imminent risk of being sued. Unlike in Altaire, according to Mr. Gardner (Argentum’s CEO), any ANDA to be filed will be filed by KVK, Argentum’s manufacturing and marketing partner & Novartis will inevitably sue KVK for patent infringement.

Second, Argentum argued that it will incur significant economic injury as its investments in developing a generic version of Gilenya® and preparing an ANDA would be at risk with a “looming infringement action by Novartis.” Novartis argued that Argentum’s alleged “economic injury,” which is entirely speculative and not personal to Argentum, does not suffice to establish injury in fact because it is not concrete or particularized. Court sided with Novartis & said that Argentum has not provided sufficient evidence to establish an injury in fact through economic harm. Argentum has failed to provide sufficient evidence that it invested in KVK’s generic Gilenya® product or ANDA. It stated only in generalities that both “KVK and Argentum have been diligent in working toward FDA submission of the ANDA” and that “Argentum has invested significant man-power and resources to the endeavor.”

Third, Argentum argued that absent relief from this court, Argentum would be estopped under 35 U.S.C. § 315(e) from raising the patentability and validity issues in a future infringement action. Novartis argued that Argentum has not shown that it will be harmed by estoppel where it has not established there is risk of an infringement suit. Court sided with Novartis & said that § 315(e) does not constitute an injury in fact when, as here, the appellant is not engaged in any activity that would give rise to a possible infringement suit.

Court held that Argentum failed to prove that it has suffered an injury in fact necessary to establish standing & thus, dismissed the appeal.

Dimethyl fumarate /Monomethyl fumarate – USA

On Apr. 21, 2020, Federal Circuit affirmed Delaware district court’s decision and found Banner’s 505(b)2 product containing monomethyl fumarate non infringing Biogen’s extended patent.

Plaintiff Biogen International GmbH owns U.S. Patent No. 7,619,001 which is listed in OB for Tecfidera® (Dimethyl fumarate). US’001 patent originally set to expire on April 1, 2018 but Biogen filed patent term extension (PTE) and thus term was extended till June 20, 2020. On January 18, 2018, Banner submitted NDA under§ 505(b)(2), seeking approval for Bafiertam (monomethyl fumarate "MMF") delayed-release capsules for the treatment of Multiple Sclerosis. Biogen sued Banner for infringement of the '001 Patent on December 27, 2018 within 45 days & obtained an automatic 30-month stay of FDA approval of Banner's Bafiertam product. Banner then moved under Rule 12(c) for judgment on the pleadings on the basis of non-infringement, reasoning that the '001 Patent's extension does not cover Banner's tentatively-approved product. On Jan 07, 2020, the district court agreed with Banner’s interpretation of 35 U.S.C. § 156 and rendered a judgment of noninfringement. You can read the detailed summary previously "reported here".

Biogen appealed.

During appeal Federal Circuit said that the Hatch-Waxman Act provided for patent term extensions in § 156 to partially compensate NDA applicants for the loss of patent life occurred during review period. Under § 156, an NDA holder is entitled to extend the term of only one patent for the corresponding approved product. Critically, for the purposes of this appeal, subsection (f) defines “product” as “the active ingredient of . . . a new drug . . . including any salt or ester of the active ingredient.”

Biogen argued that the district court misinterpreted “product” in § 156(f) as not encompassing a de-esterified form of an approved product. Biogen further argued that this court decided in Pfizer Inc. v. Dr. Reddy’s Labs., Ltd., 359 F.3d 1361 (Fed. Cir. 2004), that “product” has a different meaning under § 156(b), encompassing the de-esterified form. In that circumstance, “active ingredient” means “active moiety.” On the contrary, Banner argued that § 156(f) provides a consistent definition of “product” for the entire statute, a definition that this court expressly held in Glaxo and PhotoCure ASA v. Kappos, 603 F.3d 1372 (Fed. Cir. 2004), excludes a de-esterified form of the active ingredient.

Federal Circuit said that neither a Glaxo case nor a Pfizer case governs this particular case. It is governed by the statute. “Active ingredient” is a term of art, defined by the FDA as “any component that is intended to furnish pharmacological activity or other direct effect,” 21 C.F.R. § 210.3(b)(7), and it “must be present in the drug product when administered.” [Hoechst-Roussel Pharm., Inc. v. Lehman, 109 F.3d 756, 759 n.3 (Fed. Cir. 1997) (citation omitted)]. The active ingredient of a given drug product is defined by what is approved and is specified on the drug’s label. MMF is not the approved product, nor is it specified as the active ingredient on the Tecfidera® label. Esters are included in the statutory definition of what can be extended, but MMF is the de-esterified form of DMF, not an ester of DMF. Thus, it is not the same product under § 156(f) and does not fall within the scope of the ’001 patent’s term extension under § 156(b)(2).

Tiotropium bromide - USA

Claim Construction (District of New Jersey): Apr. 16 2020

[BOEHRINGER INGELHEIM PHARMACEUTICALS, INC. et al v. LUPIN ATLANTIS HOLDINGS SA et al;

Case : 3:2018cv12663]

This case arises out of an action for patent infringement instituted by Boehringer against Lupin. Boehringer manufactures and sells SPIRIVA® HandiHaler® (“product” or “inhaler”) for the purpose of treating bronchospasm associated with chronic obstructive pulmonary disease (“COPD”). US 7,694,676 patent is at issue, entitled “Dry Powder Inhaler.” The first claim term at issue appears in the preamble of the ’676 Patent, which states the patent is directed to “[a]n inhaler for inhaling powdered pharmaceutical compositions from capsules.” The second claim term at issue appears in Claims 1 and 13 of the ’676 patent and specifies the location of the gripping aid as “disposed proximate to an edge of the mouthpiece and proximate to the actuating member when the mouthpiece is closed.”

Claim 1. An inhaler for inhaling powdered pharmaceutical compositions from capsules, comprising: a lower part, a plate which can be latched to the lower part and with which the lower part can be closed off, and a capsule holder for receiving the capsules, this holder being adapted to be lowered into the lower part, a mouthpiece latchable to the plate, a lid which covers the mouthpiece in a closed position and latches it by means of a closure element, the lower part, the plate, the mouthpiece and the lid being hinged together by means of a single joint, and an actuating member which can be moved out a resting position and thereby interacts with at least one pin which can be made to pierce the capsule holder, wherein: the mouthpiece has a gripping aid by means of which the mouthpiece can be flipped open, away to the side, the gripping aid disposed proximate to an edge of the mouthpiece and proximate to the actuating member when the mouthpiece is closed the actuating member is constructed as a double function actuating member by means of which, in a first actuation, the closure element can be released from the lower part in order to swivel the lid, and with which, in a second actuation, the capsule is pierced, the actuating member including a recess to receive and engage the closure element when the lid covers the mouthpiece in the closed position.

Claim 13. An inhaler for inhaling powdered pharmaceutical compositions from capsules, comprising; a lower part, a plate which can be latched to the lower part and with which the lower part can be closed off, and a capsule holder for receiving the capsules, this holder being adapted to be lowered into the lower part, a mouthpiece latchable to the plate, a lid which covers the mouthpiece in a closed position and latches it by means of a closure elemental the lower part, the plate, the mouthpiece and the lid being hinged together by means of a single joint, and an actuating member which can be moved out a resting position and thereby interacts with at least one pin which can be made to pierce the capsule holder, wherein the mouthpiece has a gripping aid by means of which the mouthpiece can be flipped open, away to the side, the gripping aid disposed proximate to an edge of the mouthpiece and proximate to the actuating member when the mouthpiece is closed, the actuating member including a recess to receive and engage the closure element when the lid covers the mouthpiece in the closed position.

The chart below sets forth the parties’ proposed constructions.

Claim Language	Asserted Claims	Boehringer Construction	Lupin Construction
“inhaler for powdered pharmaceutical compositions from capsules”	’676 Claims 1, 13	Preamble term is limiting, does not require further construction	Preamble term is not Limiting. If it is limiting, should be construed as “inhalation device”
“gripping aid disposed proximate to an edge of the mouthpiece and proximate to the actuating member when the mouthpiece is closed”	’676 Claims 1, 13	“gripping aid located close to an edge of the mouthpiece and close to the actuating member when the mouthpiece is closed”	“gripping aid disposed next to or immediately before/after an edge of the mouthpiece and next to or immediately before/after the actuating member when the mouthpiece is closed”

Construction of Disputed Terms:

A. The Meaning of “inhaler for inhaling powdered pharmaceutical compositions from capsules”

Court’s construction: Court finds the preamble term, “inhaler for inhaling powdered pharmaceutical compositions from capsules” is limiting.

B. The Meaning of “proximate to”

Court’s construction: Court construes “proximate” to have its plain and ordinary meaning, which is “near or close to.”

Methylnaltrexone - USA

On Apr. 08, 2020, Federal Circuit reversed district court’s summary judgment decision of non-obviousness & remanded case back for further consideration.

Valeant (Plaintiff) owns US 8,552,025 (expiring in Apr. 2024) patent, which claims stable methylnaltrexone pharmaceutical composition. Methylnaltrexone is unstable in aqueous solution, therefore, inventors of US’025 patent discovered optimum pH of 3 to 4 to stabilise the composition. This patent is listed in Orange Book against Valeant’s approved product, Relistor® (methylnaltrexone injection) which is used to treat constipation as a side effect of taking opioid medication. Mylan submitted ANDA with USFDA to market generic equivalent and then Valenant sued Mylan in New Jersey court subsequently.

Relevant here are claim 1 and claim 8 of the ’025 patent. Claim 8 depends from claim 1, which recites:

1. A stable pharmaceutical preparation comprising a solution of methylnaltrexone or a salt thereof, wherein the preparation comprises a pH between about 3.0 and about 4.0.

8. The pharmaceutical preparation of claim 1, wherein the preparation is stable to storage for 24 months at about room temperature.

Before the district court, Valeant moved for summary judgment that claim 8 would not have been obvious, and the district court granted Valeant’s motion. The court rejected Mylan’s expert testimony and cited references as insufficient, largely because the references did not teach methylnaltrexone formulations but instead formulations of similar but different compounds, naloxone and naltrexone.

Mylan appealed.

During appeal, Mylan argued that the district court erred in at least two respects: (1) by failing to hold that Mylan established a prima-facie case that claim 8 would have been obvious because the pH range in the claim overlaps with pH ranges in the prior art for similar compounds and (2) by resolving disputed fact issues at summary judgment.

With respect to first point, Mylan argued that although cited references teach different compounds (naloxone & naltrexone) but they disclose formulations with pH ranges that overlap with the range recited in claim 8, pH between about 3 and about 4. And thus these references established a prima-facie case of obviousness. While no reference contemplates methylnaltrexone specifically, Mylan submitted that methylnaltrexone bears significant structural and functional similarity to both naloxone and naltrexone such that a person of skill in the art would seek to use prior disclosed pHs for naloxone and naltrexone when formulating solutions of methylnaltrexone. Valeant responded that overlapping ranges for different chemical compounds that fail to meet claim 8’s stability requirement do not establish obviousness. According to Valeant, the structural and functional similarities of the compounds are not relevant because claim 8 recites a solution of methylnaltrexone with a stability profile unrecognized and unattained in the prior art.

Court, however agreed with Mylan & said that a prima-facie case of obviousness typically exists when the ranges of a claimed composition overlap the ranges disclosed in the prior art. However, here is a little difference, none of the references disclose the same drug as the one claimed. But that does not make much difference because for chemical compound claims, a prima facie case of obviousness “frequently turns on the structural similarities and differences between the compounds claimed and those in the prior art.” [Daiichi Sankyo Co. v. Matrix Labs., Ltd., 619 F.3d 1346, 1352 (Fed. Cir. 2010) (citing In re Dillon, 919 F.2d 688, 692 (Fed. Cir. 1990) (en banc))]. Moreover, an obviousness analysis can also rely on prior art compounds with similar pharmacological utility in addition to structural similarity [In re Merck & Co., Inc., 800 F.2d 1091, 1097 (Fed. Cir. 1986) (holding that a person of skill in the art would have expected amitriptyline to resemble imipramine in the alleviation of depression in humans because of the drugs’ close structural similarity and similar use)].

Here, the prior arts teach stable formulations of naloxone, naltrexone, and methylnaltrexone. All these compounds are well-known opioid antagonists that operate by binding to the body’s opioid receptors without activating them. Each is an oxymorphone derivative, and the group mem-bers have remarkably similar structures, as indicated earlier. Because of the strong structural and functional similarity between the molecules, a person of skill could expect similar stability of the molecules at similar pH ranges in solution. Therefore, Mylan has at least raised a prima-facie case of obviousness. The district court erred by rejecting this inference as a matter of law at the summary judgment stage.

With respect to second point, Mylan argued that there were factual disputes precluding summary judgment. In Mylan’s view, the district court disregarded its obvious-to-try evidence because the pH ranges taught in the prior art were not sufficiently narrow. Mylan submitted that the adequacy of a prior art range is a classic question of fact and that the district court imposed a heightened predictability requirement. With respect to this argument, district court held that there was not a finite number of options between pH ranges falling between 3 and 7. As a matter of “basic math,” given any two unequal numbers, the quantity of number ranges falling between the two is infinite, not finite. The district court also rejected Mylan’s citations of expert testimony and prior art references because none of the references identified pH as the “first variable” that an experienced formulator would consider.

Federal circuit said that district court’s obvious-to-try analysis is inconsistent with precedent. The bounded range of pH 3 to 4 presents a finite number of narrower pH ranges for a skilled artisan to try. As a matter of math, there may be an infinite potential number of ranges within the range 3 to 4, but only if the realities of pH values (and the limitations of commercially available pH meters) are ignored. And in our view of basic math and based on the record, there is only one significant figure after the decimal point, in which case the range of pH variables is ten, or, if one considers two significant figures after the decimal point, one hundred, not an infinity. With respect to “first variable” requirement, Federal Circuit said that there is no requirement that for a variable to be obvious to try, it must be the first variable a person of skill would alter. And as to the stability limitation, a fact-finder could draw the inference from this record that trying a pH of 3–4 would lead to a methylnaltrexone formulation stable at room temperature. Absolute predictability that the proposed pH range would yield the exact stability parameters in the claim is not required. Moreover, it is important to note that pH is in fact the only variable in claim 8, not one of many variables that can be experimented with. Thus, the district court’s grant of summary judgment on Mylan’s obvious-to-try theory was in error.

Epinephrine – USA

On March 31, 2020, Delaware district court found epinephrine composition patent invalid & not infringed by Hospira’s 505(b)2 product.

This is a Hatch-Waxman litigation, where Plaintiff (Belcher Pharmaceuticals, LLC) sued Defendant (Hospira, Inc.) for filing NDA with USFDA to market Epinephrine Injection. Belcher is the holder of NDA No. 205029, which was approved by FDA on July 29, 2015 for a 1 mg/mL injectable l-epinephrine formulation with 1 mL of solution contained in a 2 mL ampule. Hospira’s NDA seeks FDA approval of a 0.1 mg/mL injectable l-epinephrine formulation.

Background:

Belcher’s NDA was a paper NDA, means “literature-only” based submission. It was essentially based on Sintetica’s early pharmaceutical preparations of epinephrine, which was preservative and sulphites free, had pHs of 2.8-3.3, and included 15% more epinephrine (i.e., an “overage”) than “the theoretical value to compensate the activity loss during manufacturing and storage.” As part of its NDA, Belcher sought to replace the “old” in-process pH of 2.8-3.3 with a “new” in-process pH of 2.4-2.6, and use an overage of 10-15%. But during review, FDA asked Belcher to evaluate the effect of an in-process pH of 2.4 to 2.6 on racemization of epinephrine. Belcher’s regulatory consultants – INC Research – recommended that Belcher use the in-process pH of 2.8-3.3 presented in the original NDA and Sintetica batch data, since any changes in the process from the process used to obtain the batch data would delay approval. Thus, Belcher submitted its response to the FDA, stating, they have refocused their studies on determining the effect of the in-process pH of 2.8-3.3 and not pH of 2.4 to 2.6. The FDA ultimately approved Belcher’s epinephrine product with a pH of 2.8-3.3.

During litigation, Plaintiff specifically asserted infringement of claims 6 & 7 of US 9,283,197 patent which is expiring in Aug. 2034. The patent is related to more potent and less toxic formulations of epinephrine.  The asserted claims are as follows:

6. An injectable liquid pharmaceutical formulation of l-epinephrine sterile solution; said liquid pharmaceutical formulation having a pH between 2.8 and 3.3; said injectable liquid pharmaceutical formulation compounded in an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine, and further including a tonicity agent; said liquid pharmaceutical formulation including no more than about 6% d-epinephrine and no more than about 0.5% adrenalone at release, and no more than about 12% d-epinephrine and no more than about 0.5% adrenalone over a shelf-life of at least 12 months.

7. The said injectable liquid pharmaceutical formulation of claim 6 further having a concentration of 1 mg per mL l-epinephrine.

Belcher alleged that Hospira’s bioequivalent product infringes US’197 patent under the doctrine of equivalents. Hospira contends that it does not infringe the ’197 Patent and, further, that the Patent is invalid and/or unenforceable. In June 2019, the Court held a two-day bench trial.

Infringement: Doctrine of Equivalents

The parties agreed that only one claim limitation is at issue and, thus, “the only dispute is whether Hospira’s [0.1 mg/mL] NDA Product is equivalent to a formulation ‘compounded in an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine.’” Belcher argued the two are equivalent because both are intended to use low (0-6%) overages and to deliver the same total amount (1 mg) of epinephrine to a patient (Hospira's product contains 10 ml solution). Hospira responds that the claims are directed to concentrations, not overages or amounts, and the concentrations of the claim and the Hospira NDA Product are, indisputably, not equivalent. Court agreed with Hospira.

Central to the parties’ dispute is whether the Court, in applying DOE, should look to the claimed concentration itself, or the intended purpose of that concentration. Court said that the all-elements rule mandates that the Court look only at the claimed concentration – “compounded in an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine” – and not the intended overage, amount, or use of the formulation as a whole, as none of those features are claimed. The disputed claim limitation is directed to concentration, so to prove infringement Belcher was required to prove that the accused product practices the claimed concentration, either literally or by equivalents. Having failed to do so, the Court cannot find infringement.

Invalidity:

Hospira sought to invalidate claims 6 and 7 of the ’197 Patent on three independent bases: (1) the prior art anticipates the claims; (2) the prior art renders the claims obvious; and (3) the Patent fails to list all of the correct inventors. (4) Hospira also argued that the ’197 Patent is unenforceable based on inequitable conduct.

Anticipation:

Hospira argued the ’197 Patent is invalid based on two pieces of anticipatory prior art: (1) JHP’s Adrenalin Product; and (2) Hospira’s Ampul Product. Court said that neither JHP’s Adrenalin Product nor Hospira’s Ampul Product anticipates the claimed invention, as neither teaches a “formulation compounded in an aqueous solution as 1.0 to 1.06 mg/mL l-epinephrine”. The Court construed this limitation as a product-by-process limitation, which means that, “for validity purposes, the ‘invention’ . . . is the product.” Medicines Co. v. Hospira, Inc., 827 F.3d 1363, 1374 (Fed. Cir. 2016). Hospira argued there are no structural differences between the claimed invention and JHP’s Adrenalin Product or Hospira’s Ampul Product, as all constitute a 1 mg/mL epinephrine product according to the USP. Court, however said that to anticipate the claimed invention, the prior art must have a post-compounding l-epinephrine concentration between 1.0 and 1.06 mg/mL. This does not mean at any time after compounding (like Hospira’s Ampul Product, which arguably had 1.002-1.01 mg/mL l-epinephrine at testing, but some time relatively immediately thereafter. The prior arts products have higher post-compounding overages and concentrations (e.g., 1.095-1.134 mg/mL for JHP’s Adrenalin Product and approximately 1.1 mg/mL for Hospira’s Ampul Product) than the claimed invention. Thus, this structural difference precludes a finding of anticipation.

Obviousness:

Court said that the FDA historically approved (or permitted through grandfathering) the sale of epinephrine products that complied with the USP monograph, which set the upper limit on overages at 15%. At some point, however, the FDA began rejecting products that were otherwise USP-compliant, and demanded justifications for overages in accordance with ICH Guidelines. Due to the FDA’s enforcement of the ICH Guidelines, a POSA would have been motivated to minimize the overage in any epinephrine product in order to obtain FDA approval. A POSA would have known that reducing overages would not negatively impact other relevant properties, such as racemization rate or safety. Instead, as a POSA would know, reducing overages would predominantly impact shelf life, for there would be less epinephrine available to oxidize or racemize before reaching the 90% floor set by the USP.

Both JHP’s Adrenalin Product and Hospira’s Ampul Product had ample shelf life to spare. Therefore, it would have been obvious to minimize the approximately 10-15% overages of the Products, including to between 0 and 6%, while balancing allowable shelf life. That, in turn, means it would have been obvious to compound JHP’s Adrenalin Product or Hospira’s Ampul Product at 1.0-1.06 mg/mL to produce a 1 mg/mL product, in accordance with the ICH Guidelines. A POSA would have had a reasonable expectation of success in pursuing this obvious modification of one or both of the Products.

Improper Inventorship:

Court said that under 35 U.S.C. § 102(f), one cannot obtain a valid patent if “he did not himself invent the subject matter sought to be patented.”  “Determining ‘inventorship’ is nothing more than determining who conceived the subject matter at issue, whether that subject matter is recited in a claim in an application or in a count in an interference.” [Sewall v. Walters, 21 F.3d 411, 415 (Fed. Cir. 1994)]. Conception is a question of law premised on underlying factual findings.

In this case, Hospira argued that Mr. Taneja – the sole named inventor – “neither conceived of nor reduced to practice the alleged invention of the ’197 Patent,” as his sole contribution was to suggest a pH of between 2.8 and 3.3, which was known in the prior art. Court agreed with Hospira. Court said that the record is devoid of reliable corroborating evidence to support Mr. Taneja’s claim that he conceived of the pH range limitation and communicated it to Sintetica. Additionally, as Mr. Taneja himself testified, he was aware that “as early as 2003 Sintetica manufactured 1 milligram per milliliter epinephrine products having a pH in the range of 2.8 to 3.3,” so in fact even he recognized that he was not the first to conceive of using the claimed pH range in epinephrine formulations. Even if all of this were incorrect, and even taking Mr. Taneja’s testimony in the best possible light, all he had was a “hope, or wish” that his pH would be successful, which is insufficient to constitute conception. This conception requires more than “just a general goal or research plan,” and 6+requires a “definite and permanent idea of an operative invention, including every feature of the subject matter to be patented.” [In re VerHoef, 888 F.3d 1362, 1366 (Fed. Cir. 2018)].

Inequitable Conduct:

Court said that inequitable conduct is an equitable defense to patent infringement that, if proved, bars enforcement of a patent.” Therasense, Inc. v. Becton, Dickinson and Co., 649 F.3d 1276, 1285 (Fed. Cir. 2011). To prevail on a claim of inequitable conduct, the accused infringer must prove by clear and convincing evidence that the patentee: (1) “acted with the specific intent to deceive the PTO” and (2) made a material misrepresentation or omission. “In a case involving nondisclosure of information, clear and convincing evidence must show that the applicant made a deliberate decision to withhold a known material reference.” For a misrepresentation or omission to be “material,” it must be “but-for” material. That is, the accused infringer must prove that “the PTO would not have allowed a claim had it been aware of the undisclosed prior art.”

Court said that as Chief Scientific Officer of Belcher and an active participant in the prosecution of the ’197 Patent, Mr. Rubin owed a duty of candor and good faith to the Patent Office. Despite this duty, Rubin admitted that he withheld information from Belcher’s patent prosecution attorney and the Patent Office, including Stepensky, JHP’s Adrenalin Product, and the 2003 Sintetica Products, at least some of which the Court has found to be but-for material to patentability. Rubin testified that he withheld these references because he considered them (and others) irrelevant, as they were directed to formulations that contained preservatives, used epinephrine bitartrate base, or had “high” overages. But, the Court did not find Rubin’s testimony about why he did not disclose the prior art references to the PTO to be credible or plausible.

During prosecution, in non-final rejection the Examiner relied on Helenek, which taught an epinephrine formulation with a pH range of 2.2-5.0. In counter arguing Rubin and Belcher knew that pH would be critical to persuading the Examiner to approve the patent. Certainly by this point in the prosecution, Rubin and Belcher had an unambiguous duty to disclose any material information pertinent to the claimed pH, and not just prior art limited to preservative-free or low overage formulations. Yet Rubin approved the following response from Belcher: “Helenek et al. does not make obvious the Applicant’s pH range of 2.8 and 3.3, which was unexpectedly found to be critical by the Applicant to reduce the racemization of 1-epinephrine.” The statement that Belcher’s claimed pH was “unexpected” was false. At the time this statement was made, Rubin knew about Stepensky, the JHP Adrenalin Product, and the 2003 Sintetica Products, all of which taught a pH in the range of 2.8 to 3.3. The Examiner, not knowing of these references, accepted Belcher’s representations as true and was persuaded by them to approve the Patent.

Therefore, Court found US’197 patent unenforceable because of Inequitable Conduct.

Vascepa® – USA

On March 30, 2020, Nevada district court found method of use patents related to omega-3 fatty acid product (Vascepa) infringed but invalid.

This is a Hatch-Waxman litigation, where Plaintiffs (Amarin) sued Defendants (Hikma & Dr Reddy’s Ltd) for filing ANDA with USFDA. Vascepa® is a highly purified preparation of EPA (eicosapentaenoic acid), also known as icosapent ethyl. Plaintiffs specifically asserted infringement of some of the claims of US 8,293,728; US 8,318,715; US 8,357,677; US 8,367,652; US 8,431,560 and US 8,518,929, which are expiring in Feb. 2030. These patents are related to method of treating hypertriglyceridemia.  The asserted claims are essentially directed to methods of treating severe hypertriglyceridemia having TG levels of 500 mg/dL or above with 4gm per day administration of composition containing 96% of ethyl eicosapentaenoate (EPA) for a period of 12 weeks.

Infringement:

Plaintiffs asserted that Defendants have infringed under inducement theory. Court said that appropriate inquiry should be related to specific intent & whether ANDA label encourages, recommends, or promotes infringement. Defendants mainly disputed on 3 parts of claims; (1) the limitation present in all asserted claims that the drug must be administered for at least 12 weeks; (2) the limitations present in most asserted claims that the drug either reduce TG levels by certain percentages, not increase LDL-C levels, or reduce Apo B levels (the “Other Health Benefits” claims); and (3) the limitations that exclude co-administration of the drug with a with another lipid altering drug such as a statin (the “Excluding a Statin” claims).

a) 12 Week Limitation -

With respect to this limitation, court said that number of factors weigh in favor of this finding. Court said that though “Dosage and Usage” section of label does not explicitly mention administration for 12 weeks but both Plaintiffs’ and Defendants’ experts testified that the indication and usage section of the proposed labels is directed to reducing TG levels below 500 mg/dL and then maintaining that reduction—suggesting that the applicable drugs will be prescribed long term. Trial testimony further established that severe hypertriglyceridemia generally has a genetic component, meaning that it is usually a chronic condition requiring long-term. Moreover, the “Clinical Studies” section of Defendants’ labels, like Vascepa’s label, reports the results of the MARINE study which expressly states that patients were administered icosapent ethyl 4gm per day “for 12 weeks.”

b) Other Health Benefits Claims –

Court said that a doctor would read and understand the Clinical Studies section of the labelling before prescribing Defendants’ ANDA Products because it is vital to understanding the effects of the applicable drug. The Clinical Studies section of the labelling describes how the average patient enrolled in the MARINE study received the benefits described in the Other Health Benefits claims. Specifically, ANDA label suggests to doctors that their ANDA Products will decrease TG levels without raising LDL-C levels. Indeed, Vascepa’s ability to reduce TGs without raising LDL-C, as depicted in the Clinical Studies section, is a primary reason clinicians choose to prescribe Vascepa over other available medications. Defendants’ proposed ANDA labels also suggest to treating clinicians that they can expect a decrease in Apo-B levels when they prescribe Defendants’ ANDA Product. Here, too, the Clinical Studies section of the labeling reports the statistically significant decrease in Apo-B resulting from administration of Vascepa in Table 2. Defendants’ proposed ANDA labels also suggest to doctors that they can expect certain reductions in TG levels by prescribing those ANDA Products, as required by certain other Asserted Claims.

c) Excluding a Statin Claims –

Court with respect to statin limitation said that there is text in several places on Defendants’ proposed labelling that would suggest to doctors Defendants’ proposed ANDA Products could be administered without a concurrent lipid altering therapy. First, the Indications and Usage section does not contain any instructions that Defendants’ ANDA Products must be administered with a lipid-altering drug, though FDA regulations would have required instructions to that effect were that the case. Second, and similarly, the Dosage and Administration section of the labelling would have had to mention it, but did not. Third, the Clinical Studies section of the labelling indicates that only 25% of the MARINE study participants were on a concomitant lipid-altering therapy while remaining 75% of patients in the study were not on concurrent lipid altering therapy.

The Court therefore found that the labels of Defendants’ proposed ANDA Products encourage, recommend, promote, or suggest that clinicians prescribe those products in a way that infringes all of the Asserted Claims.

Obviousness:

a) Prima facie obviousness -

The Court first discussed Defendants’ prima facie obviousness case. Most relevant prior art, Lovaza PDR, disclosed many of the limitations of the asserted claims. Only difference was that Lovanza product contains mixture of EPA & DHA, while asserted claims required purified EPA. One of the finding of Lovaza was that it causes increase in LDL-C level (bad cholesterol).  For this reason many patients who took Lovaza were also given a statin to address the LDL-C increases. Therefore, a skilled artisan would have been motivated to develop a single pill that treats severe hypertriglyceridemia without LDL-C increases.

Further, a skilled artisan would have wanted to know which active ingredient in Lovaza—EPA or DHA—was responsible for the LDL-C increase. And this issue was specifically addressed by second prior art, Mori. It disclosed that the increase of LDL-C with DHA was statistically significant and the increase with EPA was not. Thus, there was direct motivation to combine these references.

With respect to other claim limitations such as minimum reduction in triglycerides (e.g., at least about 20%); no increase in LDL-C; or a reduction in Apo-B, other prior arts such as Hayashi & Kurabayashi disclosed that EPA reduced triglycerides by at least about 20%; that EPA did not increase LDL-C; and that EPA reduced Apo-B. Court said that critically, in view of the claim language, obviousness is proven as long as there was a reasonable expectation that 4 g/day of 96% purified EPA would achieve the claimed effects (i.e., not cause an LDL-C increase) in patients with triglycerides of exactly 500 mg/dL. The Court therefore, found that Defendants established by clear and convincing evidence at Trial that all asserted claims are prima facie obvious. Plaintiffs arguments to the contrary were found unavailing because those were not supported by the evidence.

b) Secondary Considerations -

Court found Long-Felt Need & Commercial Success in favor of finding the asserted claims nonobvious whereas other factors such as Unexpected Benefits, Skepticism, Praise are not. With respect to Long-Felt Need, court held that there was a long-felt need for a drug like Vascepa that could reduce TG levels without raising LDL-C levels, primarily because both sides’ experts testified that patients are more likely to comply with a prescribed treatment regime when  they only have to take one pill, rather than two. With respect to Commercial Success, court held that the substantial and sustained increases in Vascepa prescriptions, net sales, and market share, as well as Vascepa’s positive net present value (“NPV”), demonstrate that Vascepa is a commercial success.  Court said that the Defendants’ contention that Vascepa is not a commercial success is largely based on the theory that Vascepa did not make a profit in its first six years on the market. But, Defendants ignored the reality that drugs have long lifecycles, the beginning of which involves spending vast amounts of money on R&D. Moreover, marketing spending tends to be higher at the beginning of a pharmaceutical product’s life-cycle, given the need to educate physicians about the clinical profile of the new drug in question. Therefore, the pharmaceutical industry considers the entire life-cycle of a drug in analyzing commercial success rather than just the first six years after the drug’s launch.