Carvedilol - USA

On March 28, 2018, U.S. District Judge Leonard Stark of District of Delaware found that Teva did not infringe a patent covering Coreg® as there was not substantial evidence to support the jury's decision that Teva's generic version caused doctors to infringe the patent.

Beginning on June 12, 2017, the Court held a seven-day jury trial in this patent infringement action resulting in a verdict of: (1) willful induced infringement of claims 1, 2, and 3 of U.S. Patent No. RE40,000 ("the '000 patent") by Defendant Teva during the "skinny label" (also referred to as "partial label" or "carve-out") period; (2) no induced infringement of claims 6, 7, 8, and 9 of the '000 patent by Teva during the skinny/partial label period; (3) willful induced infringement of all asserted claims ( claims 1-3 and claims 6-9) of the '000 patent by Teva during the "full label" (also referred to as "amended label") period; (4) no invalidity of the ' 000 patent; and (5) an award to Plaintiffs GlaxoSmithKline and SmithKline Beecham (Cork) Ltd. ("GSK") of $234,110,000 in lost profits and $1,400,000 in reasonable royalty damages.

Parties thereafter filed post-trial motions. Teva filed a renewed motion for judgment as a matter of law ("JMOL"), or in the alternative for a new trial, on five grounds: (1) no inducement of infringement of any claims at any time - that is, during either the skinny label or full label periods - and no lost profits; (2) no inducement of any claims during the skinny label period; (3) no inducement of claims 6 and 7 during the full label period; ( 4) no willful infringement; and (5) invalidity. GSK filed a motion for enhanced damages, attorney fees, and pre- and post-judgment interest. Finally, Teva has moved to strike multiple exhibits GSK submitted in support of its post-trial motion that Teva contends were not part of the trial record.

The Court heard oral argument on October 26, 2017.

With respect to infringement, Court held that substantial evidence does not support the jury's finding on causation, and therefore does not support its verdict that Teva is liable for induced infringement, during both the skinny and full label periods. GSK failed to prove by a preponderance of the evidence that "Teva's alleged inducement, as opposed to other factors, actually caused to directly infringe," by prescribing generic carvedilol and to do so for the treatment of mild to severe CHF. Without proof of causation, which is an essential element of GSK's action, a finding of inducement cannot stand. The Court therefore granted Teva's JMOL. Court further held that without a finding of infringement, there is no liability, so Teva cannot be found to be a willful infringer and cannot be ordered to pay GSK any damages. Accordingly, the Court granted Teva's JMOL motion on each of these grounds.

With respect to invalidity, GSK's evidence that the prior art taught away from and discouraged beta-blockers in heart failure, was sufficient to render the jury's finding that the patent was non-obvious reasonable. Therefore, the Court denied Teva's motion for JMOL or a new trial on invalidity. Also because substantial evidence does not support a finding of induced infringement, there is no basis for enhanced damages, attorney fees, and interest. Accordingly, GSK's motion and Teva's motion to strike multiple exhibits GSK submitted in support of its motion were denied as moot.

ADDERALL XR® - USA

On Mar. 22, 2018, U.S. District Judge William G. Young of district of Massachusetts found Amphetamine patents infringed by Abhai, LLC in a Hatch-Waxman case.

On Nov. 20, 2015, the plaintiffs Shire LLC and Shire US Inc. (collectively, “Shire”), brought this action against the defendant Abhai, LLC (“Abhai”), for patent infringement of the United States Reissued Patent No. RE42,096 (the “‘096 Patent) and patent infringement of the United States Reissued Patent No. RE41,148 (the “‘148 Patent”) ”), in response to Abhai’s submission of ANDA with Paragraph IV certification to ADDERALL XR patents. ADDERALL XR is marketed for the treatment of Attention-Deficit/Hyperactivity Disorder (“ADHD”). The drug contains a combination of amphetamine sulfate, amphetamine aspartate monohydrate, dextroamphetamine sulfate, and dextroamphetamine saccharate. The bench trial began on March 27, 2017 & on April 4, 2017, after four days of trial; Abhai filed a motion to amend its pretrial memorandum to include eight new trial exhibits. The exhibits purported to show that the dissolution tests reported by Abhai on its product were performed incorrectly and the data was invalid.

Shire asserted that Abhai’s ANDA Product infringes on Claim 1 of the ‘096 Patent & Claims 1, 11 and 13 of the ‘148 Patent. Adderall XR contains two types of drug-containing beads, “Immediate-Release (IR) pellets” (the “IR Beads”) and “Delayed-Release (DR) pellets”.  Abhai’s ANDA Product is a capsule filled with two types of beads: IR Beads and DR Beads. Using an in vitro dissolution method, Abhai tested all strengths of its ANDA Product to determine the amount of drug release at different time points.

A. Abhai’s ANDA Product Infringes Claim 1 of the ‘096 Patent

Claim 1 of the ‘096 patent includes:

A pharmaceutical composition for delivery of one or more pharmaceutically active amphetamine salts, comprising: (a) one or more pharmaceutically active amphetamine salts covered with an immediate release coating; and (b) one or more pharmaceutically active amphetamine salts that are covered with an enteric release coating that provides for delayed pulsed enteric release, wherein said enteric release coating releases essentially all of said one or more pharmaceutically active amphetamine salts coated with said enteric coating within about 60 minutes after initiation of said delayed pulsed enteric [release] release; wherein the pharmaceutically active amphetamine salts in (a) and (b) comprise mixed amphetamine salts.

Abhai admitted that its ANDA Product meets all limitations of claim 1 & only disputes that its ANDA Product meets the following limitations of claim 1: (1) “one or more pharmaceutically active amphetamine salts that are covered with an enteric release coating the provides for delayed pulsed enteric release”; and (2) “wherein said enteric release coating releases essentially all of said one or more pharmaceutically active amphetamine salts coated with said enteric coating within about 60 minutes after initiation of said delayed pulsed enteric release.” 

During deposition it was admitted that the Eudragit L30D-55 in Abhai’s ANDA Product was used as an enteric coating. Therefore, the DR Polymer Layer in Abhai’s ANDA Product, comprising Eudragit L30D-55, constitutes an “enteric release coating.” This “enteric release coating” covers the one or more pharmaceutically active amphetamine salts in the DR Beads of Abhai’s ANDA Product. Abhai tested 12 capsules of each strength of its ANDA Product using the FDA’s recommended in vitro dissolution method. Applying four-hour normalization to Abhai’s batch dissolution data, the results showed rapid and complete release from the DR Beads.  Percent release of drug from the DR Beads exceeded 90% for the first hour of exposure to pH 6.0 for each strength. Abhai’s ANDA Product contains an enteric release coating that releases “essentially all of said one or more pharmaceutically active amphetamine salts coated with said enteric coating within about 60 minutes after initiation of said delayed pulsed enteric release,” as stated in the ‘096 Patent. Therefore, “essentially all” of the contents of the DR Beads are released within about 60 minutes. Thus Abhai’s ANDA Product infringes claim 1 of the ‘096 Patent.

B. Abhai’s ANDA Product Infringes Claims 1, 11, and 13 of the ‘148 Patent

Claim 1 of the ‘148 patent includes:

A pharmaceutical formulation for delivery of a mixture of amphetamine base salts effective to treat ADHD in a human patient comprising: an immediate release dosage form that provides immediate release upon oral administration to said patient; a delayed enteric release dosage form that provides delayed release upon oral administration to said patient; and a pharmaceutically acceptable carrier; wherein said amphetamine base salts comprise dextroamphetamine sulfate, dextroamphetamine saccharate, amphetamine aspartate monohydrate and amphetamine sulfate; wherein said pharmaceutical formulation is sufficient to maintain an effective level of amphetamine base salts in the patient over the course of at least 8 hours without further administration of amphetamine base salt, and the peak plasma concentration of amphetamine base salts reached after release of said delayed enteric release dosage form exceeds the peak plasma concentration previously reached after release of said immediate release dosage form; and wherein said pharmaceutical formulation, when containing about a total dose of 20 mg, will produce in a human individual a plasma concentration versus time curve (ng/ml versus hours) having an area under the curve (AUC) of about 467 to about 714 ng hr/ml.

Claim 1 of US’148 require “a delayed enteric release dosage form that provides delayed release upon oral administration,” and the Court has construed it to include a “rapid and complete” release. Court further held that each of Abhai’s dosage strengths meet the Pharmacokinetic Claim Limitations in the asserted claims of the ‘148 Patent. Absorption and elimination of amphetamine in Abhai’s ANDA Product doses exhibit first-order kinetics. Moreover, the analyses discussed above relating to the pharmacokinetic elements (“peak plasma concentration,” “AUC,” and “maximum concentration”) will also apply to all dosage strengths even though Abhai performed its ANDA Studies on the 30 mg dosage strength. Therefore, the pharmacokinetic elements are met for all five dosage strengths of Abhai’s ANDA Product. Thus Abhai’s ANDA Product infringes claims of ‘148 Patent for the reasons explained above.

ABHAI’S LITIGATION MISCONDUCT AND SANCTIONS:

But above all particularly, Court lambasted Abhai for its gross negligence & misconduct during litigation. When Rule 30(b)(6) deposition of Abhai, conducted on Oct. 14, 2016, Abhai discovered that it incorrectly performed its 18 month dissolution test for the 15 mg and 25 mg sample dosage, and it incorrectly performed its 24 month dissolution test for the 10, 20, and 30 mg sample dosage for its ANDA Product. Specifically, Technicians collected samples from the dissolution medium after the ANDA Product had been in the buffer solution (pH 6.0) for three hours (5 hours after testing began), instead of one hour (3 hours after testing began). The mistakes made in Abhai’s stability dissolution testing indicate that neither the analysts nor their supervisors understood the FDA-recommended two-stage dissolution method. Abhai then revised its dissolution procedure for each strength of its ANDA Product following the investigation. Results from the re-testing which was conducted in November 2016 were submitted to FDA as the “18-month” results for the 15 and 25 mg strengths, and as the “24-month” results for the 10, 20, and 30 mg strengths.

On Nov. 9, 2016, when Shire requested production of all versions of methods of analysis, including dissolution testing protocols, Abhai produced all of KVK’s methods of analysis and dissolution protocols, except for the revisions made on October 25, 2016. On November 17, 2016, Dr. Namburi signed an errata report for his 30(b)(6) deposition but did not correct his statements regarding Abhai’s stability testing on the 18- and 24- month ANDA Products. At this time, Dr. Namburi was aware that there were errors with the data and that Abhai had retested the 18- and 24-month Products using KVK’s revised dissolution testing and methods of analysis. Abhai also failed to supplement any of its prior discovery production with the revised methods of analysis or any other documents relating to the errors in its stability testing. Abhai also failed to notify the FDA of the errors in its testing. Importantly, neither Vepuri nor Dr. Namburi notified Abhai’s attorneys of the errors in the dissolution data, despite their awareness of the error and the ongoing litigation. On March 31, 2017, KVK created an “Escalation to Management Form” & identified that the 24 month data was revised in 11/2016 and not reported to Regulatory.” Later that same day, Abhai finally informed its counsel of the errors in its data. On April 4, 2017, Abhai filed a Motion to Amend Pretrial Memorandum where it admitted to errors in its dissolution testing and that further dissolution retesting was conducted to update the 18 and 24-month data.

The Court then came very harsh on Abhai & said that the conduct of Abhai and KVK reflects an appalling lack of awareness of a litigant’s responsibility to our justice system. The FDA would be well advised to take notice of this pervasive corporate unwillingness to play by the rules. See United States v. Aegerion Pharmaceuticals, Inc., Criminal Action No. 17-10288-WGY, 2017 WL 5586728 (D. Mass. Nov. 20, 2017). The Clerk is therefore directed to send a certified copy of this opinion to the General Counsel of the FDA. Sanctions are amply warranted here. Court further said that Abhai’s litigation misconduct is not simply a private matter of adjusting the legal fees to be borne by Shire. It has a direct impact on the citizens of the United States. The necessity of a sanctions analysis has occupied an additional writing day. Thus, Abhai’s misconduct has occasioned over a full week of court time. Pursuant to the authority discussed above, and finding that Abhai has recklessly squandered five days during which this Court could better have devoted itself to teaching American jurors and attending to litigants prepared to follow the straightforward rules of civil procedure. Court thus sanctioned Abhai in the amount of $30,000.00 for causing drain on judicial resources. Based upon this array of reported misconduct, Shire also came up with a whopping $2,750,000.00 claim for attorneys’ fees.  But Court said that this is too much & asked Shire to submit a revised claim for attorneys’ fees and costs. Abhai may have fifteen days thereafter to respond. The Court then will award appropriate monetary sanctions.

Buprenorphine & Naloxone - USA

On March 22, 2018, the District Court of Delaware issued an opinion in favor of Alvogen finding non-infringement of patents related to Suboxone® sublingual film.

Alvogen filed Abbreviated New Drug Application ("ANDA") No. 205954, seeking approval for a generic version of the 2 mg/0.5 mg, 4 mg/I mg, 8 mg/2 mg, and 12 mg/3 mg dosage strengths of Plaintiffs' Suboxone® sublingual film. Suboxone® sublingual film is indicated for maintenance treatment of opioid dependence. The Court held a bench trial September 26-27, 2017. At issue in this case is the process for drying the sublingual film. Plaintiffs asserted that Alvogen's ANDA submission constitutes infringement of claim 24 of U.S. Patent No. 8,900,497 ("the '497 patent"), and claims 62, 63, 65, 69, 71, and 73 of U.S. Patent No. 8,603,514 ("the '514 patent). Alvogen did not argue that the asserted claims are invalid.

Independent claim 1 of the '497 patent reads:

1. A process for making a film having a substantially uniform distribution of components, comprising the steps of:

(a) forming a flowable polymer matrix comprising an edible polymer, a solvent and a desired amount of at least one active, said matrix having a substantially uniform distribution of said at least one active;

(b) casting said flowable polymer matrix;

(c) rapidly evaporating at least a portion of said solvent upon initiation of drying to form a visco-elastic film within about the first 4.0 minutes to maintain said substantially uniform distribution of said at least one active by locking-in or substantially preventing migration of said at least one active within said visco-e/astic film;

(d) further drying said visco-elastic film to form a self-supporting edible film having a substantially uniform distribution of said at least one active component; and wherein said substantially uniform distribution of said at least one active component is measured by substantially equally sized individual unit doses which do not vary by more than 10% of said desired amount of said at least one active.

Independent claim 62 of the '514 patent reads:

62. A drug delivery composition comprising:

(i) a cast film comprising a flowable water-soluble or water swellable film-forming matrix comprising one or more substantially water soluble or water swellable polymers; and a desired amount of at least one active; wherein said matrix has a viscosity sufficient to aid in substantially maintaining non-self-aggregating uniformity of the active in the matrix;

(ii) a particulate active substantially uniformly stationed in the matrix; and

(iii) a taste-masking agent selected from the group consisting of flavors, sweeteners, flavor enhancers, and combinations thereof to provide tastemasking of the active; wherein the particulate active has a particle size of 200 microns or less and said flowable water-soluble or water swellable film-forming matrix is capable of being dried without loss of substantial uniformity in the stationing of said particulate active therein; and wherein the uniformity subsequent to casting and drying of the matrix is measured by substantially equally sized individual unit doses which do not vary by more than 10% of said desired amount of said at least one active.

At trial, the parties stipulated that Alvogen infringes all limitations of the asserted claims except (1) the "dried" limitation of the '514 patent and "drying" limitation of the '497 patent, and (2) the "visco-elastic film" limitation of the '497 patent.

"Dried"/"drying:

The Court construed the "dried" limitation of the '514 patent and "drying" limitation of the '497 patent to mean "dried without solely employing conventional convection air drying from the top." Plaintiffs argued that Alvogen's ANDA process does not employ "conventional convection air drying" as its drying process is "extremely unusual. Second, Plaintiffs argued that Alvogen's films are "substantially dried from the bottom," and therefore are not dried "solely ... from the top." Alvogen argued that it has converted the S-Coater into a conventional top-down impingement dryer by disabling the bottom-sourced air and removing the fuses. With the bottom-sourced air having been disabled, Alvogen's dryer supplies hot air solely from nozzles above the web.

Court said that construction for the "dried"/"drying" limitation makes clear that it refers to drying technique, as opposed to drying equipment. It found Dr. Carvalho's (Alvogen's expert) testimony that Alvogen uses a modified flotation dryer to carry out a "conventional" technique more convincing. Also if Alvogen's technique actually does avoid the rippling effect, which the parties dispute, that alone cannot render the technique unconventional. Lowering oven temperature and slowing drying speed were conventional controls for preventing the rippling effect and other defects in at least some films. Alvogen's parameter control techniques were sensible and well-known for use in films generally. As a result, the techniques were conventional for use in "pharmaceutical films."

As to Plaintiffs' argument that Alvogen's films are "substantially dried from the bottom" and therefore do not "solely employ conventional convection air drying from the top," Plaintiffs point to three sources of bottom heat: (1) drag bars, (2) contact between the web and lower plenum of the dryer, and (3) air flow underneath the web. Court however, agreed with Alvogen that any bottom drying during its ANDA process is at most an insubstantial amount. Any dryer that "solely" employs "conventional convection air drying from the top" will result in some drying from the bottom. Accordingly, Plaintiffs have not demonstrated "substantial" bottom drying such that Alvogen's dryer can be said to employ anything but "conventional convection air drying from the top." Therefore for these reasons, court found that Plaintiffs have not met their burden of proving by a preponderance of the evidence that Alvogen's ANDA products and process meet the "dried" /" drying" limitation, and therefore have not proven that Alvogen infringes any of the patents.

"Visco-Elastic Film":

The Court construed the phrase "to maintain said substantially uniform distribution of said at least one active by locking-in or substantially preventing migration of said at least one active" to mean "to maintain a distribution of [an active/a pharmaceutical active] by drying to form a viscoelastic solid film, thereby limiting its migration such that individual dosage units do not vary by more than 10% from the intended amount of the active for that dosage unit." Thus, the "visco-elastic film" limitation requires "form[ing] a viscoelastic solid film."

Alvogen affirmatively argued that "visual evidence confirms that Alvogen's mix remains a liquid after four minutes of drying." Plaintiffs argued that the material is not a liquid, but rather a viscoelastic solid that has been fluidized. Court found that the temperature difference indicates that Dr. Fassihi's measured viscosities differ at least somewhat from the ANDA product's actual viscosity after four minutes of drying. This further diminishes the weight of Dr. Prud'homme's slope calculations, which rely on Dr. Fassihi's viscosity measurements. Plaintiffs have therefore failed to meet their burden of proving infringement of this limitation by a preponderance of the evidence.

Enoxaparin - USA

On March 19, 2018, the United States Court for the District of Massachusetts entered final judgment in favor of Amphastar in a patent suit related to method for analyzing an enoxaparin.

The patent-in-suit was U.S. Patent No. 7,575,886 assigned to Momenta Pharmaceuticals, Inc. On July 21, 2017, Jury found that Defendants Amphastar Pharmaceuticals, Inc. and International Medication Systems, Ltd. (collectively "Amphastar") infringe claims 6, 15, 16, 53, 54, and 62 of US’886 for use of the 15-25% procedures and Disaccharide Building Block ("DBB") procedure. But jury also found that patent is invalid because the claims are not enabled and lack written description.

The Court then entered a Memorandum and Order on Feb. 7, 2018 ruling on Amphastar's equitable defenses. The Court’s Order specified that Momenta waived its right & equitably estopped to enforce the '886 patent against Amphastar for use of its 15-25% procedures; but it did not waive its right to enforce & is not equitably estopped from enforcing the '886 patent against Amphastar for use of its DBB procedure. After that under Rule 58(d), Amphastar respectfully requested that the Court to enter the proposed final judgment.

In an another suit, on March 20, 2018, the District Court also denied Momenta’s and Sandoz’s motion to dismiss Amphastar’s antitrust lawsuit relating to Momenta’s and Sandoz’s anticompetitive conduct before the USP and the District Court provided a schedule for the antitrust lawsuit with a jury trial set for September 9, 2019.

Infliximab - Canada

On Mar 07, 2018, Federal court of Canada found patent covering use of Infliximab & Methotrexate valid & infringed by Hospira.

The trial concerned the validity of Canadian Patent No. 2,261,630 [the 630 Patent] which essentially details the adjunctive use of methotrexate [MTX] and the anti-tumour necrosis factor-α [anti-TNF-α] antibody “infliximab” for the treatment of rheumatoid arthritis [RA] and other autoimmune diseases. The Plaintiff in this action is Hospira Healthcare Corporation [Hospira], an interested party under s 60(1) of the Patent Act, RSC 1985, c P-4. Hospira markets, uses, and sells the biosimilar infliximab in Canada under the commercial name Inflectra as a treatment for RA. The Defendant in this action is the Kennedy Trust for Rheumatology Research [Kennedy]. 

INVALIDATION

With respect to common general knowledge court said that the literature and the expert evidence clearly established that MTX was a popular treatment option for severe RA and that it was one of the more popular, if not the most popular, DMARD for treating severe RA.  In terms of anti-TNF-α and other biologics, the efficacy of infliximab was part of the common general knowledge due to the publication of the Elliott studies in 1994 and 1995. The literature of the time however, does not disclose a consensus with respect to the benefit of combination therapy. The weight of the evidence, Strand notwithstanding, was that it was impossible to predict the outcome of a clinical trial of a novel therapy in RA, especially until attempted in humans. The common general knowledge, as described, pointed away from what was claimed in the 630 Patent.

Novelty:

Court held that Hospira took an improper approach in its anticipation arguments. Hospira sought to assemble an “anticipatory mosaic” by arguing that one piece of prior art should be read in conjunction with a second piece of prior art that is cited in the first. This is an incorrect approach that ignores the emphasis on a single reference. Further, it would be absolutely remarkable if all of the allegedly anticipatory documents actually anticipated the invention disclosed in the 630 Patent. The evidence does not support that conclusion & none of the allegedly anticipatory documents anticipate the invention disclosed by the 630 Patent.

Obviousness:

Hospira claimed that the 630 Patent was obvious or at least obvious to try. It contended many things but principally that the inventors had an easy time coming up with the invention because “everyone knew” it would work. Although it may have been reasonable, based on the state of the art, to carry out the combination trials that led to this invention, it was not obvious to do so. A number of potential biologic targets had been identified, and a number of methods of dealing with HACA responses had also been identified – therefore, it was not clear that anti-TNF-α was an appropriate target. It was also not clear what should be done to deal with the shortened duration of response/HACA responses that had been identified in the prior art. There was no indication in the prior art that this combination was to be preferred or that it would work to solve the problems identified. Although the POSITA may have had “good reason” to pursue the combination of anti-TNF-α and MTX, it was not self-evident that this combination would work to solve the problem identified in the prior art (i.e., shortened duration of response). Finally, although there was a great deal of motivation to develop a new treatment for RA, it is clear from the literature that this motivation was being pursued in a number of different ways (i.e., trials of different biologics, the majority of which failed). Therefore, the Court concluded that the invention was not obvious to try.

Double Patenting:

The issue was whether the invention disclosed by the 630 Patent should have been included in Canadian Patent No. 2,146,647 [the 647 Patent], which expired in 2013. The 647 Patent indicated that other anti-inflammatory drugs (such as MTX) could be administered in conjunction with the anti-CD4 antibody or the anti-TNF antibody. Hospira argued the 647 Patent could have and should have included the subject matter of the Claims in the 630 Patent. In addition, “[i]f the Claims are construed to cover the administration of anti-TNF-α antibodies to patients receiving MTX along with other DMARDs and/or antibodies, the claims are not patentably distinct from the claims of the ‘647 Patent”. The 647 Patent concerns use of anti-CD4 antibody in conjunction with an anti-tumour necrosis factor antibody for the manufacture of a therapeutic formulation. Court after analyzing the facts concluded that Hospira has not established that an entirely different combination, MTX and anti-TNF-α, ought to have been included in this patent. Further, the two inventions are “patentably distinct” – not only do the patents disclose different combinations, but the 647 Patent discloses a biologic-biologic combination and the 630 Patent discloses a biologic-DMARD combination. Therefore Hospira’s obviousness-type double patenting attack is not sustainable.

Sufficiency:

Hospira’s position was that the 630 Patent is insufficient because the POSITA would not have been able to practice the invention as of February 12, 1998. Hospira submitted that the claims are insufficient because “[t]he disclosure of the ‘630 Patent does not disclose how to perform adjunctive therapy with anti-TNF-α monoclonal antibodies with methotrexate at a dosage or timing of administration over the scope of the claims so as to achieve the Promised Utility”. Court held that Hospira’s argument with respect to sufficiency is tied to its view of the “promised utility”. Given the recent Supreme Court of Canada decision in AstraZeneca Canada Inc v Apotex Inc, 2017 SCC 36, [2017] 1 SCR 943 [AstraZeneca] and the rejection of the “promise of the patent”, Hospira’s argument with respect to sufficiency is based on a shaky foundation. Hospira has not led any evidence that would tend to establish that the 630 Patent is insufficient. Its own experts acknowledge that there is nothing unique or inventive in the way infliximab and MTX have at all times been commercially available. The doses of infliximab and MTX as well as the dosing regimens are disclosed in the Examples.

INFRINGEMENT

Kennedy submitted at trial that the Asserted Claims, Claims 1-3, 5, 6, 9, 10-12, 15, 17-19, 21, 22, 25, 26, 28, 31, 33, and 39-42, are infringed. Hospira was alleged to have infringed the Asserted Claims by making Inflectra and selling it in Canada for the treatment of RA. Kennedy asserted that the only difference between Hospira’s infliximab and Kennedy’s infliximab is that Hospira’s infliximab has a single additional amino acid at the C-terminal (the non-binding end of the antibody). This is cleaved instantaneously in vivo. Kennedy submitted that the POSITA would have known, in 1998, that this additional amino acid “could not impact the antibody’s ability to bind to TNFα and impede binding to TNFα receptors”. Relying on Di Battista’s evidence with respect to glycosylation, Kennedy submitted that there is “no material difference between the amounts and types of glycosylation structures present in Hospira’s infliximab and those present on the infliximab described in the 630 Patent”. Further, there are detectible glycosylation differences even within samples of Hospira’s infliximab because of microheterogeneity.

Even if the court construes the asserted claims to include the combination of a TNF-α antibody and MTX, Hospira claimed that it has not infringed the asserted claims because there is no evidence that Hospira marketed or sold the combination of MTX and Inflectra. Infringement of a combination requires “a taking of the entire combination, i.e. a taking of all the essential elements of the combination as claimed”. Hospira submitted that as the Swiss-type claims refer to the manufacture of a medicament and Inflectra is not made in Canada and is not sold to Hospira in Canada, the Swiss-type claims are not infringed. Further, the pharmaceutical composition claims cannot be infringed for the same reason.

Court held that on a balance of probabilities, Inflectra is to be used for treatment of MTX incomplete responders. At this time, it is only necessary for the Court to conclude that Inflectra is used in MTX incomplete responders – the extent to which Inflectra is used in MTX incomplete responders is a question best left to the damages phase of this litigation. However, the reimbursement criteria and the IMS data indicate that at least some of the patients receiving Inflectra are MTX incomplete responders. That is sufficient for this infringement analysis. Although Inflectra may be produced for use in treating diseases other than RA, this does not establish that it is not produced for use in treating RA. Therefore on a balance of probabilities, that Inflectra is produced for the treatment of RA in combination with MTX. Thus Hospira has infringed the 630 Patent.

Tadalafil - Netherlands

On Mar 14, 2018, District Court The Hague handed down its decision in CIALIS® case & revoked Dutch part of EP 1173181 patent for lack of inventive step.

Icos (an Eli Lilly and Company subsidiary) holds EP 1 173 181 B3 (‘EP 181’) entitled: ‘Compositions comprising phosphodiesterase inhibitors for the treatment of sexual dysfunction.’  In the Netherlands, Icos filed a lawsuit against, among others, Teva Nederland BV (a sister company of Teva). In doing so, it essentially sought an infringement ban on EP 181, due to the circumstance that generic tadalafil 5 mg products have been introduced on the market by (among others) Teva Nederland BV from 14 November 2017. Teva sought to revoke the Dutch part of EP 181.

Teva's argument that the conclusions of EP 181 lack inventiveness, comes down in essence to the fact that, in view of the information about tadalafil disclosed in Daugan and given his knowledge about sildenafil (Viagra®), the professional would proceed to further development of tadalafil for the treatment of sexual dysfunctions, by going through different phases of drug development, including dose ranging studies, in which the person skilled in the art would arrive at a dosage within the range of 1 to 5 mg claimed by EP 181 without inventive work.  Teva has argued that the person skilled in the art would have set a maximum safe dose after the Phase I study and that he would have the IC50 value (2-2.5 Nm), half-life (17.5 hours), Tmax ( 2 hours) 14 and Cmax (350 micrograms / l based on a 20mg dose), the molecular weight determined in the laboratory (389.14 g / mol). The dispute then focuses on the question of which doses would be tested in a phase IIb study and whether or not a 5 mg dose would be included. Expert 4 of Teva used graphs to show that calculations show that a 5 mg dose or tadalafil results in a PDE5 activity which is 50 mg dose or sildenafil.

Icos's argument that expert 4, in view of the occasional use of Viagra® known in the state of the art , wrongly assumes that the person skilled in the art at tadalafil would pursue a daily dosing regimen also misses the target. Icos' argument that the person skilled in the art would have no motivation to go to a lower dose of tadalafil, also not expecting the efficacy to be comparable to that of higher doses while at the same time having minimal side effects.

The court after hearing both the parties ruled that the man skilled in the art when starting from the prior art would get to the claimed dosage range in various non-inventive steps. Court held that it is an important objective of the phase IIb study to determine the relationship between dose and efficacy (ie the dose-response relationship) to come. As long as the professional would encounter a plateau, he would not yet have established this dose-response relationship and he would therefore be motivated to carry out research into lower doses (although this may even be compulsory in a regulatory framework). Apart from that, a professional will always strive for the best result, ie an effective dose with as few side effects as possible. It is therefore obvious that even lower doses, including a dose of 5 mg, would have been tested. The phase IIb study would show at the daily dosages that a 10 mg dose would still be as effective as the higher doses tested. It is therefore obvious that even lower doses, including a dose of 5 mg, would have been tested with minimal side effects.

The court thus destroyed the Dutch part of EP’181.

The same patent was also litigated in other jurisdictions .In the United Kingdom, a procedure to destroy (the British) part of EP 181 has been initiated by amongst others, Teva UK Limited and Teva Pharmaceutical Industries Limited. By judgment of 10 August 2016, the High Court stated briefly that, according to Daugan, the skilled person would further develop tadalafil as a medicinal product, but would not have come up with a dosage of 5 mg without inventive work. The High Court therefore found EP 181 to be valid. By judgment of November 1, 2017 however, the Court of Appeal unanimously ruled that this conclusion, as well as conclusions 1 and 10, in the light of Daugan, are invalid because of a lack of inventiveness.

In Germany, a procedure to destroy EP 181 has also been started. The Bundesgerichtshof has destroyed the German part of EP 181 by ruling of October 24, 2017, written statement not yet provided.

Bevacizumab - USA

IPR decision (Mar. 09, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Final Written Decision
IPR2016-01771	09/09/2016	03/16/2017	Hospira Inc.	US 7,622,115	Claims 1–5 are unpatentable

US 7,622,115 (Genentech Inc; Exp: May 28, 2024)

1. A method for treating cancer in a patient comprising administering an effective amount of bevacizumab and assessing the patient for gastrointestinal perforation during treatment with bevacizumab.

Olopatadine - USA

On Mar. 01, 2018, Judge Gregory M. Sleet of Delaware held that Defendants failed to present a primafacie case that the asserted claims of the patents-in-suit are invalid as obvious in Pazeo® Hatch-Waxman litigation.

In this patent infringement action, Alcon Research, Ltd. alleged that Watson Labs., Inc., Lupin Ltd., and Lupin Pharma. Inc., (collectively, "the Defendants") infringed the asserted claims of the patents-in-suit. Alcon has asserted claims 4-6, 8-10, 12-14, and 20-27 of US 8,791,154 Patent. The US’154 relates to "High Concentration Olopatadine Ophthalmic Composition”. The court held a four-day bench trial in this matter beginning on October 2, 2017. Presently before the court are the parties' post-trial proposed findings of fact and conclusions of law concerning the validity of the patents-in-suit, specifically whether the asserted claims are invalid as obvious under 35 U.S.C. § 103.

The obviousness analysis hinges on the core elements of the independent claims asserted, 8 and 21 which require: (1) an aqueous ophthalmic solution for treatment of ocular allergic conjunctivitis comprising; (2) at least 0.67 w/v% but no greater that 1.0 w/v % olopatadine dissolved in the solution; (3) 2.0 w/v% to 1.0 w/v% PEG having a molecular weight of 300 to 500; (4) 2.0 w/v% to 6.0 w/v% polyvinylpyrrolidone ("PVP") at least 0.5 w/v% but no greater than 2.0 w/v% hydroxypropyl-y cyclodextrin ("HPyCD"); and (5) water.

Defendants argued that the asserted claims were obvious for six reasons:  

(1) that it would have been obvious to select a concentration of 0.67% to 1.0% w/v olopatadine;

(2) a POSA would have been motivated to develop a solution;

(3) a POSA would have known how to achieve a 0.67 to 1.0% olopatadine solution;

( 4) it was well within the level of ordinary skill to determine suitable amounts of the solubilizing agents for use with olopatadine;

(5) Dr. Olejnik's opinions are conclusory and unsupported; and

(6) claims 9 and 21- 24 require only standard ophthalmic excipients and physical properties that would have been obvious to a POSA.

It was clear after a recitation of the prior art, a 0.67-1.0% w/v olopatadine concentration at a near-neutral pH was not disclosed in the references that pre-date the patent-in-suit. Defendants argued that a combination of Hayakawa, Yanni 2002, and Yanni 2008 would make the selection of 0.67 to 1.0 % w/v olopatadine at a near neutral pH obvious to a POSA. The court however, disagreed & found that persons having ordinary skill in the art would not have selected a concentration of 0.67 to 1.0% w/v olopatatdine to treat allergic conjunctivitis in light of the asserted prior art because reference does not teach an ophthalmic solution with at least 0.67% olopatadine. Court further said that while Defendants suggested that the POSA would have been motivated to formulate a solution in order to improve upon the efficacy of Pataday® between 16 and 24 hours, they presented no evidence that the POSA recognized such a need. The court found that a POSA would be concerned that a more than three-fold increase in the concentration from 0.2% (as in Pataday®) to at least 0.67% would increase redness.

Court further held that with only general teachings and no disclosures in the art of the claimed ternary system, the POSA would have had no guidance to choose the correct combination of excipients, at the proper concentrations, to solubilize 0 .67-1.0% olopatadine at near-neutral pH. Court concluded that routine optimization would not lead a POSA to develop the claimed solution given the complexity of ophthalmic formulation. More specifically, the POSA would not have been motivated, based on what was known in the prior art, to make the claimed solution by combining all of the elements of the claims in the particular way they are recited, and have a reasonable expectation of success in doing so.

In sum, Defendants have failed to present a primafacie case that the asserted claims of the patents-in-suit are invalid as obvious. Additionally, the court found that the secondary, objective indicia point towards a finding of non-obviousness. Thus, the asserted claims were not invalid as obvious.