Tenofovir disoproxil fumarate & Emtricitabine - Denmark

On Oct. 26, 2017, the Danish Maritime and Commercial High Court issued a decision rejecting Gilead's motion for preliminary injunction against Accord Healthcare & found Gilead's Danish SPC for the combination of tenofovir disoproxil (as fumarate) and emtricitabine (Truvada®) invalid. Accord counterclaimed by arguing non-infringement and invalidity of the asserted SPC (CR 2005 00032) which was issued on the basis of the patent DK / EP 0915894.

Accord claimed that the disputed certificate protects emtricitabine and tenofovir disoproxil only where the latter is in the form of its fumarate acid salt (i.e., tenofovir disoproxil (like fumarate)). Accord stated that their product is not in the form of fumarate acid, but instead in a free base form. Gilead claimed that the contested certificate protects medicines, which includes a combination of emtricitabine and tenofovir disoproxil in all forms. But court sided with Gilead & held that Accord's generic combination product was covered by the SPC as tenofovir is covered in all its forms if SPC held valid.

Turning to the validity of SPC, the contested claim 27 of the base patent protects a pharmaceutical composition, which contain such an active ingredient as tenofovir disoproxil as Fumarate salt, together with a pharmaceutically acceptable salt thereof Carrier and optionally with other active ingredients. Gilead claimed that the disputed certificate has been issued in accordance with Article 3 (a) of the SPC Regulation and that the combination of tenofovir disoproxil and Emtricitabine is protected by requirement 27 of the basic patent. Gilead however agreed with Accord that the basic patent does not describe emtricitabine by name, chemically name or structure. But Gilead's said that emtricitabine must be considered sufficient functionally specified in claim 27. Because the basic patent focuses on the treatment of HIV, a professional would therefore know that the combination of NRTIs would be preferable and would read requirements 27 in light of this.

Court however disagreed with Gilead. Court held that use of tenofovir disoproxil in combination with another therapeutic component does not constitute a "central aspect" of the claimed invention. The basic patent describes no trial in which tenofovir disoproxil is used in combination with another therapeutic ingredient. Furthermore, the basic patent does not contain any mention or just a hint, of a functional definition or indication indicating that emtricitabine could constitute any further therapeutic component. Emtricitabine was neither approved nor launched on the basic patent priority date. Emtricitabine was first approved in Europe in 2003, i.e. seven years after the priority date of the base patent in 1996. Overall, court finally held that Accord's drug does not violate the contested certificate & the disputed SPC is invalid. 

Glatiramer acetate - UK

On Oct 26, 2017, UK High Court of Justice has issued a decision in favor of Mylan and its European partner Synthon, finding Teva's patent EP (UK) 2949335 (EP’335) relating to Copaxone® 40 mg/mL invalid based on lack of inventive step.

The Claimants ("Mylan" and "Synthon") sought revocation of EP’335 patent entitled "Low frequency glatiramer acetate (GA) therapy." The EP’335 patent is directed to a dosage regimen for the administration of GA for the treatment of relapsing forms of multiple sclerosis ("MS") consisting of three subcutaneous injections of 40 mg GA every seven days with at least one day between each injection ("40 mg TIW"). The Claimants contend that the Patent is invalid on the grounds of lack of novelty, lack of inventive step and insufficiency.

Before the priority of patent ie Aug 2009, both parties agreed that the skilled person would have been aware that the 20 mg QD regimen for GA appeared to have been somewhat arbitrarily selected and that no Phase II dose-ranging studies had been carried to determine the optimum dose of GA for treating MS, and in particular RRMS. Court after analyzing the prior arts concluded the teachings as:

a  a) there was no statistically significant difference in efficacy between the 40 mg dose and the 20 mg dose;

b  b) both were safe and well tolerated;

c  c)  in terms of tolerability, there was a disadvantage in administering a 40 mg dose rather than a 20 mg dose.

The skilled person would be aware from his common general knowledge & literatures that there were investigations on less frequent administration of 20 mg GA.

Obviousness over the prior art:

The sole difference between Pinchasi and claim 1 of the Patent was that Pinchasi discloses a regimen of 40 mg every other day (QOD) while claim 1 requires a regimen of 40 mg every seven days with at least one day between each injection (TIW). The difference amounts to one dose every fortnight. Claimants argued that 40 mg TIW was an obvious alternative to 40 mg QOD because the skilled person would think that missing one dose a fortnight was unlikely to have a detrimental effect on the efficacy of the treatment, and TIW would have the advantages that it was likely to increase the tolerability of the medication and would be more convenient for patients who wanted fixed-day administration and weekends injection-free. Secondly, counsel for the Claimants argued that, if the skilled person considered the matter in more detail in the light of his common general knowledge and his literature search, then 40 mg TIW would be an obvious regimen to try in a Phase III clinical trial and the skilled person would have a fair expectation of success, both in the sense that the regimen would be efficacious compared to placebo and in the sense that it would be comparable in efficacy to 20 mg QD.

As to this, the Defendants contended that it was not obvious to try 40 mg TIW, for a combination of three reasons. First, the Defendants contend that the skilled person would not have been interested in improving the administration of GA, because of the new treatments on the horizon. Secondly, the Defendants contend that the skilled person would not be motivated to consider a 40 mg TIW regimen. If the skilled person was interested in reducing the frequency of administration, then the obvious regimen to consider would be 20 mg QOD as suggested by the Fletcher 2002 and Khan 2008 publications. Thirdly, and most importantly, the Defendants contend that the skilled person would be dissuaded from trying a 40 mg dose because of the increase in the severity of ISRs and IPIRs reported in Cohen 2007 and Comi 2008B, and in particular the increase in early terminations due to adverse events mainly due to ISRs which had been reported in Comi 2008B, given that it had been found that 40 mg QD was no more efficacious than 20 mg QD.

Court after analyzing the all facts & expert testimonies held that the skilled person had a clear motivation to reduce the frequency of administration of GA in order to increase tolerability, adherence and convenience. Moreover, a TIW regimen had the advantages of fixed-day administration and injection-free weekends. Given that Prof Comi's overall conclusion in Comi 2008B was that 40 mg QD was safe and well tolerated, and given that a reduction in the frequency of administration from QD to TIW would be expected to reduce the incidence of ISRs (and IPIRs), therefore the skilled person would not be dissuaded from trying 40 mg TIW in a Phase III trial. Overall, court concluded that 40 mg TIW was obvious to try and that the skilled person would have had a fair expectation of success, both in the sense that the regimen would be efficacious compared to placebo and in the sense that it would be comparable in efficacy to 20 mg QD.

CONCLUSION:

1  1.       claims 1 and 3 of the Patent are novel over Pinchasi;

2  2.       claims 1 and 3 of the Patent are obvious over Pinchasi, and therefore invalid.

Mesalamine - USA

On Oct. 24, 2017, Judge Rodney Gilstrap of Eastern district of Texas dismissed Allergan’s suit against Teva & Mylan for alleged infringement of Delzicol® (Mesalamine delayed release capsules, 400 mg) patent. Delzicol is used in the treatment of ulcerative colitis. The patent-in -suit was US 6,649,180 listed in Orange Book which is expiring on Apr 13, 2020. US’180 patent claims a hard capsule formed of a film composition comprising a hydroxypropyl methyl cellulose as a base, a gelling agent, and a gelling aid with certain percentage of methoxyl groups and hydroxypropoxyl groups.

Previously on Sep 28, 2017, the magistrate judge (Roy Payne) granted the motions for summary judgment of non-infringement with respect to US’180 patent in favor of Teva & Mylan. After that bench trial was concluded on Oct 24, 2017 & Judge Gilstrap affirmed the decision of magistrate judge.

Other generic player is Zydus which has settled the case in Dec 2016.

Ertapenem – USA

On Oct. 26, 2017, Federal circuit affirmed the Delaware court’s decision of obviousness in Invanz® case.

Merck Sharp & Dohme Corp. appealed from the decision of the United States District Court for the District of Delaware concluding, after a bench trial, that claims 21–34 (“the asserted claims”) of U.S. Patent 6,486,150 are invalid under 35 U.S.C. § 103. Merck owns the ’150 patent, which is directed to a process for preparing a stable formulation of ertapenem. Ertapenem is known to be unstable because of two degradation reactions—hydrolysis of the lactam nitrogen and dimerization via the pyrrolidine nitrogen. The method of the ’150 patent claims a manufacturing process for a final formulation of the antibiotic that purportedly minimizes both dimerization and hydrolysis degradation pathways. On May 29, 2014, Hospira, Inc. notified Merck that it had filed an abbreviated new drug application (“ANDA”), seeking approval to engage in the commercial manufacture, use, or sale of generic versions of Merck’s Invanz® product, the principal component of which is the carbon dioxide adduct of ertapenem. In response, Merck sued Hospira for infringement of two patents—the ’150 patent and U.S. Patent 5,952,323 (OB listed).

The district court concluded that the asserted claims of the ’323 patent were not invalid and were infringed and that the asserted claims of the ’150 patent would also be infringed, but were invalid as obvious over the ’323 patent and PCT publication WO 98/18800. The district court found that, while none of the three steps of claim 21 of the ’150 patent was individually taught by the prior art, the “recipe” for the final formulation was disclosed and the three steps leading to that formulation were nothing more than conventional manufacturing steps that would have been obvious from the disclosures and thus were the product of routine experimentation. The court found that both references expressly taught that the formation of the carbon dioxide adduct is pH-dependent and requires a pH range of about 6.0 to about 9.0; sodium hydroxide could be used to adjust the pH; and the carbon dioxide adduct could be produced using “standard lyophilization techniques.” The district court reviewed Merck’s objective evidence and concluded that commercial success and copying by others were shown, but that the objective evidence could not overcome the “strong prima facie case of obviousness” established by Hospira.

On appeal from a bench trial, Federal circuit reviewed the district court’s conclusions of law de novo and its findings of fact for clear error. On appeal, Merck argued that the district court erred in finding that the claims would have been obvious over either the ’323 patent or Almarsson because it is undisputed that none of the claimed steps is disclosed in the prior art. Merck contended that the court erred in relying solely on the “knowledge, creativity, and common sense” of a skilled artisan because “common sense” is properly invoked to provide a motivation to combine, not to supply a missing claim limitation. Furthermore, Merck said, the prior art focused solely on degradation by dimerization, not hydrolysis. In that way, Merck argued, the prior art taught away from the claimed invention because pH values favorable for reducing dimerization result in increased hydrolysis, and vice versa. Hospira responded that the district court properly evaluated the claims as a whole and determined that they recite nothing more than an obvious implementation of the disclosures of the ’323 patent and Almarsson. Hospira contended that claim 21 recites three broad, general processing steps that constitute nothing more than the routine way a skilled artisan would have implemented the teachings of the ’323 patent. Finally, Hospira maintained that the prior art taught that the carbon dioxide adduct could be obtained by “standard lyophilization techniques,” and claim 21 does not require any specific lyophilization conditions.

Federal circuit agreed with Hospira & held that the district court did not err in finding that the claimed process would have been obvious at the time the invention was made. The court found that both references expressly taught minimizing dimerization by forming the carbon dioxide adduct of ertapenem at pH 6.0–9.0, that sodium hydroxide could be used to adjust the pH, and that the final adduct was to be obtained using “standard lyophilization techniques.” The court also found that, while the claimed temperature range was not explicitly taught in the prior art, it was understood that degradation is minimized at low temperatures, so one of ordinary skill would have wanted to keep the temperature as low as possible without freezing. The only elements of that process that were not expressly disclosed in the prior art are—namely, the order of the steps, the simultaneous addition of base, the specific temperature range, and a final moisture content of less than 10%. But, as the court found, those are all experimental details that one of ordinary skill would have utilized via routine experimentation, armed with the principles disclosed in the prior art. Thus, Federal circuit concluded that the district court did not err in its conclusion of obviousness & therefore affirmed the decision of the district court.

Cyclosporine – USA

On Oct. 16, 2017, Judge Bryson of Eastern District of Texas issued an opinion & found Restasis® (Cyclosporine) patents invalid as obvious.

Restasis is an emulsion consisting of various components, including the active ingredient cyclosporin A, an immunosuppressant, which is dissolved in castor oil, a fatty acid glyceride. Restasis, is protected by six related patents, which are listed in orange book (OB) & are expiring on same date ie. Aug 27, 2024. The six Restasis patents are U.S. Patent Nos. 8,629,111 (“the ’111 patent”), 8,633,162 (“the ’162 patent”), 8,642,556 (“the ’556 patent”), 8,648,048 (“the ’048 patent”), 8,685,930 (“the ’930 patent”), and 9,248,191 (“the ’191 patent”). The defendants, Teva,  Akorn and Mylan are generic drug manufacturers that wish to manufacture and sell generic drug before expiration of OB listed patents.

A limitation that is common to all of the claims is the formulation for Restasis, which is an emulsion “comprising cyclosporin A in an amount of about 0.05% by weight; castor oil in an amount of about 1.25% by weight; polysorbate 80 in an amount of about 1.0% by weight; acrylate/C10-30 alkyl acrylate cross-polymer in an amount of about 0.05% by weight; glycerine in an amount of about 2.2% by weight; sodium hydroxide; and water”.

Invalidity Based on Obviousness:

The issue before court was whether the asserted claims of the Restasis patents would have been obvious in light of various combinations of prior art references, including the Ding I and Ding II patents and Sall.

The obviousness dispute in this case centered on Allergan’s assertion that the Restasis formulation exhibited unexpected results compared to the prior art. Allergan stated that the Ding I patent discloses ranges of amounts of cyclosporin (0.05% to 0.40%) and castor oil (0.625% to 5.0%) that cover Restasis. Allergan arguesd however, that the particular combination in Restasis of 0.05% cyclosporin and 1.25% castor oil is a critical value that produces unexpected results far better than would be expected for the range of values disclosed in Ding I. For that reason, Allergan contended that the critical value of 0.05% cyclosporin with 1.25% castor oil is patentable, even though it falls within the ranges disclosed and claimed in Ding I.

During the prosecution of the ’857 application Allergan “concede[d] [to the PTO] that it would have been obvious to modify examples 1A-1E of the Ding reference to arrive at Composition II [the Restasis formulation] of the present application.”  Allergan explained that the differences between Examples 1A-1E of the Ding I patent and the Restasis formulation “are insignificant”; that one of ordinary skill in the art “would readily envisage” the Restasis formulation; and that “there would have been a reasonable expectation of success” with the Restasis formulation. More than four years later, while prosecuting what became the Restasis patents, Allergan withdrew its concession and argued that the applications claiming the Restasis formulation were patentable over the Ding I patent because they showed unexpected results for the Restasis formulation as compared to the ranges claimed in Ding I and the particular examples disclosed in the specification of Ding I. As evidentiary support for that position, Allergan submitted Dr. Schiffman’s declaration to the examiner.

The Court found that statistical significance is an important component in establishing the reliability of the clinical data for a person of skill in the art. Stevenson’s paper, the published account of the Phase 2 results sponsored by Allergan, demonstrated the importance of statistics in drawing conclusions. Stevenson reported that there was no observed dose response, concluded that all tested concentrations performed effectively and safely, and counseled a person of skill to investigate both the 0.05% and 0.1% cyclosporin formulations. That peer-reviewed paper does not go so far as to say that the 0.1% formulation did best, or even that the 0.1% formulation did better than 0.05%.

Stevenson’s conclusions were corroborated by other persons of skill in the art, including Allergan’s own drug developers. Upon presenting the Phase 3 results to the FDA, Allergan explained that the performance of the 0.05% cyclosporin formulation was not surprising because the lack of a dose response—i.e., the similar level of efficacy for formulations containing 0.05% or more of cyclosporin—was observed earlier in Phase 2. After presenting the FDA with its plan to test the 0.1% formulation in Phase 3, Allergan acknowledged that “[b]ecause we did not show a clear differentiation in effect among the doses [in Phase 2], it was recommended [by the FDA] that we include a lower concentration [0.05% cyclosporin] in one Phase 3 clinical trial to confirm that we have chosen the lowest effective concentration.”

For those reasons, the Court found that a person of skill reviewing Stevenson alone, or even Stevenson in combination with all the underlying Phase 2 data, would not conclude that the 0.1% cyclosporine /1.25% castor oil formulation was more effective than the 0.05% cyclosporin/0.625% castor oil formulation. A person of skill reviewing those papers would come to the conclusion that neither formulation was more effective than the other in Phase 2. That person of skill would reach the same conclusion for Phase 3.

Court further said that to the extent Allergan relies on Dr. Schiffman’s presentation to the PTO, it found that the presentation made to the examiner in 2013, including Dr. Schiffman’s declaration and the accompanying exhibits, painted a false picture of the comparative results of the Phase 2 and Phase 3 trials. Also the FDA’s Medical Review does not support Allergan’s claim of unexpected results & the success of Restasis would not have been surprising to a person of skill in the art in 2003.

Allergan had also pointed to evidence of objective considerations such as commercial success and long-felt unmet need, however the force of that evidence is considerably blunted by the fact that, based on protection from a succession of patents, Allergan was able to foreclose competition in cyclosporin/glyceride emulsion formulations from the early 1990s until 2014. And the issuance of the Restasis patents has barred any direct competition for Restasis since then. The evidentiary value of the objective consideration evidence has thus been considerably weakened by the existence of blocking patents during the critical period.

Thus court finally held that based on the extensive amount of pertinent prior art and the Court’s factual assessment of Allergan’s showing of unexpected results, the Court has concluded that Allergan is not entitled to renewed patent rights for Restasis in the form of a second wave of patent protection. The Court therefore holds that while Allergan has proved by a preponderance of the evidence that the defendants have infringed the asserted claims of the Restasis patents, the defendants have proved by clear and convincing evidence that the asserted claims of the Restasis patents are invalid for obviousness.

Ethinylestradiol & Etonogestrel - USA

On Oct 19, 2017, in a nonprecedential opinion Federal circuit reversed District court of Delaware’s decision on obviousness in NuvaRing® (Ethinylestradiol/etonogestrel) on improper hindsight (Merck Sharp & Dohme B.V., v. Warner Chilcott Co. LLC.). Previously district court held that claims 4 and 11 of U.S. Patent No. 5,989,581 are invalid as obvious. Merck appealed.

The ’581 patent relates to a vaginal ring used for contraception, and its commercial embodiment is sold under the brand name NuvaRing®. Warner Chilcott is seeking to introduce a generic version of NuvaRing®, and concedes that its generic product would infringe the ’581 patent if the claims are found valid. Importantly, claims 4 and 11 both require at least a single-compartment that includes a progestogenic steroidal compound and an estrogenic steroidal compound. Warner Chilcott argued that the asserted claims are anticipated or rendered obvious by International Patent Application WO 97/02015.

Like the ’581 patent, PCT ’015 also discloses a vaginal ring that prevents contraception by releasing ETO and EE. PCT ’015, however, relies on a two compartment design, in which a first compartment includes ETO only, and a second compartment includes ETO and EE. PCT ’015 criticizes one-compartment vaginal rings, stating that:

“These above-mentioned one-compartment rings have the disadvantage that, when loaded with more than one active substance, release patterns of these substances cannot be adjusted independently. Such devices usually show suboptimum release patterns for the different substances, whereas it is generally preferred that all substances are released in a controlled rate and during a similar duration of time. As a consequence the release ratio of the active substances undergoes a change after a period of time”.

After a four-day bench trial, the district court found that PCT ’015 renders obvious the ’581 patent claims. Specifically, the court reasoned that “a person of ordinary skill would have been motivated to optimize PCT ’015 such that the second compartment released physiologically required amounts of ETO and EE.”

Federal circuit however disagreed with district court & said that PCT ’015 does not actually disclose a ring with a second compartment that comprises 97% of the ring, and includes a higher concentration of ETO than EE in the second compartment. Instead, PCT ’015 provides a broad range of values for the relative size of each compartment as well as concentrations of each compound.  To arrive at the hypothetical ring that the district court relied on for obviousness, the person of ordinary skill must make the second compartment 97% of the total ring, which is outside of the usual or preferred range disclosed in PCT ’015. Also prior art was silent on possible combinations of ETO (high end) & EE (low end) concentrations.

Instead, the only way to arrive at the hypothetical ring is by using the ’581 patent as a roadmap to piece together various elements of PCT ’015. That represents an improper reliance on hindsight. The district court’s reliance on hindsight is further underscored by the prior art’s criticism of the one compartment solution. PCT ’015 expressly states that one compartment rings are undesirable because it is difficult to control the release rates for both compounds. Therefore the person of ordinary skill would not be motivated to modify PCT ’015 to make a one-compartment ring.

Because it was not obvious to load the claimed concentrations of progestogenic compounds and estrogenic compounds in one compartment, Federal circuit thus reversed the district court’s finding of invalidity.

Dronedarone - USA

On Oct. 23, 2017, Court of Delaware issued a trial opinion in Multaq® case & found asserted patent valid & infringed by ANDA filers.

Plaintiffs Sanofi brought this consolidated patent infringement case against Defendants Watson Laboratories, Inc. and Sandoz Inc. This opinion addressed allegations of infringement and invalidity with respect to U.S. Patent No. 9,107,900. Sanofi-Aventis U.S. LLC is the holder of approved New Drug Application No. 022425 for dronedarone tablets, 400 mg, which are prescribed under the trademark Multaq®. The '900 patent, entitled "Use of Dronedarone for the Preparation of a Medicament for Use in the Prevention of Cardiovascular Hospitalization or Mortality” & is expiring on Apr 16, 2029.

Infringement: Plaintiff asserted claims 1, 6-9, and 14 of the '900 patent against Defendants. Plaintiff argued that Defendants' product labels will induce infringement of the asserted claims under 35 U.S.C. § 271(b). Defendants argued that they do not induce infringement of claims 1, 7, 9, and 14. Those four claims are directed to patients with coronary heart disease and who meet the Age Criteria. With respect to the label generally, Plaintiffs' expert, Dr. Kim, acknowledged that there is no express reference to a patient who has coronary heart disease and is over 70 years of age. The Indications and Usage section of Defendants' labels indicates administering dronedarone tablets for reducing "the risk of hospitalization for atrial fibrillation in patients in sinus rhythm with a history of paroxysmal or persistent atrial fibrillation." This section does not expressly indicate the drug for patients with coronary heart disease. However, the Clinical Studies section (ATHENA study) of Defendants' labels supports the conclusion that the labels teach that dronedarone could be used for some patients with coronary heart disease. But the words "coronary heart disease" do not expressly appear anywhere in said section (14.1).

Section 14.2 discusses the EURIDIS and ADONIS study. This study followed 1,237 patients treated with either dronedarone 400 mg twice daily or placebo. Section 14.2 states, "The most common co-morbidities were hypertension (56.8%) and structural heart disease (41.5%), including coronary heart disease (21.8%)." This language suggests that coronary heart disease is a subset of structural heart disease. Overall, in the context of Defendants' labels, a POSA would understand "structural heart disease" to include “coronary heart disease” and that a person with coronary heart disease would be described as having structural heart disease.

Court held that there is encouragement to prescribe dronedarone to some patients within the Age Criteria. Defendants' labels suggest that dronedarone could be used in patients in the Age Criteria. The ATHENA patients ranged from 23-97 years old, where 42% were 75 years old or older. Dr. Zusman (Defendants' expert) conceded that assuming the label discloses use in coronary heart disease patients, a physician "might have inferred" that dronedarone would provide a benefit in terms of reduction in cardiovascular hospitalization and death in patients consistent with the overall ATHENA population." Dr. Zusman estimates that based on his experience, approximately 80% of dronedarone patients do not have both coronary heart disease and meet the Age Criteria.

In sum, while the Indications and Usage section does not expressly instruct the administration of dronedarone to patients with coronary heart disease who meet the Age Criteria, it directs a POSA to review, and a POSA would review, the Clinical Studies section. From the Clinical Studies section, it would be readily apparent to a POSA that the use of dronedarone for patients with coronary heart disease and who meet the Age Criteria would reduce the risk of cardiovascular hospitalization. The labels encourage a POSA to prescribe dronedarone to some patients within the Age Criteria. Therefore Plaintiffs have met their burden of showing that Defendants' labels would induce infringement of claims 1, 7, 9, and 14 of the '900 patent.

Defendants further argued that they do not induce infringement of claims 6 and 8, which is directed to patients with New York Heart Association Class III congestive heart failure. Defendants' labels contain a Black Box warning on the first page that discourages physicians from using dronedarone in patients with "decompensated heart failure." Dr. Zusman believes that the warning applies "very definitely" to Class III patients & label "clearly teaches away" from the use of dronedarone in Class III patients.  Considering all of the evidence as a whole, court held that Plaintiffs have not shown that Defendants' labels instruct a POSA to use dronedarone for patients with stable NYHA Class III CHF. A POSA would not be encouraged by Defendants' labels to prescribe dronedarone to such patients.

Obviousness: Defendants argued that claims 1, 7, 9, and 14 of the '900 patent are invalid as obvious. Dr. Zusman testified that a common cause of hospitalization for AF patients is the recurrence of AF resulting in problems such as fainting, chest pain, heart failure, palpitations, stroke or systemic embolization, and tachycardia (the rapid heart rate associated with AF). Dr. Zusman acknowledged that as of 2008, it was not known whether the maintenance of sinus rhythm actually prevents stroke in patients with AF. Dr. Zusman acknowledges that as of 2008, it would be a significant finding if a company could demonstrate that dronedarone would reduce heart failure.

Comparing the Prior Art and the Claimed Subject Matter the central dispute is whether a POSA would reasonably expect dronedarone to reduce the risk of cardiovascular hospitalization in Atrial Fibrillation (AF) patients with coronary heart disease and within the Age Criteria. Considering all the evidences, Court do not think that Defendants have sufficiently shown that a POSA at the time of the priority date would have a reasonable expectation that dronedarone would reduce hospitalization for the sicker, older patients that make up claims 1, 7, 9, and 14 of the '900 patent. While the EURIDIS/ADONIS post-hoc analysis, Hohnloser, and some internal Sanofi statements form the bulk of evidence weighing in Defendants' favor, I think this evidence is significantly undermined by evidence such as the CAST trials, the rate versus rhythm trials, SWORD, PROMISE, ANDROMEDA, the FDA/EMEA rejections, and also some internal Sanofi statements. There is substantial evidence teaching away from the conclusion that dronedarone would reduce hospitalizations in the claimed patient population. Thus Defendants have failed to meet their burden of showing that US'900 patent is invalid as obvious.

Tenofovir disoproxil fumarate & Emtricitabine - Switzerland

The Complementary Protection Certificate C00915894 / 01 is based on basic patent EP0915894 B1. The Swiss SPC covers product “tenofovir disoproxil fumarate + emtricitabine“. A first marketing authorization for the active substance combination Tenofovir Disoproxil fumarate together with Emtricitabin the defendant for the Product Truvada® at no. 57316 on March 21, 2006. Tenofovir disoproxil, a nucleoside reverse transcriptase inhibitor (NRTIs) as an active ingredient with antiviral action is undisputed because it has the structure that was claimed in claim 1 of EP’894 patent. The fumarate salt of tenofovir disoproxil will also be detected but salts of the active substance are expressly mentioned in claims 1 and 2. Further references to co-formulations can be found in the paragraphs [0061] but without specific reference to further therapeutic agents.

As stated above and not questioned by the parties, the base product protects the active substance tenofovir disoproxil as a fumarate salt. This is the subject of the right of protection in the protection area of the base. Claim 27 of the base patent protects a pharmaceutical composition, which contain such an active ingredient as tenofovir disoproxil as Fumarate salt, together with a pharmaceutically acceptable salt thereof Carrier and optionally with other active ingredients. This is also described in [0047] basic patent. Further this combination of tenofovir disoproxil as a fumarate salt in the claims of the basic patent expressly specified in combination with another active ingredient, if only as an option. The individual concrete further active substance emticitabine, appears neither in a claim in combination with tenofovir disoproxil as a fumarate salt, or else in the description mentioned.

Against this point of view, however, would be the ECJ decision Actavis / Sanofi, according to which tenofovir disoproxil the core contribution of the basic patent, but not the further active ingredient and certainly not the specific selection of the further Active substance as emticitabine (not the subject of the basic patent). Even if one were to try the ECJ jurisprudence Medeva for the present case, one would not get a clear one answer, whether the law of suitability is legal, because the Medeva criteria are not clear. However the injury test, as described by the Federal Court in the decision Fosinopril has been confirmed, is simple and comprehensible and leads great legal certainty. Therefore the application for annulment of SPC dismissed accordingly. The decision may be appealed against within 30 days of the opening of the Federal Supreme Court.

[Mepha Pharma AG, V Gilead Sciences Inc; Case No. O2017_001; Oct 03, 2017]

Metaxalone - USA

On Oct 17, 2017, by Rule 36 judgment Federal circuit affirmed District court of Maryland’s decision (Sep 27, 2016) of non-infringement of U.S. Patent No. 6,584,472 in Skelaxin® (Metaxalone) under safe harbor  provision.

On May 13, 2015, the Federal Circuit vacated and remanded Judge Quarles’ 2012 judgment of non-infringement in favor of Elan. In its opinion remanding this case to this Court, the Federal Circuit concluded that “the district court correctly decided that § 271(e)(1) exempts Elan’s activities reasonably relating to developing clinical data on its approved drug Skelaxin® (“Skelaxin”) and submitting that information to the Food and Drug Administration (“FDA”) in a citizen petition and a supplemental new drug application (“sNDA”).” Classen, 786 F.3d at 894. However, the court also found that because Judge Quarles’ opinion did not address Plaintiff’s “assert[ion] that certain activities that occurred after the FDA submissions infringed the ‘472 patent and that those activities are not exempt under the safe harbor of § 271(e)(1),” remand was appropriate.

Accordingly, the sole question before the court was whether Elan’s “post-submission activities constituted infringement of the ‘472 patent or whether they were exempt under the safe harbor.” In its decision remanding this case to this Court, the Federal Circuit offered the following guidance with respect to Plaintiff’s claims:

1.       Filing a patent application is generally not an infringement of a patent. It is not the making, using, offering to sell, selling, or importing of an invention.

2.       Placing the information submitted to the FDA on the product label after sNDA approval generally cannot be an infringement. Information obtained from exempt activities does not cease to be exempt once the sNDA is approved.

Elan argued that summary judgment is appropriate because its allegedly infringing activities are protected by 35 U.S.C. § 271(e)(1)’s safe harbor provision. In its Opposition, Classen argues that Elan’s post-submission activities—that is, submission of clinical data to the FDA—are aimed at commercialization and thus, in Classen’s view, fall outside of the safe harbor of § 271(e)(1). The allegedly infringing activities are: (1) “reanalyzing the clinical data to identify patentable information and filing patent applications;” and (2) “making and selling Skelaxin with the revised label that contained the information derived from the clinical study.”

Court in view of Federal Circuit’s guidance said that Elan’s alleged “reanalyzing the clinical data to identify patentable information and filing patent applications,” and “making and selling Skelaxin with the revised label that contained the information derived from the clinical study” fall squarely within the safe harbor of § 271(e)(1). Therefore court granted defendant’s motion for Summary Judgment of Non-infringement (Classen Immunotherapies, Inc. v. Elan Pharms., Inc. , 2016 BL 318007, D. Md., No. 1:04-cv-03521-RDB, 9/27/16). 

Naltrexone & Bupropion – USA

On Oct. 13, 2017, District court of Delaware issued an opinion & found Contrave® patents valid & infringed by Actavis.

Plaintiff (Orixegen) brought this patent infringement action on June 3, 2015, alleging that Defendant (Actavis) had infringed seven of Plaintiffs patents by filing Abbreviated New Drug Application ("ANDA") No. 208043 seeking to enter the market with a generic version of Plaintiffs Contrave® (Naltrexone HCl and Bupropion HCl ER Tablet) product. The Court held a three day bench trial on June 5-7,2017 for three patents-in-suit: U.S. Patent Nos. 7,462,626 ("the '626 patent"), 7,375,111 ("the ' 111 patent"), and 8,916,195 ("the ' 1 9 5 patent"). The '626 patent is directed to methods of treating overweight or obesity using a combination of naltrexone and bupropion. The '111 patent is directed to compositions for use in weight loss treatments comprising a combination of sustained release formulations of bupropion and naltrexone. The '195 patent is directed to methods of treating overweight or obesity using a combination of naltrexone and bupropion. Defendant contends that it does not infringe any of the asserted claims. Defendant also argues that claim 11 of the '195 patent is invalid for lack of written description and all asserted claims of the '111 and '626 patents are invalid as obvious in view of the prior art.

WRITTEN DESCRIPTION:

Defendant argued that claim 11 of the '195 patent is invalid for lack of written description because the ranges given for the claimed dissolution profile "were improperly cobbled together" and were measured using a different method than that required by the claim. Plaintiff responded that simply because the claims draw support from different parts of the specification does not mean that a person of ordinary skill would not believe that the inventor was in possession of the invention. Plaintiff also argued that there is no legal requirement that all claim limitations be set out in a single place in the specification. Plaintiff pointed to the prosecution history, which shows the applicant cited to specific portions of the specification as support for claim 11, resulting in a notice of allowance for this claim.

Court agreed with Plaintiff that the specification would indicate to a person of ordinary skill that all of the dissolution data reported in the patent was obtained "using Apparatus 2 ... at a spindle rotation speed of 100 rpm and a dissolution medium of water, at 37° C., or other test conditions substantially equivalent thereto." Therefore Defendant has not proven by clear and convincing evidence that claim 11 of the '195 patent is invalid for lack of written description.

OBVIOUSNESS:

Defendant argued that claims 26 and 31 of the '626 patent and claim 1 of the '111 patent are invalid as obvious over the prior art.2 (D.I. 162 at 22, 27-28). Specifically, Defendant argued that a person of ordinary skill in the art would have been motivated to combine the teachings of the Jain and O'Malley references to administer the combination of naltrexone and bupropion for treating overweight and obesity with a reasonable expectation of success. Jain discloses a placebo-controlled study of sustained release bupropion for reducing weight and depressive symptoms in obese patients. Jain does not discuss naltrexone, nor does it suggest combining bupropion with naltrexone or any other drug. O'Malley discloses the use of an opioid antagonist, such as naltrexone, during smoking cessation to minimize weight gain. O'Malley also discloses that the opioid antagonist may be administered "in combination with at least one withdrawal attenuating agent ... such as clonidine, acamprosate, antihypertensives, antidepressants, antianxiety agents, agents which alter serotonergic function or other agents. One of the antidepressants disclosed in O'Malley is bupropion.

Court agreed with Plaintiff that Defendant's suggestion that bupropion would be an obvious choice for further study in the treatment of overweight and obesity suffers from impermissible hindsight bias. It seems clear that the weight loss effects of bupropion were known to be relatively modest at best. There is also no dispute that the prior art references reported potential risks associated with bupropion, including the risk of seizure. Based on the lack of knowledge of the mechanism of action, combined with the modest effectiveness, Court do not think a person of ordinary skill would have found bupropion to be an obvious starting point for further study. Court also agreed with Plaintiff that the prior art cited by Defendant does not teach a person of ordinary skill that naltrexone was effective for weight loss.

INFRINGEMENT:

Plaintiff asserted that Defendant directly infringes claim 1 of the '111 patent and indirectly infringes claim 11 of the '195 patent and claims 2, 15, 26, and 31 of the '626 patent. Prior to trial, the only non-infringement argument raised by Defendant as to the '111 patent was that it could not be infringed because it was invalid. Therefore Defendant infringes claim 1 of the '111 patent. Defendant's non-infringement arguments as to claim 11 of the '195 patent all center on whether its proposed ANDA product meets the claimed dissolution profile. Plaintiff has adduced sufficient evidence to prove by a preponderance of the evidence that at least some of Defendant's tablets will meet the claimed dissolution profile. Plaintiff presented evidence that Defendant's proposed label induces infringement by meeting all limitations of claims 26 and 31 of the '626 patent.

CONCLUSION:

Defendants failed to prove by clear and convincing evidence that claims 26 and 31 of the '626 patent, claim 1 of the '111 patent, and claim 11 of the '195 patent are invalid. Plaintiff proved by a preponderance of the evidence that Defendant directly infringes claim 1 of the '111 patent and indirectly infringes claims 26 and 31 of the '626 patent and claim 11 of the '195 patent.

Rituximab – Netherlands

On Sep 27, 2017, Court of Hague issued decision in Rituximab case & revoked Roche/Genentech’s patent EP1951304B1, because it lacks novelty since priority was denied. EP’304 is entitled "Method for Treating Joint Damage". The patent - in short - refers to a use of rituximab in the treatment regimen for joint disease in rheumatoid arthritis (RA).

Celltrion by judgment seeks declaration that defendants are not entitled to enforce the Dutch part of EP’304 against Celltrion & ask to pay the reasonable and proportionate costs of the proceedings. In support of its claim, Celltrion stated that EP’304 is not entitled for priority because inventors have not validated their rights of priority and transferred in time to defendants, thus rendering the Keystone- publication becomes novel harmful state of the art. Defendants argued that the priority right at the time of its creation was automatically transferred on the basis of the agreement between inventors and his employer from 2004. The court must therefore first assess whether the text of the agreement is clear as to the alleged automatic transfer of priority rights.

Celltrion claims that the agreement does not regulate that a priority right automatically passes.  Article 10 of the agreement shows that a separate legal act is required for the transfer of a priority right. Defendants contest that and argue that Articles 4 and 5 show that there is an automatic transfer, in which they rely on an explanation of the agreement in accordance with the parties' intention.

The court after analysing the facts said that the agreement does not contain an explicit provision governing the manner in which priority rights are transferred. Indeed, the term ' priority right' does not appear as such in the agreement. The court rejected the defendant’s argument that the active assignment contained in Article 5 should be considered not only refers to Proprietary Information, but also to priority rights as belonging to the group of patent-related rights.

Now, in the judgment of the court of the agreement, no automatic transition from the priority right derived from inventor can be deduced, and it has not been found that this right is otherwise transferred to one of the defendants in a timely manner. In principle, the priority date will be November 6, 2006. Therefore, based on a priority date of 6 November 2006, Keystone's publication is prior art & thus EP’304 lacks novelty and is revoked.

Pemetrexed - Italy

On Sep 10, 2017, Court of Milan issued decision in pemetrexed case & found Fresenius pemetrexed ditrometamine product non-infringing. In this proceedings Fresenius sought declaration of non-infringement with respect to their product - pemetrexed ditrometamine before expiration of EP1313508 patent. EP’508 patent is expiring in Jun 2021 which claims use of pemetrexed disodium in combination with vitamin B12 for treatment of cancer.

Fresenius argued that the EP’508 patent claims were limited to pemetrexed disodium alone. Specifically, "File history" of EP'508, from which it appeared that Eli Lilly had limited the scope of protection to only salts of pemetrexed disodium from broad antifolate after Examiner’s objection during prosecution. In addition, the replacement of pemetrexed disodium with pemetrexed ditrometamine was not obvious, because it was not suggested, not implicitly, by the EP’508 patent of Eli Lilly. Also Fresenius product is intended to reconstitute with glucose solution and not with saline solution. Therefore, no source of sodium was introduced at any stage of production or preparation for administration.

Eli Lilly in counter statement said that the replacement of the pemetrexed diacid and tromethamine compound by the Fresenius was an obvious solution that could be achieved by routine experimentation. Eli Lilly also argued that the marketing of the Fresenius product would be a case of indirect infringement even if it required dilution in glucose, as the manufacturer's prescriptions would not be followed by the oncologist's physician and pharmacist whom they are referring to, they would be expected to use saline instead of that glucose, prescribed in the Fresenius product.

Court of Milan after hearing both the parties said that the interpretation of the claim, the description, of the entire patent text, the examination of the modifications made during the patent granting procedure, uniquely and independently, for the clear delimitation of patent protection to pemetrexed disodium alone, excluding that it may extend to other compounds. In the present case, in the absence of a restriction on pemetrexed disodium, the patent would have been granted and, if granted, it would have been declared null under the provisions of art. 123(2). In order to overcome this invalidity profile, the inventor has limited the patent patent to sodium pemetrexed, explaining in the description that "antifolate medicinal products of which the invention refers exclusively to Pemetrexed Disodium (Alimta)”.

After a thorough and in-depth analysis, court stated that the pemetrexed diacid in combination with trometamine, which characterizes the FRESENIUS product, can not to be considered a vice-versa equivalent to what is covered by EP'508, in the light of patent instruction "strictly limited” to the use of pemetrexed disodium alone in combination with vitamin B12 always in the antitumour treatment. Also Fresenius product exclusively would dilute in a 5% glucose solution, which is non-chemically different, and not equivalent, to the saline solution. In the presence of manufacturer's opposite instructions in drug label, replacement is not foreseeable.

This Court of Milan’s decision directly contradicts with the recent UK supreme court’s judgment where UKSC found Actavis product infringing. The UK SC also found that Actavis' product containing pemetrexed ditrometamine directly infringed the Italian designation of Lilly's patent. This difference is mainly because Milan court gave more preference to “file history” and applied estoppel.

Posaconazole – USA

On Sep 29, 2017, District court of New Jersey issued a ruling in Noxafil® case and found Merck’s compound patent valid.

This patent infringement action was brought by Merck against Actavis for filing an Abbreviated New Drug Application (“ANDA”) with the Food & Drug Administration (“FDA”) for approval to engage in the commercial manufacture, use or sale of a generic version of Merck’s Noxafil® (posaconazole) before expiration of U.S. Patent No. 5,661,151.

In this action, a seven-day bench trial was held in July 2017. During trial, Actavis set forth the defense that filing of the ANDA application does not infringe the ’151 patent because the asserted claims 11 and 12 of the ’151 patent are invalid. In particular, Actavis asserted that—(i) claim 11 of the ’151 patent is invalid because it is inherently anticipated by the European Patent Application EP 0 539 938 A1 (“EP ’938”); and (ii) claim 12 is invalid because it is obvious to a person of ordinary skill in the art (“POSA”) in view of the EP ’938 reference.

In contrast, Merck argued that claims 11 and 12 of the ’151 patent are valid because Actavis has not shown by a clear and convincing evidence that the asserted claims are rendered inherently anticipated or inherently obvious in view of the EP ’938 reference. Further, Merck argued that the EP ’938 reference is not a prior art reference under 35 U.S.C. §§ 102(a) and 103(a) because the inventive concepts recited in claims 11 and 12 of the ’151 patent were invented on April 14, 1993, and diligently reduced to practice prior to or soon thereafter. As such, antedating the EP ’938 reference, published on May 5, 1993.

The parties agree that the earliest priority date of the ’151 patent is December 21, 1993.The issues litigated before the Court were whether Merck can antedate the EP ’938 reference by showing that the claimed subject matter of claims 11 and 12 were conceived before the publication date of the EP ’938 reference, and diligently reduced to practice soon thereafter.

On April 14, 1993, Dr. Pramanik configured the chemical structure in his notebook of Metabolite A after reviewing the mass spectra provided by mass spectrometrist Dr. Heimark. In his configuration of the chemical structure (SCH 51048 Metabolite), Dr. Pramanik provided substantial detail and specificity of the SCH 51048 metabolite. That is, Dr. Pramanik drew out—(i) all the components of the azole core, (ii) all the components of the piperazine linker, (iii) all the components of a side chain; and (iv) where the side chain is attached to the piperazine linker.

Dr. Pramanik discussed his findings with Drs. Giri and Saksena the very same day, April 14, 1993. In this meeting, it was determined that there are seven possibilities for the chemical structure, which included two primary alcohols, four secondary alcohols, and one tertiary alcohol. During this meeting on April 14, 1993, Drs. Giri and Saksena (inventors of the ’151 patent) had conceived of the chemical structure or formula of a potential antifungal drug that would result in posaconazole. Moreover, Actavis agrees that the structure of posaconazole was conceived on April 14, 1993.

With respect to actual reduction to practice court determined that the reduction to practice took place on April 14, 1993, when inventors of the ’151 patent discovered the hydroxyl or OH group on the side chain of metabolite A. This hydroxyl group was missing from the parent compound, Compound IIc or SCH 51048. The Court finds that the reduction to practice of posaconazole was envisioned on April 14, 1993, but some further testing and analysis was required on part of Schering’s scientists to determine and confirm which one of the six alcohols had adequate antifungal activity such that it could be commercially used.  Although such further testing and analysis is not a requirement for showing actual reduction to practice. (Scott, 34 F.3d at 1061-62).

After careful review and consideration of the evidence presented at the bench trial, the Court found that Merck has provided that the subject matter recited in claims 11 and 12 of the ’151 patent was conceived on April 14, 1993, which was diligently reduced to practice thereafter. Thereby, rendering the EP ’938 reference not a prior art reference to the ’151 patent. As such, the Court found that claim 11 of the ’151 patent is not invalid under 35 U.S.C. § 102(a); and claim 12 of the ’151 patent is not invalid under 35 U.S.C. § 103(a).