Mesalamine – USA

On Dec 12, 2018, Federal Circuit affirmed (Rule 36 judgment) Texas district court’s decision which granted summary judgment of non-infringement to ANDA filers in Delzicol® Hatch-Waxman case.

Previously on Oct 24, 2017, District Judge R. Gilstrap accepted Magistrate Judge Payne’s report & recommendations (Sep 28, 2017) regarding claim construction & summary judgment of non-infringement to Teva & Mylan. Allergan objected to the report and recommendation on a number of grounds. Allergan argued that the Magistrate Judge re-construed the term “gelling agent” to a “substance that gels the film composition, but which cannot be water or heated water” in US 6,649,180 & thus excluded the accused product. However, court found no error in this construction. Court said that Allergan’s infringement theory, its expert’s opinion, and the literature upon which it relies all recognize that water merely plays a passive role in the gelling process. This evidence, as the Magistrate Judge correctly concluded, establishes that a person of ordinary skill in the art would not recognize water as a “gelling agent” in the context of the ’180 patent because water at most permits the hydroxypropyl methyl cellulose (HPMC) to gel on its own when an aqueous solution of HPMC is heated. Similarly, in citing the inventor’s admission that water is not a “gelling agent,” the Magistrate Judge did not improperly rely on the inventor’s subjective intent regarding the meaning of a claim term. More importantly, the Magistrate Judge’s clarified claim construction was one of two alternative grounds for recommending summary judgment. The second basis relied on the original claim construction to conclude that, even when all disputed facts are construed in Allergan’s favor, no evidence could support a finding that water gels the film composition in the accused products. Thus, court granted Teva and Mylan’s motions for summary judgment.

Colchicine - USA

On Dec 12, 2018, U.S. District Court of Delaware granted summary judgment of non-infringement & recovery of damages on bond to Hikma / West-Ward pharmaceuticals.

Background:

Plaintiff Takeda Pharmaceuticals manufactures and markets Colcrys®, a branded 0.6 mg colchicine tablet used for the treatment of gout prophylaxis and acute gout flares. Plaintiffs owned several patents directed to a method of treating acute gout flares with colchicine by administering 1.2 mg oral colchicine at the onset of an acute flare, followed by 0.6 mg oral colchicine one hour later  (U.S. Patent Nos. 7,964,647;  7,981,938; 8,415,39). Defendants Hikma / West-ward received FDA approval of a paper New Drug Application ("paper NDA") for Mitigare® on September 26, 2014. Mitigare is a 0.6 mg colchicihe capsule indicated solely for the prophylaxis of gout. Shortly thereafter, on October 3, 2014, Plaintiff filed suit against Defendants. After the Federal Circuit affirmed the denial of a preliminary injunction on January 9, 2015 Defendants launched Mitigare and its authorized generic (Mitigare AG). The Court then granted Plaintiffs Motion to Alter Judgment of Dismissal and for Leave to amend its Complaint on December 15, 2016. Plaintiffs Second Amended Complaint alleges Defendants induced infringement of the Acute Gout Flare Patents through post-launch marketing efforts for Mitigare. Defendants filed a motion for summary judgment on May 4, 2018.

Defendants asserted that summary judgment should be granted because (1) there is no support for Plaintiffs allegations that Defendants' marketing materials and insurance contracts induced infringement, and (2) there is no evidence of any identified direct infringement tied to the allegation that a Mitigare sales representative encouraged infringement. Plaintiff responded that evidence in the record gives rise to a genuine issue for trial on the following allegations: (1) Defendants' promotional materials, labeling of Mitigare, and sampling activities evidence Defendants' intent to induce infringement; (2) Defendants induced infringement by negotiating exclusive agreements with payers; and (3) Defendants induced infringement by engaging in off-label promotion.

A. Promotional Activities:

Plaintiff alleged that Mitigare's labeling, promotional materials, and samples show that Defendants intended to induce infringement. The Court disagreed & said that the Federal Circuit has already determined that the Mitigare and Mitigare AG label language directing patients to consult their doctor if they suffer an acute gout flare does not induce infringement. Takeda, 785 F.3d at 632-33. Second, Defendants' promotional materials do not create an inference that Defendants intended to induce infringement. Defendants' promotional materials generally reference the specific sections of the Guidelines related to Mitigare's indicated non-patented use-the treatment of gout prophylaxis. Finally, intent to induce cannot be inferred from Defendants' sampling activities. Plaintiff pointed to a few statements from physicians consulted in third-party market research as evidence of Defendants' intent to induce infringement through providing samples. Court said that however, these statements support only the inference that Defendants knew that some doctors would provide samples of Mitigare to their patients for an infringing use. Other quotations of physicians were provided in this research which indicated that samples would likely be used for gout prophylaxis. Defendants' distribution of samples of a product with a substantial non-infringing use is not any different from the lawful sale of that same product. The mere knowledge that the third-party recipient may engage in infringing use upon receipt of the product therefore cannot create an inference of intent to induce.

B. Exclusive Payer Contracts:

Plaintiff next asserted that Defendants induced infringement by (1) offering insurance payers substantial financial incentives in the forms of rebates to enter exclusive agreements for Mitigare/Mitigare AG with (2) the intention to drive a complete conversion from Colcrys/Colcrys AG to Mitigare/Mitigare AG (3) without regard to the indicated use of prescriptions. Plaintiff alleged that a complete conversion of the market from Colcrys/Colcyrs AG to Mitigare/Mitigare AG through the "blocks" and "step edits" included in these contracts would necessarily cause infringement of the Acute Gout Flare Patents. Court found that it is clear that negotiating an exclusive contract with an insurance payer is comparable to a lawful sale of the product. As with lawful sales of a product with substantial non-infringing use, the knowledge that an exclusive payer contract may result in infringing use cannot support an inference of intent to induce by itself. Second, Plaintiff has not provided sufficient evidence to create a reasonable inference that Defendants intended to induce infringement. Defendants' Mitigare has a substantial non-infringing use-gout prophylaxis. Therefore, efforts to encourage the sale of Mitigare cannot be converted into an attempt to induce infringing behavior without more evidence. Third, even if there was sufficient evidence to create a genuine issue of Defendants' intent to induce for trial, there is no evidence that the contracts have actually induced infringement.

C. Off-Label Promotion:

Plaintiff finally asserted that Defendants induced infringement by engaging in off-label promotion. Plaintiff identified a single doctor, Dr. Elmahdi Saeed, who it alleges was induced to write infringing prescriptions by a Mitigare sales representative. Dr. Saeed stated that he prescribed Mitigare off-label for acute gout flares about 4-6 times because of the sales representative's statements. However, the parties have not discovered any record of a Mitigare prescription written by Dr. Saeed for the treatment of acute gout flares. Court further said that proving of induced infringement would require that a patient (1) actually filled the prescription, (2) actually had a gout flare, and (3) actually took the prescribed Mitigare according to the very particular method of treatment. Given the lack of any evidence beyond Dr. Saeed's statements, there is insufficient evidence to infer that at least one of Dr. Saeed's patients used Mitigare/Mitigare AG in an infringing manner due to the statements of the sales representative.

Thus, court granted summary judgement of non-infringement to defendants.

Court also simultaneously granted defendants motion for recovery of damages on bond because of improper temporary restraining order (TRO) imposed on defendants. In conclusion court granted defendants' motion to recover damages for wrongful restraint in the amount of $31,407,800 in lost profits and $463,272.09 in prejudgment interest.

Insulin glargine (LANTUS) - USA

IPR decision (Dec .12, 2018):

AIA Review	Filing Date	Institution Date	Petitioner	Patent No.	Final Written Decision
IPR2017-01526	06/05/2017	12/13/2017	Mylan Pharmaceuticals Inc.,	7,476,652	Claims 1–25 are unpatentable
IPR2017-01528	06/05/2017	12/13/2017	Mylan Pharmaceuticals Inc.,	7,713,930	Claims 1–20 are unpatentable

US 7,476,652 (Sanofi-Aventis Deutschland GmbH; Exp: 01/23/2024 with PED) – OB listed

1. A pharmaceutical formulation comprising Gly(A21), Arg(B31), Arg(B32)-human insulin; at least one chemical entity chosen from polysorbate 20 and polysorbate 80; at least one preservative; and water, wherein the pharmaceutical formulation has a pH in the acidic range from 1 to 6.8.

7. A pharmaceutical formulation comprising Gly(A21), Arg(B31), Arg(B32)-human insulin, at least one chemical entity chosen from polysorbate and poloxamers; at least one preservative; and water, wherein the pharmaceutical formulation has a pH in the acidic range from 1 to 6.8.

24. A pharmaceutical formulation comprising Gly(A21), Arg(B31), Arg(B32)-human insulin: at least one chemical entity chosen from polysorbate and poloxamers; at least one preservative chosen from cresol; and water, wherein the pharmaceutical formulation has a pH in the acidic range from 3.5 to 4.5.

US 7,713,930 (Sanofi-Aventis Deutschland GmbH; Exp: 12/13/2023 with PED) – OB listed

1. A pharmaceutical formulation comprising Gly(A21), Arg(B31), Arg(B32)-human insulin; at least one chemical entity chosen from esters and ethers of polyhydric alcohols; at least one preservative; and water, wherein the pharmaceutical formulation has a pH in the acidic range from 1 to 6.8.

Fingolimod - USA

On Dec 07, 2018, Federal Circuit affirmed district court’s decision that obviousness-type double patenting does not invalidate an otherwise validly obtained PTE under § 156.

This case concerns the interplay between a patent term extension (PTE) granted pursuant to 35 U.S.C. § 156 and the obviousness-type double patenting doctrine. Ezra filed ANDA for Novartis’s branded multiple sclerosis drug Gilenya®. Novartis filed an infringement suit against Ezra in response, asserting certain claims of US 5,604,229 (claims fingolimod compound). Because the ’229 patent was filed before the effective date of the Uruguay Round Agreements Act of 1994 (URAA), its patent term is governed by the law in effect at that time—the rule of 17 years from issuance. The ’229 patent thus was set to expire on Feb. 18, 2014, but Novartis secured a PTE of five years on the patent pursuant to 35 U.S.C. § 156 & thus extended the expiry till Feb. 18, 2019. Novartis also owned another patent, US 6,004,565 (claims a method of administering fingolimod). Because the ’565 patent issued from a patent application filed after the effective date of the URAA, its term expired on Sep. 23, 2017—20 years from its earliest effective filing date. The ’229 patent is thus a pre-URAA patent whereas the ’565 patent is a post-URAA patent, governed by different statutory patent term regimes.

On Sep. 22, 2016, district court denied Ezra’s motion for judgment on the pleadings, where Ezra argued that the ’229 patent should be ruled invalid, or otherwise terminally disclaimed for the patent term past the expiration date of the unasserted ’565 patent. Specifically, Ezra argued that the granted extension of the ’229 patent’s term beyond the life of the ’565 patent is impermissible because it: (1) de facto also extends the life of the ’565 patent, and thereby violates § 156(c)(4)’s requirement that only “one patent be extended”; (2) violates the “bedrock principle” that the public may practice an expired patent; and (3) renders the ’229 patent invalid for statutory- and obviousness-type double patenting because Novartis’s ’229 patent claims are not patentably distinct from its ’565 patent claims. With respect to first point, the district court concluded that Ezra’s argument regarding the de facto extension of the ’565 patent required reading “effectively” into the statute as a modifier of “extended.” The district court found that such a reading did not make sense when compared to other uses of the word “extend” in the same statute, which the district court found to “refer to the legal status conferred upon a patent chosen to benefit from PTE.” Further, the district court relied on the decision of Merck, where federal circuit concluded that a terminally disclaimed patent could still have its term extended with a PTE because “Congress chose not to limit the availability of a patent term extension to a specific parent or continuation patent but instead chose a flexible approach which gave the patentee the choice.” Thus, the district court concluded that the ’229 patent’s term extension was permissible under § 156. With respect to second point, the district court explained that “expiration of a patent does not grant the public an affirmative right to practice a patent; it merely ends the term of the patentee’s right to exclude others from practicing the patent.” The district court then pointed to other ways in which the ’565 patent subject matter could still be blocked from public use, e.g., other patent rights or contractual obligations. With respect to third point, the district court found that a judgment on the pleadings was improper for Ezra’s double patenting challenge because the analysis included factual issues underlying a “construction of the claims in the earlier patent and later patent” and a “determination of whether differences between claims render them patentably distinct.” Thus, the district court found the ’229 patent valid, unexpired, and enforceable with the PTE, found infringement of the ’229 patent, and imposed an injunction on Ezra’s ANDA product until the expiration of the ’229 patent in 2019.

Ezra appealed on the issues of statutory construction of § 156 and obviousness-type double patenting. Ezra argued that Novartis violated § 156(c)(4) because, in its view, two patents were extended here: the extension of the ’229 patent’s term “effectively” extended the ’565 patent’s term as well, because the ’229 patent covers a compound necessary to practice the methods claimed by the ’565 patent. Federal circuit however, agreed with the district court, that there is no reason to read “effectively” as a modifier to “extend” in the language of § 156(c)(4).

Ezra also contended that in order to comply with § 156, “Novartis had to make a choice [as to which patent to extend] in such a way as to ensure that ‘in no event shall more than one’ patent be extended.” Federal circuit however, disagreed & said that there is nothing in the text, structure, or history of § 156 that imposes such a requirement on patent owners. Federal circuit further said that although § 156 recognizes that a patent owner may own multiple patents relating to a product, nothing in the statute restricts the patent owner’s choice for patent term extension. In striking a balance between the competing interests of new drug developers and low-cost generic competitors, Congress limited a PTE grant for such a patent owner to only one of its patents. Here, only the ’229 patent was selected and then legally extended with a certificate of extension. Therefore, as long as the requirements for a patent term extension recited in § 156(a) are met, the Director “shall” grant a PTE on the patent of patentee’s choice. Thus, federal circuit concluded that Novartis’s selection of its ’229 patent for term extension does not violate § 156(c)(4).

Federal circuit next addressed the question, whether the ’229 patent is invalid due to obviousness-type double patenting because the term extension it received causes the ’229 patent to expire after Novartis’s allegedly patentably indistinct ’565 patent. Relying on its decision in Merck & Co. v. Hi-Tech Pharmacal Co., federal circuit concluded that obviousness-type double patenting does not invalidate a validly obtained PTE in such a scenario. Federal circuit agreed with the district court’s observation that if a patent is terminally disclaimed to another patent to overcome an obviousness-type double patenting rejection and then term-extended under § 156 (as in Merck), it necessarily will expire after the patent to which it had been subject to an obviousness-type double patenting rejection.

With respect to Ezra’s policy concerns, federal circuit said that this case does not raise the traditional concern with obviousness-type double patenting of a patent owner “extending his exclusive rights to an invention through claims in a later-filed patent that are not patentably distinct from claims in the earlier filed patent.” Here, it is the earlier-filed, earlier issued ’229 patent, not the later-filed, later-issued ’565 patent, that has the later expiration date, due to a statutorily-allowed term extension under § 156. Also there is no potential gamesmanship issue through structuring of priority claims as identified in Gilead Sciences, Inc. v. Natco Pharma Ltd., 753 F.3d 1208 (Fed. Cir. 2014). This court prevented such an outcome by holding that expiration dates were what “really mattered” for an obviousness-type double patenting analysis in this context. Here, Ezra does not identify any similar tactics on the part of Novartis.

By applying statutory construction principles, following the precedent in Merck, and addressing traditional obviousness-type double patenting principles, federal circuit held that a PTE pursuant to § 156 is valid so long as the extended patent is otherwise valid without the extension. Thus, the district court was correct in finding that the ’565 patent is not a double patenting reference to the ’229 patent and that the ’229 patent is valid through the end of its PTE.

Everolimus - USA

On Dec 07, 2018, Federal Circuit reversed district court’s decision regarding post-URAA patent as double patenting reference for pre-URAA patent.

Novartis appealed the district court’s decision to invalidate U.S. Patent No. 5,665,772 (claims everolimus compound) based on obviousness-type double patenting over Novartis’s U.S. Patent No. 6,440,990 (claims MoU & composition), which was filed after, and issued after, but expired before the ’772 patent. Both patents claimed the same priority date. The ’990 patent expired before the ’772 patent because the ’990 patent was filed after the June 8, 1995 effective date of the Uruguay Round Agreements Act of 1994 (URAA) and thus expired on September 23, 2013 (20 years from its earliest effective filing date). The ’772 patent, on the other hand, was filed before the effective date of the URAA and— pursuant to the URAA transition statute 35 U.S.C. § 154(c)(1)—expired 17 years from its issuance, on September 9, 2014. Due to a five-year patent term extension (PTE) under 35 U.S.C. § 156, the ’772 patent’s term expires on September 9, 2019.

Applying decision of Gilead Sciences, Inc. v. Natco Pharma Ltd., 753 F.3d 1208, 1212 (Fed. Cir. 2014), which held that a later-filed but earlier-expiring patent can serve as a double patenting reference for an earlier-filed but later-expiring patent, the district court found the ’990 patent to be a proper double patenting reference for the ’772 patent &thus invalidated the US’772 patent. The only issue on appeal was whether US’990 (post-URAA) patent is a double patenting reference for US’772 (pre-URAA) patent.

On appeal federal circuit said that Gilead addressed a different question that is not applicable here. In Gilead, both patents were post-URAA and court concluded that a patent that issues after but expires before another patent can qualify as a double patenting reference against the earlier-issuing, but later-expiring patent. Here, however, Novartis owns one pre-URAA patent (the ’772 patent) and one post-URAA patent (the ’990 patent), and the 17-year term granted to the ’772 patent does not pose the unjustified time extension problem that was the case for the invalidated patent in Gilead.

Specifically, there are shortcomings while relying on Gilead & issuance dates for patents in the post-URAA context. One such shortcoming is that patent terms could be subject to significant gamesmanship during prosecution. Another shortcoming of using the issuance date for post-URAA patents is that a mere day’s difference in the issuance of multiple patents could result in a significant difference in an inventor’s period of exclusivity. Gilead had “crafted a separate ‘chain’ of applications, having a later priority date than the first patent family” such that the later-filed but earlier-issued patent expired second, thus unduly increased the life of patent. Here, the present facts do not give rise to similar patent prosecution gamesmanship because the ’772 patent expires after the ’990 patent only due to happenstance of an intervening change in patent term law. Both the ’772 and the ’990 patents share the same effective filing date of September 24, 1993. If they had been both pre-URAA patents, the ’990 patent would have expired on the same day as the ’772 patent by operation of the terminal disclaimer Novartis filed on the ’990 patent, tying its expiration date to that of the ’772 patent. And if they had been both post-URAA patents, then they would have also both expired on the same day. Thus, the current situation does not raise any of the problems identified in our prior obviousness-type double patenting cases. Also at the time the ’772 patent issued, it cannot be said that Novartis improperly captured unjustified patent term. The ’990 patent had not yet issued, and the ’772 patent, as a pre-URAA patent, was confined to a 17-year patent term. Moreover, federal circuit applied traditional, pre-URAA obviousness-type double patenting practice because looking to the patent issuance dates pre-URAA serves as a reliable guide for assessing whether a patent may serve as a double patenting reference against another patent. Under this analysis, the ’990 patent is not a proper obviousness-type double patenting reference for the ’772 patent. When the ’772 patent issued, the ’990 patent had not yet issued and thus did not exist as a double patenting reference against the ’772 patent. This approach is most consistent with the URAA transition statute, which ensures that patent owners, like Novartis with its pre-URAA ’772 patent, enjoy the greater of a 20-year from earliest effective filing date or 17-year from issuance patent term.      

    

The district court thus erred in finding that the post-URAA ’990 patent is a proper obviousness-type double patenting reference for the pre-URAA ’772 patent. Therefore, federal circuit reversed the district court’s decision.

Fulvestrant - Netherlands

On Nov 27, 2018, Court of Appeal reversed first instance decision (Court of Hague) & upheld the validity of AstraZeneca’s patents.

AstraZeneca markets FASLODEX® which is used for the treatment of oestrogen hormone dependent breast cancers. AstraZeneca is the proprietor of European patents, EP 1250138 & EP 2266573 (same family). Claims are related to use of fulvestrant in preparation of pharmaceutical formulation for breast cancer wherein formulation comprises excipients such as recinoleate vehicle, non-aqueous ester solvent, and alcohol to attain plasm concentration for at least 2 weeks.  District court previously found that patents lack inventive step based on some prior arts.  Specifically, district court held that the person skilled in the art knew that there had to be a formulation which showed the positive therapeutic effects, sustained release and few side effects disclosed in Howell, in which 250 mg of fulvestrant was dissolved in 5 ml of castor oil. According to the person skilled in the art, it was not possible to dissolve 250 mg of fulvestrant without excipients in 5 ml of castor oil. This provides an important motivation to search for a formulation containing 5 ml (this is the maximum amount that can be comfortably injected intramuscularly). In McLeskey a formulation is disclosed with three excipients (15% w / v BzBz, 10% w / v BzOH and 10% w / v EtOH) where fulvestrant is dissolved in the desired concentration in castor oil. In addition, it is stated in McLeskey that the solution in castor oil is pre-formulated ready for use. Thus person skilled in the art, starting from the objective technical problem and encountering the castor oil formulation of McLeskey, will examine the suitability of that formulation with standard tests with a reasonable expectation of success. In doing so, he will find that the formulation in in vivo animal testing on rabbits is appropriate for the treatment of breast cancer, does not precipitate and that there with a therapeutically significant plasma concentration is obtained for at least two weeks after administration of 5 ml by intramuscular injection, at least for five days in rabbits.

Court of appeal however, disagreed & said that the district court overlooked some important pointers. In summary, court of appeal said that prior art discloses 20% alcohol (10% benzyl alcohol and 10% ethanol) which is quite high when considering injectable preparations. It was not disputed that alcohol will diffuse rapidly from an injected site due to its volatile nature solution and so much of that alcohol diffuses away from that fulvestrant in the castor oil in a (supersaturated) concentration normally too high to be present as a solution, so that, normally spoken, fulvestrant precipitates. AstraZeneca has stated that the alcohol percentage of 20% is so high that the professional would definitely expect precipitation. The person skilled in the art would reasonably expect fulvestrant to crystallize and thus causing irritation. According to Sandoz's claim, the percentage of 20% is true on the high side, but not in such a way that the professional would worry about it. Because the formulation is not a solution of fulvestrant in water where the alcohol is present freely and as a result dissipates fully in the tissue', but a solution in oil, in which' the alcohol is not present freely and will not dissipate fully and directly into the tissue. Court further said that the aforementioned Sandoz assertion - for which there is no specific evidence - remains unproven. Therefore, court sided with AstraZeneca that the alcohol percentage of 20% in prior art is so high that the skilled person would expect the occurrence of precipitation on the priority date. District court thus erred in its analysis & its judgment of invalidity is therefore reversed.

Methylphenidate – USA

On Nov 20, 2018, Federal Circuit vacated invalidity decision of Delaware court as it was based on inadequate fact-findings & remanded the case for further considerations.

Tris Pharma markets Quillivant XR®, an extended release methylphenidate (MPH) formulation for the treatment of Attention Deficit Hyperactive Disorder (ADHD). When Actavis submitted ANDA to USFDA, Tris sued Actavis for infringement of U.S. Patent Nos. 8,465,765, 8,563,033, 8,778,390, 8,956,649, and 9,040,083. Patent claims are directed to pharmacokinetic (PK) and pharmacodynamic (PD) properties of the Quillivant XR® extended release formulation. These properties include: (1) an extended duration of action of about 12 hours; (2) a single mean peak PK profile; (3) a Tmax of about 4 to 5.25 hours (early Tmax); and (4) a 45-minute onset of action/therapeutic effects. After a five-day bench trial, the district court found all asserted claims of the patents-in-suit invalid under 35 U.S.C. § 103. The prior art consists of a number of commercially available, second-generation, extended release formulations of MPH including Concerta®, Daytrana®, Focalin XR®, Metadate CD®, and Ritalin LA®;2 scientific articles; and U.S. Patent Application Publication No. 2010/0260844 (Scicinski). Specifically, district court credited Actavis’s expert’s testimony that a skilled artisan would have no trouble achieving early onset of action and extended duration of effect with a single mean peak PK profile based on disclosures in prior arts. District court also considered secondary indicia of non-obviousness but found unpersuasive. Tris then appealed.

Tris raised three primary issues on appeal:

1. Tris argued that a skilled artisan would not have reasonably expected to successfully combine the claimed single mean peak PK profile with the claimed 45-minute onset of action and 12-hour duration of effect (PD characteristics) because the PK-PD relationship was unknown.

2. Tris contended that the district court failed to address why the combination of an early Tmax and 12-hour duration of effect would have been obvious.

3. Tris claimed that the district court mistakenly disregarded Tris’s evidence of unexpected results based on a belief that Tris’s experts did not compare the claimed invention to the closest prior art.

Federal circuit said that district court failed to make adequate findings of fact to support their holding. First, while the district court found that one would have expected from the prior art that a single mean peak PK profile could provide for rapid onset of action and extended duration of effect,  it never articulated which prior art references do so and how. Specifically, the district court never made explicit findings that Daytrana®, Concerta®, Metadate CD®, and/or Scicinski also teach a 45-minute onset of action or 12-hour duration of effect. With respect to the 45-minute onset of action limitation, the district court cited a concession by Tris’s expert that second-generation MPH formulations could have an onset of action in as early as 30 minutes, but it did not explain the significance of this concession. As for the 12-hour duration of effect limitation, the district court’s opinion is vague as to whether any of the prior art formulations actually teach the 12-hour duration of effect limitation. Throughout its analysis, the district court imprecisely states that certain prior art discloses “efficacy that last[s] throughout the day,” a “long duration of effect,” or an “extended duration of action.” It is unclear, however, whether the district court intended this language to equate to the claimed 12-hour duration of effect.

Second, and importantly, the district court does not address a fundamental aspect of the obviousness inquiry—i.e. why a skilled artisan would have been motivated to use a single mean peak PK profile to achieve a formulation with a 45-minute onset of action and/or 12- hour duration of effect with a reasonable expectation of success. Tris argued on appeal that the acute tolerance theory as well as the prior art taught away from using a single mean peak PK profile to achieve a 45-minute onset and 12-hour duration of effect. Actavis argued that the acute tolerance theory is irrelevant to whether a drug has a single or bimodal peak PK profile, attempts to discredit the theory, and asserts that skilled artisans did not regard the number of peaks as important when formulating a drug. But the district court made none of these findings. It is thus unclear whether the district court found that (1) the theory is not applicable because it does not affect the shape of the plasma concentration curve; (2) the theory is unreliable; or (3) the theory is applicable, but even acknowledging it, a skilled artisan would have a reasonable expectation of success to combine a single mean peak curve with a 45-minute onset of action and a 12-hour duration of effect. Without the requisite factual findings and adequate explanation, federal circuit declined to affirm the district court’s conclusion of obviousness & remanded for further consideration.

Federal circuit further said that district court’s analysis with respect to early Tmax and 12-Hour Duration of Effect is very cursory. The entirety of the district court’s discussion of Tmax appears amounts to a mere recitation of Actavis’s experts’ testimony. And, yet again, the district court fails to articulate whether it credited this testimony or explain why and how the testimony supports its conclusion. The district court’s opinion lacks any response to Tris’s argument that formulations with an early Tmax (such as Metadate CD® and Ritalin LA®) did not achieve 12 hours of effect while those with 12 hours of effect (Concerta® and Focalin XR®) had later Tmax values. Therefore, federal circuit remanded the obviousness of the combination of an early Tmax with 12-hour duration of effect to the district court for further consideration.

Federal circuit agreed with the Tris on the issue of secondary considerations such as unexpected results & long-felt need. Federal circuit said that with respect to unexpected results district court’s analysis is deficient because it addresses the single mean peak PK limitation. The district court does not explain why—separately, and more importantly together with the single mean peak PK profile limitation—the Tmax, 45-minute onset, and 12 hour duration of effect limitations were not unexpected. With respect to long-felt need district court opinion identified various prior art products that meet each of the three individual needs above, but never identified a prior art product that contains all three properties. Thus in view of these errors federal circuit asked district court to reconsider all the evidence of objective indicia in its overall determination of obviousness.

Buprenorphine & Naloxone - USA

On Nov 20, 2018, Federal Circuit vacated preliminary injunction granted by district court which was on erroneous interpretation of claim scope.

Indivior markets Suboxone® Film for the treatment for opioid dependency. Suboxone Film is covered by U.S. Patent Nos. 9,931,305 and 8,603,514 which are from same family. The ’305 patent is the only patent at issue in this case. The Delaware Court previously determined that Dr Reddy’s (DRL) ANDA process does not infringe the asserted ’514 patent claims because the drying process was conventional. After the Delaware Court entered its judgment of non-infringement, Indivior amended certain claims of a then pending application that ultimately issued as the ’305 patent. Indivior amended the claims to remove the words “dried” and “drying,” and to add “continuously” and “continuously cast” in their place. DRL launched ANDA on the day of FDA approval when the suit regarding ‘305 was pending.

District court after hearing granted preliminary injunction. In granting the same, the district court concluded that Indivior was likely to succeed on the merits of its infringement claim. It concluded that the claims, which lack an express “drying” limitation, do not exclude any particular drying method. The district court credited Indivior’s expert over DRL’s and declined to import a drying step into the “continuously cast” limitation—the limitation that Indivior added during prosecution to replace the terms “drying” and “dried.” According to the district court, the ’305 claims do not include a drying limitation. Based largely on this reasoning, it determined that Indivior’s suit was not barred by claim preclusion in light of the Delaware Case. The district court considered it likely that Indivior would be able to show that the ’305 claims are “patentably distinct” from the ’514 claims, and thus would likely show that the suit was not barred by claim preclusion. DRL appealed the district court’s grant of the preliminary injunction.

Federal circuit concluded that the district court abused its discretion in granting the preliminary injunction. The ’305 patent specification disclaims solely using conventional top air drying to produce films with the claimed content uniformity. Because the ’305 claims thus do not cover such films, Indivior has not shown that it is likely to succeed on the merits of its infringement claim. Specifically, the patent specification states that “conventional drying methods themselves are unable to provide uniform films.” Conventional drying methods that dry only the top of the film produce a “ripple effect” that results in “an uneven and therefore non-uniform film.” The specification teaches that the rippling effect produced by conventional drying methods can be “avoided by the present invention by “applying heat to the bottom surface of the film with substantially no top air flow”. The ’305 patent also discloses two examples that further disparage the use of conventional drying. The patentee expressly disclaimed the sole use of conventional top air drying to produce the claimed films. Such disavowal places films formed by these methods outside the scope of the ’305 claims.

Indivior argued that removal of the drying terms during prosecution removes any limitation on how the film is dried. According to Indivior, the specification disclaimer found by the Delaware Court in its analysis of the ’514 patent was “rooted in the meaning of the claim language ‘dried’ and ‘drying,’” and does not apply to the ’305 claims because those terms are absent. Court however, disagreed & said that the drying limitation has a textual basis in the term “continuously cast film,” which appears in claims 1 and 26 of the ’305 patent. The “continuously cast film” in claims 1 and 26 requires drying as the film starts out as a liquid and ends up as a solid that can be cut into individual dosages. In the absence of this also for that matter the specification makes clear that the invention does not include films that were dried using conventional top air drying.

Court further held that claim preclusion likely bars Indivior’s suit as the ’514 claims and the ’305 claims are patentably indistinct. The ’305 patent has the same specification as the ’514 patent. The only difference between the ’305 claims asserted here and the ’514 claims asserted in the Delaware Case is that the ’305 claims contain the term “continuously cast” in place of “dried” and “drying.” While the language of the claim terms changed, the scope of the claims did not materially change. The claims of the ’305 patent are thus “patentably indistinct” from those of the ’514 patent. It is further substantiated by Indivior’s filing of a terminal disclaimer over ‘514 patent.

Federal circuit thus vacated & remanded district court’s ruling as it abused its discretion in granting the preliminary injunction.

Naproxen & Esomeprazole - USA

On Nov 19, 2018, New Jersey court found claims covering Vimovo® invalid as indefinite in summary judgment proceeding.

Defendants Dr. Reddy’s & Mylan moved for summary judgement of invalidity of U.S. Patent Nos. 9,220,698 and 9,393,208 on the ground of indefiniteness.

Claim 1 of the ‘698 patent is representative:

A method for treating osteoarthritis, rheumatoid arthritis, or ankylosing spondylitis comprising orally administering to a patient in need thereof an AM unit dose form and, 10 hours (+/-20%) later, a PM unit dose form, wherein:

the AM and PM unit dose forms each comprises: naproxen, or a pharmaceutically acceptable salt thereof, in an amount to provide 500 mg of naproxen, and esomeprazole, or a pharmaceutically acceptable salt thereof, in an amount to provide 20 mg of esomeprazole; said esomeprazole, or pharmaceutically acceptable salt thereof, is released from said AM and PM unit dose forms at a pH of 0 or greater, the AM and PM unit dose forms target: i) a pharmacokinetic (pk) profile for naproxen where: a) for the AM dose of naproxen, the mean C.sub.max is 86.2 .mu.g/mL (.+-.20%) and the median T.sub.max is 3.0 hours (.+-.20%); and b) for the PM dose of naproxen, the mean C.sub.max is 76.8 .mu.g/mL (.+-.20%) and the median T.sub.max is 10 hours (.+-.20%); and ii) a pharmacokinetic (pk) profile for esomeprazole where: a) for the AM dose of esomeprazole, the mean area under the plasma concentration-time curve from when the AM dose is administered to 10 hours (.+-.20%) after the AM dose is administered (AUC.sub.0-10,am) is 1216 hr*.mu.g/mL (.+-.20%), b) for the PM dose of esomeprazole, the mean area under the plasma concentration-time curve from when the PM dose is administered to 14 hours (.+-.20%) after the PM dose is administered (AUC.sub.0-14,pm) is 919 hr*.mu.g/mL (.+-.20%), and c) the total mean area under the plasma concentration-time curve for esomeprazole from when the AM dose is administered to 24 hours (.+-.20%) after the AM dose is administered (AUC.sub.0-24) is 2000 hr*.mu.g/mL (.+-.20%);

and the AM and PM unit dose forms further target a mean % time at which intragastric pH remains at about 4.0 or greater for about a 24 hour period after reaching steady state that is at least about 60%.

Defendants moved for summary judgment of invalidity of the ‘698 and ‘208 patents on the ground that the claims are indefinite due to the target clauses. In short, Defendants argued that, given the Court’s construction of “target” as “set as a goal,” the “patents provide no guidance regarding how often, if ever, the recited ranges must be met or how close one must come to those ranges to infringe the asserted claims.”

Since the court construed “target” to mean, “set as a goal,” this requires that the PK and PD profiles stated in the target clauses define the goals to be set. The fact that a goal is clearly defined does not mean that the act of targeting that goal is clearly defined, and this is the crux of the definiteness problem here. The fundamental difficulty is that both key phrases here are incomprehensible: “the AM and PM unit dose forms target:” and “the AM and PM unit dose forms further target.” It is not possible to comprehend what these phrases mean, because pills cannot be said to set goals. In ordinary usage, one understand a goal to be something that people, or perhaps living creatures, set; inanimate objects set no goals.

Therefore claim 1 & claims dependent thereupon of ‘698 and ‘208 patents are invalid as indefinite.

Asenapine - USA

On Nov 15, 2018, Delaware court found that Sigmapharma’s ANDA infringes claim 1 of U.S. Patent No. 5,763,476 which covers Saphris®.

The ’476 patent, relates to “Sublingual or Buccal Pharmaceutical Composition” & claims composition which disintegrates within 30 seconds. Forest sets its specification as that it can release a batch of its drug product if: (1) the number of sample tablets that disintegrate within 30 seconds is less than 3/6 tablets or between 4 – 15/18 tablets; and (2) the number of sample tablets that disintegrate within 55 seconds is 6/6, 16/18, or 17/18. Dr. Kupiec (Sigmapharma’s expert) concluded that there were no 6/6 test results from two of Sigmapharm’s batches. However, court found testing method unreliable & called it questionable. First, Dr. Kupiec only measured the temperature of the water once, before putting the basket in the water, and he did not check the temperature during or after his experimentation. Second, Dr. Kupiec testified that he did not probe all of the remaining cores, only a “majority” or a “fair amount.” Third, Dr. Kupiec’s lab notebook provides insufficient details, especially compared to Dr. Myers’ (Plaintiff’s expert) lab notebook. Finally, after careful examination of each expert’s background and experience, court concluded that Dr. Kupiec did not have the same level of expertise with USP as Dr. Myers.

With respect to internal testing in SIgmapharma, CEO, Dr. Spiridon Spireas, testified that only 2 tablets out of the 564 total tablets tested across the 94 runs disintegrated within 30 seconds. In other words, Dr. Spireas contends that for all but a couple of runs, zero tablets (0/6) disintegrated within 30 seconds. But court did not find this testimony credible because Dr Spireas did not perform or supervise the test results. Also the lab notebooks do not state how many tablets out of 6 remained after 30 seconds. Instead, the lab notebooks simply report, with few exceptions, “At 30 Seconds: Fails.” Under the Sigmapharm monograph governing these testing procedures, “fails” means a test result of 0/6, 1/6, 2/6, or 3/6. In other words, many more than zero tablets could have disintegrated within 30 seconds, and the internal scientist would have been in compliance with the Sigmapharm monograph by recording “At 30 Seconds: Fails.” Thus, how many tablets actually disintegrated within 30 seconds is simply unknown. Moreover, both Dr. Spireas and the internal scientists (whose testimony was heard via video deposition) admitted that they were at times not conducting disintegration tests in accordance with USP<701>. In addition, one scientist indicated that she was not palpating any remaining cores to determine if it was hard or soft. These practices all undermine the reliability of the internal test results.

Court said that Sigmapharm’s current specification has two disintegration tests: a “30-Seconds Test,” in which the tablets must “fail” USP at 30 seconds, and a “55-Seconds Test,” in which the tablets must “pass” USP at 55 seconds. But claim 1 does not literally claim a pharmaceutical composition that “passes” USP at 30 seconds. Rather, it claims a pharmaceutical composition that “disintegrates within 30 seconds in water at 37°C.” At no time has the court construed “disintegrates within 30 seconds in water at 37°C” to mean that tablets must “pass” USP<701>. This means that, in order to prove infringement, Forest must prove that Sigmapharm’s generic sublingual asenapine tablets will “disintegrate within 30 seconds in water at 37°C.” Sigmapharm can attempt to undermine this proof by showing that the tablets will not “disintegrate within 30 seconds in water at 37°C.” But Sigmapharm cannot short-cut the infringement analysis by focusing only on whether its tablets “pass” or “fail” USP<701>. The problem is that “failing” USP<701> is not sufficient proof that a batch of tablets will not disintegrate within 30 seconds in water at 37°C, meaning “failing” is not proof of non-infringement. Experts from both sides agreed that a test designed to show that a batch of tablets will not disintegrate within 30 seconds—and therefore not infringe claim 1—requires a higher standard of proof than just “failing” USP<701> . Specifically, to establish non-infringement, experts from both sides required 0/6 tablets to completely disintegrate within 30 seconds, meaning there is some hard core remaining for all 6 tablets. If a hard core remains for only 4 or 5 tablets, then the experts would proceed to stage-two testing on an additional 12 tablets. After stage-two testing, and again to establish non-infringement, a hard core must remain for 16 or 17 out of the 18 total tablets tested. Thus, consistent with the procedure established by USP<701> , the experts would require anywhere between 89% and 100% of the sample tablets to not disintegrate within 30 seconds in order to impute the characteristics of those samples onto an entire batch.

On the other side, Forest has proven by a preponderance of the evidence that Sigmapharm’s accused product literally infringes claim 1 of the ’476 patent, because Sigmapharm’s accused product disintegrates within 30 seconds in water at 37°C. Forest has proven that 6/6 tablets disintegrated within 30 seconds for at least one run each from representative batches PD0054:43, PD0054:44, and PD0054:33.

Thus, court held that Forest has proven by a preponderance of the evidence, that Sigmapharm infringes claim 1 of the ’476 patent.