Bortezomib - Netherlands

On July 25, 2017 The Hague district court delivered its judgment in Bortezomib SPC challenge brought by Teva.

The present dispute concerns an alleged infringement of the rights of Millennium Pharmaceuticals Inc. (“Millennium”) as vested in the Dutch Supplementary Protection Certificate (NL300151) for ‘Bortezomib or a pharmaceutically accepted ester thereof, if desired in the form of a pharmaceutically accepted salt thereof’.  EP 0788360 (“EP 360”) is the basic patent for Millennium’s Dutch SPC, which covers the compound ‘Bortezomib’ which patent expired on October 26, 2015. EP 360 is the base patent for Supplementary Protection Certificate (NL) 300151 for 'Bortezomib or a pharmaceutically acceptable ester thereof, optionally in the form of a pharmaceutically acceptable salt thereof' & in force until 27 April 2019. This compound is a so-called proteasome inhibitor, used for the treatment of multiple myeloma and mantle cell lymphoma.

Teva Nederland B.V. is the holder of a market authorization for ‘Bortezomib Teva’, a mannitol ester of Bortezomib that falls under the scope of protection of Millennium’s SPC. Bortezomib Teva is registered on the name of Pharmachemie B.V. in the so-called “G-Standaard“, which is the Dutch database containing information on all remedies (medicines, medical devices and homeopathic medicines) that are or may become available at pharmacies, as published by “Z-Index“, a subsidiary of the Dutch professional association for pharmacists. Teva in the present summary proceedings primarily argues that Bortezomib concerns a non-inventive selection from the compounds disclosed in the closest prior art, WO 81/13904 (“WO 904”), and alternatively, for the event Bortezomib is not considered to be a selection from the compounds disclosed in WO 904, that Bortezomib is not inventive because the technical problem to be solved would then be ‘providing an alternative compound to those disclosed in WO 904 that does not bring about a novel or unexpected effect’.

The Summary Judge for its validity assessment assumes that Bortezomib can be seen as a selection from the compounds disclosed in WO 904 (as argued by Teva) and takes this patent as the starting point for the application of the problem-solution-approach. The Summary Judge considers that the difference between WO 904 and the relevant patent claim is that the latter concerns a specific selection from the millions of compounds disclosed in WO 904 and that the technical effect of this selection is (a compound with) increased proteasome inhibition. Summary Judge formulates the technical problem to be solved as ‘providing a compound with increased proteasome inhibition in the set of compounds disclosed in WO 904’. The Summary Judge said that the patent claims that improved inhibition is sufficiently plausible. Millenium has made this insight in the light of subpoena using Tables II-VII, which summarizes the results of a number of experiments. Bortezomib is one of the clearly better compounds in all these experiments, both in terms of activity and selectivity. In addition, Teva did not perform any experiments or show that it should be seen (at present), while on the contrary, its expert acknowledges that bortezomib was one of the better compounds investigated by the inventors. The Summary Judge subsequently considers that Teva did not submit any documents containing pointers to the solution of the technical problem and rejects Teva’s arguments that the (increased) effect of Bortezomib would be in line with the expectations of the skilled person and the (alleged) invention (thus) merely consists of a non-inventive selection from a broad field as meant in the Annex to Part G of Chapter VIII of the European Patent Office’s Guidelines (under 3.1 (iv) (b)).

Finally Summary Judge considers Millennium’s SPC to be valid, grants the preliminary injunction and orders Bortezomib Teva to be removed from the G-Standard. In Germany and Portugal, nullity proceedings in relation to parallel national SPC’s are pending and the Federal Court of Ottawa in its judgment dated 26 February 2016 considers the Canadian basic patent corresponding to EP 360 to be invalid due to a lack of inventive step.

Tiotropium - Ireland

On Jul 26, 2017, High court of Ireland issued judgment in favor of Boehringer Ingelheim in inhalation capsule patent litigation. This capsule is used in Spiriva (Tiotropium) Handihaler device.

The capsule is used in an inhalation device which has generated worldwide sales of more than €3.5 billion. Norton (Waterford) Ltd, trading as Teva Pharmaceuticals Ireland, sought the revocation of the “EP1379220 patent” issued in Ireland in 2002 to Boehringer Ingelheim International GMBH under which it produces “Spiriva” medication used with its “Handihaler” device.

Teva argued none of the claims of the patent related to a “patentable invention” in that it did not involve an inventive step obvious to a person skilled in the art, and having regard to the state of the art at the time it was patented. Teva also claimed the specification of the patent did not disclose the alleged invention “clearly and completely enough for it to be performed by a person skilled in the art”. Boehringer denied all the claims. It said, among other things, that Teva’s objective in seeking revocation was to ensure it (Teva) could make or market a product which would compete with the Spiriva Handihaler. It also said this would mean Teva, as a generics company, would be able to compete without having had to carry out research and development work.

Mr Justice Max Barrett of High court said the challenge failed in its invalidity claim that the specification of the ‘220 patent did not disclose the invention clearly and completely enough for it to be performed by a person skilled in the art, or what is called the “insufficiency challenge”. The claim by Teva that the patent was invalid because the invention protected was obvious in light of prior publications in this area also failed, he said. It also failed in its claim that the patent was invalid because the invention protected was obvious for lack of technical contribution to this particular art. None of the grounds put forward by Teva was accepted by the court and the judge therefore declined to grant the order sought.

The said patent issue was also litigated in other European jurisdictions such as Germany, UK & Netherland. By judgment in Germany (12 January 2016), Netherlands (7 September 2016) & UK (16 December 2016) the EP’220 patent was revoked.

Enoxaparin - USA

On Jul. 21, 2017, federal jury handed Amphastar Pharmaceuticals Inc a big win after it was accused of infringing on a patent held by Momenta Pharmaceuticals Inc through its production of a generic version of the blood-thinner Lovenox (Enoxaparin). The verdict by the jury in Boston came in a lawsuit by Cambridge, Massachusetts-based biotechnology company Momenta and Novartis' unit Sandoz that sought nearly $940 million in damages. The jury found that while Amphastar had infringed Momenta's patent, it was invalid and unenforceable.

The patent in suit was US, 7.575,886 which claims a method for analyzing enoxaparin. Momenta and Sandoz filed the lawsuit in 2011 after the USFDA approved Amphastar's generic version of Sanofi's blockbuster Lovenox, an anticoagulant used to treat and prevent blood clots. Momenta claimed Amphastar infringed its patent covering a method used to confirm the structural signature of Lovenox, known generically as enoxaparin. Momenta, whose generic version Lovenox was the first to receive FDA approval in 2010, claimed Amphastar's infringement and subsequent sales of its own generic caused it to suffer a significant loss of profits.

Before the trial, the case reached the U.S. Federal Circuit Court of Appeals twice, leading to reversals of an injunction against Amphastar in 2012 and a later ruling granting judgment in Amphastar's favor in 2015.

Aripiprazole - USA

On Jul 20, 2017, Federal circuit affirmed the decision of lower court to toss the patent suit in Abilify (Aripiprazole) ANDA case. The patent in suit was US 8,759,350 expiring on March 02, 2027. US'350 patent claims pharmaceutical composition comprising Aripiprazole & Serotonin reuptake inhibitor such as citalopram or escitalopram.

The parties to the suit stipulated non-infringement of US'350 patent previously. Otsuka appealed the decision in various cases and this is now consolidated with main Zydus appeal (16-1962). Oral argument was heard on Jul. 10, 2017.

During oral argument Otsuka said that pharmaceutical composition means separate dosage forms containing Aripiprazole & serotonin reuptake inhibitor. While defendants argued that claims when interpreted means single dosage form where Aripirazole & serotonin reuptake inhibitor in same dosage form as correctly decided by district court previously.

Federal circuit finally affirmed the district court's decision of non-infringement via Rule 36 judgment.

Natalizumab - Netherlands

On Jul 12, 2017, a District Court The Hague revoked the Dutch part of the patent on Tysabri® (Natalizumab).

Biogen holds EP 1485127, which relates to the treatment of Multiple Sclerosis (“MS”). Swiss Pharma seeks to invalidate the Dutch part of the patent. Swiss Pharma seeks in these proceedings that the court verdict to the extent possible enforceable: (1) the Dutch part of EP 127 will destroy; and (2) Biogen will pay the sum of the reasonable and proportionate costs under Article 1019h of the Code of Civil Procedure (CCP).

Court after analyzing the evidences at hand determined that claims 1, 3 and 4 are invalidated due to lack of novelty as these were disclosed in a conference abstract. This document indeed describes the research results at the 17th ECTRIMS congress in Dublin on September 15, 2001 were presented by Miller. It is disclosed that in this study, 213 patients were randomized with RRMS or SPMS three groups who received 3 mg / kg or 6 mg / kg natalizumab, or placebo followed by a follow-up of 6 months. The fact that in the Conference Abstract mention is made in so many words of "chronic pathological inflammation" Biogen is unable to benefit, now MS, such as was considered in the above, in the light of the patent as such an ignition is to be seen. Biogen further has also not denied that the features of claims 3 and 4, starting from the explanation of claim 1 are disclosed in the sense described above in the abstract. Claims 1, 3 and 4, therefore, are not new and therefore void.

Claim 2 is found to be non-inventive as a man skilled in the art would prolong treatment for chronic MS patients based on his common general knowledge combined with the conference abstract. Claim 2 cannot therefore be maintained for lack of inventive step. The court noting that the right-hand in answering the question whether an invention may or may not belong to the state of the art, or from it to the obvious way arises, it is not required thereby increasing the so-called problem-and-solution -approach 'to apply.

The Dutch part of the patent is therefore revoked. Parties agreed that the provisions of the Enforcement Directive should apply to costs as the nullity proceedings should be seen as proceedings anticipating an infringement claim. Biogen has to pay EUR 200 000 in costs as agreed earlier between parties.

Bortezomib - USA

On Jul 17, 2017 Federal circuit reversed the district court’s finding and upholds the validity of patent on Bortezomib.

Millennium Pharmaceuticals, Inc. is the exclusive licensee of U.S. Patent No. 6,713,446 (“the ’446 Patent”), issued March 30, 2004 and assigned to the United States. Millennium developed the patented product for treatment of oncology disease, particularly multiple myeloma and mantle cell lymphoma. The product has the brand name Velcade®. ANDA filers (collectively “Sandoz”) filed abbreviated new drug applications (“ANDAs”), admitting infringement and seeking to invalidate various claims of the ’446 Patent. Based on the litigation that ensued, the district court held that claims 20, 31, 49, and 53 of the ’446 Patent were invalid, leading to this appeal.

The ’446 Patent describes the chemical compound Dmannitol N-(2-pyrazine)carbonyl-L-phenylalanine-Lleucine boronate. The compound is described as a boronate ester of bortezomib (a boronic acid) and D-mannitol (a hydroxy compound). The lyophilized compound “D-mannitol N-(2- pyrazine)carbonyl-L-phenylalanine-L-leucine boronate” was claimed in Claim 20.

The district court held that the claims were obvious because they were the inherent result of an allegedly obvious process, viz., lyophilizing bortezomib in the presence of the bulking agent mannitol. Millennium argued that a person of ordinary skill would avoid lyophilization in developing a formulation involving bortezomib because “bortezomib was known to be unstable even in the dry state as a freestanding solid compound.” The court was not persuaded by this argument and instead relied on the testimony of Sandoz’s witness, Dr. Repta, to find that, as of the ’446 Patent’s priority date, lyophilization “was well-known in the field of formulation” and that it was considered an obvious alternative “when a liquid formulation provided limited success.” The district court received testimony from the inventor and others that the formation of this new compound was not expected or intended when they conducted the lyophilization. There was no contrary evidence. Nonetheless, the district court held the claims invalid on the ground of obviousness, agreeing with Sandoz that “Millennium conceded as a matter of law that the ester is the ‘natural result’ of freeze-drying bortezomib with mannitol.” The court reasoned that the “natural result” of a chemical procedure is inherent in the procedure, and thus the product thereof “would have been obvious to a person of ordinary skill,” in the words of § 103. On the evidence of objective indicia of obviousness, the district court found that Millennium did not establish unexpected results because it did not compare the claimed invention to a glycerol ester of bortezomib. The court also rejected long-felt need as objective evidence of non-obviousness, stating that “the lyophilized mannitol ester of bortezomib did not solve any problem having persisted over a long period of time without resolution by the prior art.”

Federal circuit said that, recognizing our obligation to give deference to a district court’s greater familiarity with the record and authority to reach factual conclusions therefrom, we conclude that the district court erred in its evaluation of obviousness. In the case at bar, the question is whether a person of ordinary skill, seeking to remedy the known instability and insolubility and to produce an efficacious formulation of bortezomib, would obviously produce the D-mannitol ester of bortezomib, a previously unknown compound.  The prior art contains no teaching or suggestion of this new compound, or that it would form during lyophilization. Sandoz identifies no reference or combination of references that shows or suggests a reason to make the claimed compound. No reference teaches or suggests that such a new compound would have the long-sought properties of stability and solubility, and sufficiently dissociate to release bortezomib at an effective rate in the bloodstream, all critical to effective use for treating multiple myeloma.

The D-mannitol ester of bortezomib is a new compound with distinct chemical properties. We consider whether the prior art “would have supplied one of ordinary skill in the art with a reason or motivation to modify a lead compound to make the claimed compound with a reasonable expectation of success.” Otsuka Pharm. Co., Ltd. v. Sandoz, Inc., 678 F.3d 1280, 1292 (Fed. Cir. 2012); see also Bristol-Myers Squibb Co. v. Teva Pharm. USA, Inc., 752 F.3d 967, 973 (Fed. Cir. 2014). The parties agree that bortezomib is the proper lead compound for this analysis. It is not disputed that the Velcade® compound provided unexpected properties, solving the problems that accompanied bortezomib. The district court clearly erred in its obviousness analysis. There is no teaching or suggestion in the references to produce the claimed mannitol ester. No reference shows or suggests ester formation at freeze-drying conditions, or that any such ester might solve the problems of instability and insolubility of the free acid while dissociating rapidly in the bloodstream. No reference provides a reason to make the mannitol ester of bortezomib.

Sandoz argues that lyophilization was generally known in formulating pharmaceutical products. It states that bulking agents were known for use in lyophilization, and that mannitol was a known bulking agent. All true. However, the prior art does not teach or suggest that lyophilization of bortezomib in the presence of mannitol would produce a chemical reaction and form a new chemical compound, or provide a reason to make this specific new chemical compound, or that this new compound would solve the previously intractable problems of bortezomib formulation. Although mannitol was a known bulking agent, and lyophilization was a known method of drug formulation, nothing on the record teaches or suggests that a person of ordinary skill should have used mannitol as part of a synthetic reaction to make an ester through lyophilization. Sandoz failed to show that it was obvious to use mannitol to make an ester during lyophilization, or that the ester would solve the problems experienced with bortezomib.

The district court also clearly erred in its determination that lyophilizing bortezomib with mannitol to form an ester was a “suitable option from which the prior art did not teach away.” Millennium offered persuasive evidence that the chemical modification of bortezomib would have been unattractive to a person of ordinary skill for fear of disturbing the chemical properties whereby bortezomib functions effectively as an anti-cancer agent; in particular, a person of ordinary skill would have noted that the ester blocks a portion of the bortezomib molecule. We agree with Millennium that a person of ordinary skill would have avoided creating an ester with mannitol because several different esters, each with different chemical and possibly biological properties, could have formed.

The district court also clearly erred in its consideration of inherency. “A party must . . . meet a high standard in order to rely on inherency to establish the existence of a claim limitation in the prior art in an obviousness analysis.” The district court stated that Millennium “conceded as a matter of law that the ester is the ‘natural result’ of freeze-drying bortezomib with mannitol.” Sandoz argues that although lyophilization in the presence of mannitol produced an unexpected result, the result was “inevitable” and thus “inherent,” and thus not “inventive.” No expert testified that they foresaw, or expected, or would have intended, the reaction between bortezomib and mannitol, or that the resulting ester would have the long-sought properties and advantages.

We conclude finally that the district court clearly erred in its examination of the objective indicia of unexpected results and long-felt need. We conclude that the district court should have treated bortezomib as the closest prior art compound, and acknowledged the unrebutted evidence that the D-mannitol ester of bortezomib exhibited unexpected results compared with bortezomib, including unexpectedly superior stability, solubility, and dissolution. The district court clearly erred in attributing Velcade®’s commercial success to bortezomib alone, as bortezomib is not a viable commercial product and had been denied FDA approval because of its instability. The D-mannitol ester was responsible for Velcade®’s successful results, for the D-mannitol ester is necessary to provide the required solubility and stability.

CONCLUSION: We conclude that the Sandoz group of defendants did not establish the obviousness of the asserted claims of the ’446 Patent by clear and convincing evidence. The district court’s judgment of invalidity is reversed, and judgment is entered in favor of Millennium as to the Sandoz defendants.

Naproxen & Esomeprazole - USA

On Jul 10, 2017 a New Jersey district court ruled that Dr. Reddy’s Laboratories Ltd. and Mylan Pharmaceuticals Inc. are infringing on a patent held by Horizon Pharma for Vimovo (Naproxen & Esomeprazole) tablet.

This case arises out of Defendants’ submission of Abbreviated New Drug Applications (“ANDAs”) to the FDA pursuant to the Hatch-Waxman Act, 21 U.S.C. § 355(j), for the purpose of obtaining FDA approval for the commercial manufacture, use, import, offer for sale, and sale of a generic version of Vimovo. Specifically, DRL filed ANDA No. 202461 (“DRL ANDA I”) and ANDA No. 204206 (DRL ANDA II”). Mylan filed ANDA No. 204920 (“Mylan ANDA”). All three ANDAs included so-called “Paragraph IV” certifications to U.S. Patent No. 6,926,907 (“the ’907 patent”) and No. 8,557,285 (“the ’285 patent”). In response to those Paragraph IV certifications, Horizon asserted infringement of claims 5, 15, 52, and 53 of the ’907 patent. Horizon has also asserted claims 1 through 4 of the ’285 patent.

Mylan has stipulated that its ANDA product would infringe the Asserted Patents. Court previously granted summary judgment in DRL’s favor that its ANDA II product does not infringe the ’907 patent. Accordingly, the only infringement dispute at trial was whether DRL’s ANDA II Product infringes the ’285 patent.

Claim 1 of the ’285 patent

(i) “a pharmaceutical composition in unit dosage form”

Horizon provided unrebutted testimony that the DRL ANDA II Product is “a pharmaceutical composition in unit dosage form.” (Tr. 833:18-834:1.)

(ii) “therapeutically effective amounts of: (a) esomeprazole, wherein at least a portion of said esomeprazole is not surrounded by an enteric coating”

Horizon provided unrebutted testimony that the DRL ANDA II Product includes a “therapeutically effective amount of esomeprazole.” Further, the esomeprazole in the DRL ANDA II Products is not surrounded by an enteric coating.

(iii) “therapeutically effective amounts of: (b) naproxen surrounded by a coating that inhibits its release from said unit dosage form unless said dosage form is in a medium with a pH of 3.5 or higher”

Horizon provided unrebutted testimony that the DRL ANDA II Product contain therapeutically effective amount naproxen surrounded by a coating that inhibits its release

(iv) “wherein said unit dosage form provides for release of said esomeprazole such that upon introduction of said unit dosage form into a medium, at least a portion of said esomeprazole is released regardless of the pH of the medium”

Horizon provided unrebutted testimony that DRL’s ANDA II Product will provide some release of esomeprazole in medium.

Because DRL’s ANDA II Product satisfies each limitation of claim 1 of the ’285 patent, we find that Horizon has proven by a preponderance of the evidence that DRL’s ANDA II Product infringes that claim. Similarly claims 2 to 4 which depend on claim 1 and contain further limitations regarding particular amount of naproxen and esomeprazole would also encompass product at issue. Thus DRL’s ANDA II Product infringes claims 1 to 4 of US’285 patent.

Defendant also raised invalidity challenges under 35 U.S.C. § 103 or § 112 but court concluded that Defendants have not shown by clear and convincing evidence that the Asserted Patents should be invalidated.

Conclusion:

For the reasons discussed court find that the DRL ANDA II product infringes claims 1, 2, 3, and 4 of the ’285 patent and that those claims are not invalid under 35 U.S.C. § 112. For the reasons discussed here court find that the claims of the ’907 and ’285 patents are not invalid under 35 U.S.C. § 103 or § 112.

Tadalafil - USA

July 12, 2017 -- Eli Lilly and Company has entered into a settlement agreement with generic companies to resolve pending patent litigation in the U.S. District Court for the Eastern District of Virginia regarding the Cialis® (tadalafil) unit dose patent (US 6,943,166). This patent was previously set to expire on April 26, 2020. As part of the agreement, Cialis exclusivity is now expected to end at the earliest on September 27, 2018. The parties have settled the case just before the bench trial which was set to begin on Jul 17, 2017. Many generic companies Actavis/Teva, Alembic, Aurobindo, Mylan, Sun, Zydus, Cipla, Accord, Apotex, Ajanta, Hetero & Dr. Reddy’s have challenged the OB listed patent(s).

"The unit dose patent for Cialis is valid and infringed by companies seeking to market a generic version of Cialis. This is a royalty-bearing license agreement that provides us with more certainty regarding our U.S. exclusivity," said Michael J. Harrington, senior vice president and general counsel for Lilly. "Protection of intellectual property and the assurance of market exclusivity are extremely important to Lilly as we work to support the development of the next generation of innovative medicines."

Patent expiration for Adcirca (tadalafil) is still expected on November 21, 2017, or on May 21, 2018, if the U.S. Food and Drug Administration grants the company's application for pediatric exclusivity.

Pemetrexed - UK

On Jul 12, 2017 the Supreme Court of UK published its judgment in Eli Lilly v Actavis case over a cancer drug Alimta (Pemetrexed). It’s five-year dispute and with both parties getting permission, the issue of direct and indirect infringement subject to the June 2015 Court of Appeal decision was up for grabs. In June 2015, Lord Justices Kitchin, Floyd and Longmore upheld Arnold’s decision in respect of direct infringement, but the three judges reversed the indirect infringement finding. The question before the Supreme Court's was whether a three products (pemetrexed diacid, pemetrexed ditromethamine, or pemetrexed dipotassium) manufactured by Actavis UK Limited and others infringes Eli Lilly and Company’s patent and its foreign designations either indirectly under s. 60(2) of the Patents Act 1977 (matter for appeal) or directly under a proper interpretation of Article 69 of the Europe Patent Convention 2000 (matter for cross-appeal).

Facts of this case are that Eli Lilly hold a patent (EP 1313508) with a Swiss form claim relating to the use of pemetrexed, in a disodium salt, in combination with vitamin B12 for inhibiting tumour growth. Actavis sought a declaration of non-infringement (DNI) in respect of its products which use pemetrexed in different salt forms, one of which was pemetrexed dipotassium.

Lilly argue direct infringement on the footing that, when properly construed Actavis’ products do fall within claim 1 of the patent, in view of the equivalence between pemetrexed disodium and the salt forms Actavis use. Lilly emphasised that the invention of its patent was the combination of the pemetrexed (which was already known to be effective at inhibiting tumour growth) with vitamin B12 (which Lilly had discovered to reduce the toxicity of pemetrexed to safe levels) and was not related to the salt-form of the pemetrexed. Lilly argued that in the field of the patent, the skilled person would readily appreciate that other salt-forms existed that would work in exactly the same way as pemetrexed disodium and so – if used in combination with vitamin B12 – would be making use of the disclosed invention. Thus, on a purposive construction, the patent is directly infringed.

Actavis argued that it was a relevant consideration that during prosecution of the patent Lilly had been required to set out a specific salt-form. Actavis submitted, extending a line of argument expressed in Virgin [2009] EWCA Civ 1062 on the knowledge of patent law that the skilled person is deemed to possess, that the skilled person was aware of the patent file and could look at the prosecution history to help them interpret the patent. They would then see that a specific salt-form was required before grant of the patent and conclude that this meant the claim should be narrowly construed to only protect the particular salt-form claimed.

The court adopted revised infringement test in this case. Court considered that infringement is best approached by addressing two issues, each of which is to be considered through the eyes of the notional addressee of the patent. These are:

1.       does the variant infringe any of the claims as a matter of normal interpretation; and, if not,

2.       does the variant nonetheless infringe because it varies from the invention in a way or ways which is or are immaterial?

If the answer to either issue is “yes”, there is an infringement; otherwise, there is not.

Applying the above issues to Actavis’ products, the Supreme Court held that they directly infringe Lilly’s patent, and pointed out that the Court of Appeal took an approach which placed too much weight on the words of the claim and not enough on the Protocol. In the view of the Supreme Court, the addressee of the Patent would understand that the reason why the claims were limited to the disodium salt was because that was the only pemetrexed salt on which the experiments described in the specification had been carried out. But it did not follow that the patentee did not intend any other pemetrexed salts to infringe. Therefore the Court concluded that, subject to considering the prosecution history, the Actavis products would infringe claim 1 of the Patent. 

Prepopik® – USA

On Jul 11, 2017 Delaware court issued its opinion in Prepopik ANDA case. Plaintiffs Ferring Pharmaceutical brought this patent infringement action against Par Pharmaceutical, Inc. on February 20, 2015. Defendant filed an Abbreviated New Drug Application ("ANDA"), seeking to engage in the commercial manufacture, use, and sale of a generic version of Ferring's Prepopik (sodium picosulfate, magnesium oxide, and citric acid) product. Plaintiffs allege that Defendant's submission of this ANDA infringes U.S. Patent Nos. 8,450,338 ("the '338 patent") and 8,481,083 ("the '083 patent"). The Delaware court held a bench trial on November 8-9, 2016. Prior to trial, Defendants dismissed all invalidity defenses with prejudice. Therefore, the only issue addressed at trial was whether Defendant's proposed ANDA product and process infringe the '338 and '083 patents.

Plaintiffs assert claims 1, 4-6, 8, 9-12, and 17-18 of the '338 patent and claims 1 and 7-11 of the '083 patent. The parties agree that if Defendant's ANDA product meets all limitations of claim 1 of the '338 patent and if the process by which it makes its ANDA product meets all limitations of claim 8 of the '338 patent, then all limitations of the asserted dependent claims of the '338 patent are met.

Claim 1 is a composition claim and reads as follows:

1. A composition comprising sodium picosulphate coated granules having a spray-coated layer of sodium picosulphate coating a potassium bicarbonate core.

Claim 8 is a process claim and reads as follows:

8. A process for the preparation of a composition according to claim 1 wherein said process comprises steps of: (a) spray coating a solution of sodium picosulfate on to potassium bicarbonate; and (b) drying the sodium picosulfate and potassium bicarbonate thereby obtaining sodium picosulphate coated granules, Wherein the sodium picosulfate coated granules have a layer of sodium picosulfate coating a potassium bicarbonate core.

There is no dispute that Defendant's ANDA product is a composition comprising sodium picosulfate and potassium bicarbonate. There is also no dispute that Defendant's ANDA product contains granules.

The parties also agree that if Defendant's ANDA product meets all limitations of claim 1 of the '083 patent, then all limitations of the asserted claims of the '083 patent are met.

Claim 1 is a composition claim and reads as follows:

1. A pharmaceutical composition comprising: (a) magnesium oxide coated granules which have a layer of magnesium oxide coated on a core of citric acid; and (b) sodium picosulphate coated granules having a spray-coated layer of sodium picosulphate coating a potassium bicarbonate core.

There is no dispute that Defendant's ANDA product is a pharmaceutical composition comprising magnesium oxide coated granules which have a layer of magnesium oxide coated on a core of citric acid. The only disputed issue, therefore, is whether Defendant's ANDA product comprises a "spray-coated layer of sodium picosulfate coating a potassium bicarbonate core."

The essence of the parties' disputes as to both limitations revolves around the plain and ordinary meaning of the terms "coated," "coating," and "layer." Plaintiffs' expert, Dr. Davies, opined that "coated" and "coating" mean "a layer of a substance, which is on the outer surface of another substance or material." Defendant's expert, Dr. Augsburger, disagreed, opining that these terms mean a "process resulting in the production of a layer of sodium picosulfate substantially evenly surrounding the potassium bicarbonate core." Dr. Augsburger further opined that a "layer" is "a structural component of the sodium picosulfate/potassium bicarbonate granules that substantially evenly surrounds the potassium bicarbonate core."

Defendant argues that the term "coated" is used in the claims as an adjective while the term "coating" is used as a verb. (Id. at 9). This means, according to Defendant, that Plaintiffs' proposed plain and ordinary meaning "cannot be correct" because Plaintiffs' meaning requires these terms to be nouns. Judge disagreed and said that rather the dispute is whether the sodium picosulfate layer must "substantially evenly surround" the core, as Defendant contends. Judge cast doubts on Dr. Augsburger's purported reliance on scientific literature for arriving at his plain and ordinary meaning. Furthermore, none of Defendant's citations support Dr. Augsburger's proposal that the layer must "substantially evenly surround" the core. Judge agreed with Plaintiffs that Dr. Augsberger' s opinion amounts to an attempt to reargue claim construction. Plaintiff’s expert Dr. Davies explained that a person of ordinary skill in the art would expect the magnesium oxide layer coated on the citric acid core to be continuous because of the relative proportions of the two compounds given in the patent. On the other hand, because of the relative proportions of potassium bicarbonate and sodium picosulfate, a person of ordinary skill would expect the sodium picosulfate layer to be discontinuous. Dr. Davies further explained that it would be impossible to create a layer of sodium picosulfate "substantially evenly surrounding" the core because of the random nature of the spray-coating process.

The parties dispute whether Defendant's process involves spray-coating or wet granulation. While both processes can be performed using the same equipment, they are distinct processes that produce different sized particles. Plaintiffs' expert, Dr. Johnson, opined that Defendant's ANDA product is made using a spray-coating process. Dr. Johnson evaluated Defendant's process conditions and equipment configuration in arriving at his opinion. Defendant argues in response that its product is manufactured by "agglomeration via a wet granulation process." Judge said that he process must be considered as a whole, as Dr. Johnson persuasively opined during direct examination. Furthermore, while Defendant sometimes refers to the process as wet granulation, Plaintiffs pointed out at trial that some of Defendant's own lab notebooks reference using a spray-coating process.

Defendant next argues that its manufacturing equipment is configured for agglomeration via wet granulation, and that this configuration is not appropriate for spray-coating. Defendant further argues that its process parameters, including temperature and humidity, indicate that the process is wet granulation. Defendant further argues that the separate drying step it employs is evidence that its process is wet granulation. Defendant also criticizes Dr. Johnson for failing to cite to scientific literature that would show how a person of skill in the art would distinguish between spray-coating and wet granulation. Judge denied all arguments & said that I find Dr. Johnson's detailed testimony about Defendant's ANDA manufacturing process persuasive and more credible than Dr. Augsburger's. I hold that Defendant's process employs spray-coating.

CONCLUSION: Plaintiffs have met their burden of proving by a preponderance of the evidence that Defendant's proposed ANDA product infringes claims 1, 4-6, 8, 9-12, and 17-18 of the '338 patent and claims 1 and 7-11 of the '083 patent.

Adalimumab - USA

Decision on IPR:

AIA Review	Filing Date	Institution Date	Petitioner	US Patent	Respondent	Status
IPR2016-00408 & IPR2016-00409	12/29/2015	07/07/2016	Boehringer Ingelheim GmbH	8,889,135	AbbVie Biotechnology Ltd.	Final Written Decision - Jul 6, 2017 (Claims 1-5 are unpatentable)

The ’135 patent, titled “Methods of Administering Anti-TNFα Antibodies,” issued on November 18, 2014. The ’135 patent discloses methods of treating rheumatoid arthritis (“RA”) with a human anti-tumor necrosis factor α (“TNFα”) antibody.

Esomeprazole – Canada

On Jun 30, 2017 in a unanimous decision, the Supreme Court held that the promise doctrine is not the correct approach to determine whether a patent has sufficient utility. As a result, the lower court decisions finding the patent CA 2,139,653 at issue directed to optically pure salts of esomeprazole invalid for want of utility, were set aside [AstraZeneca Canada Inc. v. Apotex Inc., 2017 SCC 36 (on appeal from 2014 FC 638 and 2015 FCA 158)].

Apotex sought to sell a generic version of NEXIUM, applying for a Notice of Compliance to the federal Minister of Health to enable it to do so. AstraZeneca then applied to the Minister of Health to stop the issuance of a Notice of Compliance to Apotex. This application was dismissed by Justice Hughes in 2010, allowing Apotex to launch. AstraZeneca brought an action for patent infringement against Apotex. Apotex counterclaimed for invalidity.

At first instance, Justice Rennie found that the '653 was novel and inventive, but lacked utility.  Although the patent proved to be useful for some purposes, it was invalid because "it promised more than it could provide".  Thus, falling foul of the Promise Doctrine.  The Federal Court of Appeal dismissed AstraZeneca's appeal.  AstraZeneca appealed to the Supreme Court arguing that the Promise Doctrine was unsound. The Supreme Court agreed.

The ruling spells an end to the so-called “Promise Doctrine”. This allowed a patent on a drug to be ruled invalid if a court decided the medication had not lived up to all the promises that a firm had made to be granted the patent in the first place. The Court found that the Doctrine is excessively onerous in two ways: (1) it determines the standard of utility that is required of the patent by reference to the promises expressed in the patent; and (2) where there are multiple expressed promises of utility, it requires that all be fulfilled for a patent to be valid.

The Court stated that utility requires the subject matter of an invention to be useful.  This means that the invention must be capable of an actual use relevant to the subject matter and not devoid of utility.  The Court stated: "A single use related to the nature of the subject-matter is sufficient and utility must be established by either demonstration or sound prediction as of the filing date."

To determine whether a patent discloses an invention with sufficient utility, the courts should adopt a two-stage test:

1      1. Courts must identify the subject-matter of the invention as claimed in the patent

2  2. Courts must ask whether that subject-matter is useful - is it capable of a practical purpose (ie. actual result)

In the case at issue the subject of the patent that must be useful for the purposes of section 2 is the "optically pure salts of the enantiomer of omeprazole". It was accepted at first instance that at the filing date the optically pure salts of the enantiomer of omeprazole would be useful as a proton pump inhibitor to reduce the production of gastric acid.  Use as a proton pump inhibitor is related to the subject matter of the patent, thereby making it useful within the meaning of section 2.  This is sufficient utility to satisfy the requirements of section 2.

The doctrine, which came into force in 2005, has already been used to invalidate almost 30 medical patents.

Asenapine – USA

On Jun 30, 2017 a Delaware court issued opinion in SAPHRIS® (Asenapine) case & upheld validity and partly an infringement of U.S. Patent No. 5,763,476.

This consolidated case arises out of the filing of Abbreviated New Drug Applications ("ANDAs") by defendants Sigmapharm Laboratories, LLC ("Sigmapharm"); Breckenridge Pharmaceutical, Inc. ("Breckenridge"); Hikma Pharmaceuticals, LLC, Hikma Pharmaceuticals, PLC, and West-Ward Pharmaceutical Corporation (collectively, "Hikma"); Alembic Pharmaceuticals Ltd., Alembic Global Holding S.A., and Alembic Pharmaceuticals, Inc. (collectively, "Alembic"); and Amneal Pharmaceuticals, LLC, Amneal Pharmaceuticals of New York, LLC, and Amneal Pharmaceuticals Co. India PVT.LTD (collectively, "Amneal"). All defendants may be collectively referred to as "defendants." Each of the defendants has submitted an ANDA in an attempt to market generic versions of asenapine before the expiration of U.S. Patent No. 5,763,476 ("the '476 patent"), which claims sublingual or buccal compositions of asenapine and methods of using such compositions to treat mental disorders, including schizophrenia. Plaintiffs Forest Laboratories, LLC and Forest Laboratories Holdings, Ltd. (collectively, "Forest" or "plaintiffs") brought patent infringement suits against each of the defendants, which suits were consolidated into the above captioned suit.

In the case tried before the court, each of the defendants conceded infringement of claim 1 of the '476 patent and two of the four defendants (Amneal and Hikma) conceded infringement of claim 4. Therefore, the focus of the trial (conducted in the fall of 2016) was infringement of claim 4 and the validity of the '476 patent. Based on the invention as disclosed in the specification, asserted claim 4 recites:

"A method for treating tension, excitation, anxiety, and psychotic and schizophrenic disorders, comprising administering sublingually or buccally an effective amount of a pharmaceutical composition comprising trans-5-chloro-2-methyl-2,3,3a, 12b-tetrahydro- 1Hdibenz[2,3:6,7]oxepino[4,5-c]pyrrole [asenapine] or a pharmaceutically acceptable salt thereof."

Infringement:

As noted, all defendants have conceded infringement of claim 1, as well as dependent claims 2, 5, and 6 of the '476 patent. Only defendants Alembic and Breckenridge challenge infringement of claim 4. Consistent with the parties' dispute, claim 4 contains essentially three relevant limitations: "A method for treating ... [1] excitation ... disorders, comprising [2] administering sublingually or buccally an [3] effective amount of a pharmaceutical composition [asenapine] or a pharmaceutically acceptable salt thereof." Defendants Alembic's and Breckenridge's proposed labels provide literal instructions to carry out elements [2] and [3] of the claim i.e., [2] sublingually administering [3] an effective amount of asenapine maleate to treat the indicated disorder, that is, manic episodes associated with bipolar I disorder. The only issue for the court to decide concerns limitation [1] in the claim, that is, whether defendants infringe claim 4 even though their generic asenapine products are indicated only for the treatment of "manic episodes" associated with bipolar I disorder & not for excitation.

1. Direct infringement under the doctrine of equivalents

The court construed the phrase "tension, excitation, anxiety, and psychotic and schizophrenic disorders" as not literally including the treatment of bipolar disorder, including manic or mixed episodes associated with bipolar I disorder. The court explained that the word "bipolar" was not used or described in the specification and, indeed, the use of asenapine to treat bipolar disorder was claimed in a later patent application. Forest argued that the term "excitation" in the claim includes within its literal scope "mania" and, therefore, the claim covers the treatment of the manic component of bipolar disease. To put the point differently, Forest argues that, to the extent there are any differences between the treatment of manic episodes associated with bipolar I disorder with asenapine and the treatment of excitation with asenapine recited in claim 4, such differences are insubstantial; i.e., the two treatments are equivalent.

Despite Dr. Mcintyre's efforts to convince the court that those of skill in the art in 1994, as a general proposition, equated the term "excitation" with "mania," the court remains unconvinced. In the first instance, there is no reference of record that literally describes "excitation" as the defining feature of mania. Instead, the references refer to "excitement" (and the words Dr. Mcintyre equates with excitement) as one of several criteria that must be present to properly diagnose a manic episode of bipolar I disorder. In sum, there is no dispute that "excitation" is not itself a disorder. There is also no dispute that "excitation" can be symptomatic of many disorders. The court, however, finds no persuasive objective evidence that those of skill in the art in 1994 considered "excitation" the sine qua non of "mania" such that the two terms would be equated for purposes of treating a patient with asenapine.

2. Indirect infringement

In the absence of direct infringement, there can be no liability for indirect infringement. Nevertheless, the court will address Forest's evidence relating to inducement for completeness. Alembic's and Breckenridge's original ANDA submissions (like the other defendants at bar) contained proposed labels that included all of the Saphris approved indications - schizophrenia and manic and mixed episodes associated with bipolar I disorder. Subsequent to the court's claim construction order, Alembic and Breckenridge submitted new labels to the FDA that proposed removing schizophrenia as an indication. According to Forest, the proposed labels also provide sufficient instructions for doctors and patients to administer the generic asenapine products sublingually, and to use an "effective amount" of asenapine to treat schizophrenia, as required by claim 4. More specifically, defendants' proposed labels include a section titled "Dosage Forms and Strengths," which indicates that their asenapine sublingual tablets are available in 5 mg and 10 mg doses. The recommended dosing for schizophrenia and bipolar mania are similar. The Saphris label indicates that the starting dose for schizophrenia is 5 mg sublingually twice daily, with a recommended dose of 5 to 10 mg sublingually twice daily and a maximum dose of 10 mg sublingually twice daily.

Despite these essentially undisputed facts, the Federal Circuit has held that even the "knowledge of off-label infringing uses" will not establish inducement. The facts at bar are unusual, 17 but not more compelling than the facts reviewed by the Federal Circuit in Takeda. The court concludes that the evidence proferred by Forest in this regard is insufficient to establish a specific intent on the part of Alembic or on the part of Breckenridge to induce infringement of claim 4 of the '476 patent.

Invalidity due to Obviousness

Defendants rely on the teachings of three different prior art combinations to demonstrate that the subject matter of claim 1 of the '476 patent is obvious: (1) Sitsen (PTX 37) 19 in view of the '516 patent (PTX 28); (2) Van der Berg '434 patent (PTX 133) in view of the '516 patent; or (3) Van der Berg '434 patent in view of the '423 application (PTX 30), each combined with the knowledge of the ordinarily skilled artisan. Defendants argue that the prior art identified above would have motivated persons of skill in the art to formulate asenapine ("a new and promising antipsychotic in 1994," D.I 288 at 26) as a rapidly disintegrating composition (consistent with the improved composition platforms disclosed in the '516 patent and '423 application) with a reasonable expectation of success.

The court discerns no motivation from the record evidence to use a sublingual formulation-a formulation that had never before been used for an antipsychotic drug. Courts have recognized that solving an unrecognized problem in the art can itself be an nonobvious patentable invention, even where the solution is obvious once the problem is known. Eibel Process Co. v. Minn. & Ontario Paper Co., 261 U.S. 45, 68 (1923). The record at bar demonstrates that it was unknown in the art that oral or IV administration of asenapine could cause severe cardiotoxic side effects. There were numerous other formulations that could have been experimented with to try to solve the problem, but no reasonable expectation that any of them would have. Accordingly, the use of a sublingual formulation was not obvious.

Invalidity due to Lack of Written Description

Defendants allege that the claims of the '476 patent lack adequate written description because the specification does not adequately describe asenapine free base. The evidence adduced at trial demonstrates that a skilled artisan would understand that the inventors of the '476 patent were in possession of compositions comprising asenapine free base and methods of using these compositions to treat the claimed conditions. Not only does the '476 patent explicitly describe asenapine in its free base form, it indicates that "[t]he invention therefore relates to a sublingual or buccal pharmaceutical composition comprising [asenapine free base. The fact that there is no explicit example of a sublingual or buccal composition containing asenapine free base or use of such a composition is not dispositive. Under controlling precedent, explicit examples are not needed to provide adequate written description support. Ariad, 598 F .3d at 1352; Fa/ko-Gunter, 448 F .3d at 1366.

Invalidity due to Lack of Enablement

Defendants' non-enablement contention rests on the allegation that a single embodiment (a composition comprising asenapine free base) out of many is not enabled. This argument is legally insufficient. See In re Angstadt, 537 F.2d 498, 502- 503 (C.C.P.A. 1976) (holding that patent applicants are not required to enable every species encompassed by their claims). Defendants have failed to establish, by clear and convincing evidence, that the asserted claims are not enabled.

Objective indicia

The record at bar demonstrates that it continues to be a surprising and unexpected result of the claimed invention that the sublingual route of administration successfully resolved the serious cardiotoxic event reported in the '476 patent. Based on the IV study, even the inventors of the '476 patent believed that sublingual administration would also result in a negative outcome. (D.I. 311 at 269:24-270:18) And there is nothing in the prior art suggesting that sublingual administration could be used to resolve this type of side effect.

Given the problems with typical antipsychotics and the two atypical antipsychotics available as of 1994, skilled artisans recognized the need for additional antipsychotic drugs that had minimal EPS symptoms as well as a favorable weight gain, metabolic, and prolactin profile. Asenapine met the criteria for Long-felt need.

CONCLUSION: For the reasons stated, Forest has not carried its burden to prove, by a preponderance of the evidence, that defendants Alembic and Breckenridge infringe claim 4 of the '476 patent. Defendants have failed to carry their burden to prove, by clear and convincing evidence, that claims 1 and 4 of the '476 patent are invalid by reason of obviousness, lack of written description, or lack of enablement.