Ezetimibe & Simvastatin – France

 

On Sep 25, 2020, Court of appeal of Paris found SPC for combination of ezetimibe & simvastatin product invalid.

Background:

Merck owns European Patent No. 0720599 (EP 599) entitled "Hydroxy-substituted azetidinone compounds effective as hypocholesterolemic agent” which is expired on September 14, 2014. It claims novel compound ie. Ezetimibe and also combination with other agents such as cholesterol biosynthesis inhibitor for the treatment of atherosclerosis. Specifically, dependent claims 9 to 18 claim the combination which cover simvastatin among other inhibitors. Merck granted first SPC (n°03C0028 – expired on April 17, 2018) on this basic patent which covers single ezetimibe product, EZETROL.  Merck also obtained second SPC (n°05C0040 – expired on April 2, 2019) on the same patent which covers ezetimibe & simvastatin combination product, INEGY.

Teva launched generic version of EZETROL  on April 18, 2018 and of INEGY on April 24, 2018 & requested invalidity of claims 9 to 18 of EP’599 patent and of the SPC No. 040 before court. Tribunal de Grande Instance of Paris court rejected Teva’s request & ordered Teva to pay the cost and to pay Merck the sum of 100,000 euros. Teva appealed.

Appeal courts analysis:

Article 3 of Regulation (EC) No 469/2009: SPC shall be granted if –

(a) the product is protected by a basic patent in force;

(b) a valid authorisation to place the product on the market as a medicinal product has been granted in accordance with Directive 2001/83/EC or Directive 2001/82/EC, as appropriate;

(c) the product has not already been the subject of a certificate;

(d) the authorisation referred to in point (b) is the first authorisation to place the product on the market as a medicinal product.

Court said that aforementioned articles of the Regulation must be interpreted in the light of the case law of the CJEU, in particular with regard to the Sanofi C 443/12 (Irbesartan + HCTZ) decision dated December 12, 2013, which deals with similar facts. Merck argued that this Sanofi case law is not applicable to the case at hand in that the product in question concerned the combination of irbesartan with HCTZ (hydrochlorothiazide) and that the patent did not contain a claim expressly mentioning HCTZ.  Here, in present case, claim 17 specifically mentions simvastatin and thus it is protected. The Court said that the CJEU, in its Sanofi decision, held that even if the condition laid down in Article 3(a) of Regulation No 469/2009 were satisfied, for the purpose of the application of Article 3(c) of that regulation, it cannot be accepted that the holder of a basic patent in force may obtain a new SPC, each time he places a product on the market. Court further said that Person skilled in the art after reading the patent specification would not assume this combination as “distinct product”. The description of the patent, which uses the singular to designate the invention, and uses the formula "in yet another aspect" to present the combination of a hydroxy-substituted azetidinone, object of the invention, with a cholesterol biosynthesis inhibitor, refers indifferently for hydroxy-substituted azetidinones alone and for their combination with a cholesterol biosynthesis inhibitor.

In the present proceeding, as in the Sanofi case, the EP 599 patent protecting the active ingredient in particular ezetimibe, has already led to the grant of a SPC on this active ingredient to its holder, and this first SPC relating to ezetimibe alone allowed Merck to oppose to the marketing of a drug containing ezetimibe in combination with a statin such as simvastatin and having a therapeutic indication similar to that of the drug Ezetrol. Thus, the supplementary protection certificate FR05C0040 is null and void.

Parallel proceedings related to this SPC:

France: On Feb 14, 2020 this appellate court reversed the decision of preliminary injunction granted against Sandoz & Mylan.

Norway: On December 21, 2018, Borgarting Court of Appeals affirmed lower court decision which granted preliminary injunction.

Czech Republic: On August 28, 2018, Prague Court of Justice issued preliminary injunction.

Portugal: On September 7, 2018, Portuguese Arbitral Tribunal issued preliminary injunction.

Belgium: On December 21, 2018, Commercial Court of Brussels issued preliminary injunction.

Austria: On July 10, 2019, Vienna Court of Appeals affirmed preliminary injunction.

Netherlands:  On October 23, 2018, Court of Appeal of The Hague affirmed & held SPC invalid.

Germany:  On March 15, 2019, Court of Appeal of Düsseldorf affirmed & held SPC invalid.

Spain:  On September 12, 2018, Regional Court of Barcelona found SPC invalid.

Ibrutinib - USA

 

IPR decision: Sep. 24, 2020

 

AIA Review #	Filing Date	Institution Date	Petitioner	Patent	Respondent	Final Written Decision
IPR2019-00865	03/21/2019	09/26/2019	Sandoz Inc.	9,795,604	Pharmacyclics Inc.	Some Challenged Claims Unpatentable

US 9,795,604 (Pharmacyclics LLC; Exp: 10/24/2034):

1. A method of treating chronic graft versus host disease (GVHD) comprising administering to a patient having chronic GVHD a therapeutically effective amount of a compound of the structure: (Ibrutinib) thereby treating the chronic GVHD in the patient. 

54. A method of treating chronic graft versus host disease (GVHD) comprising administering to a patient having chronic GVHD from 140 mg/day to 840 mg/day of a compound of the structure: (Ibrutinib)

55. A method of treating chronic graft versus host disease (GVHD) comprising administering to a patient having chronic GVHD about 420 mg/day of a compound of the structure: (Ibrutinib)

 

PTAB decision summary:

PTAB found claims 1, 6–10, 24, 35, 39, 55 unpatentable & claims 4, 13, 15, 28–31, 43–46, 50–53 patentable. Petitioner primarily relied on US 2015/0140085 reference which disclosed ibrutinib, treatment of GVHD, dose range & administration part. PTAB found that US’085 anticipated those claims (1, 6–10, 24, 35, 39, and 55). With respect to other claims which PTAB found patentable were related to treatment of cGVHD where patients received prior steroid therapy. PTAB held that the field was not fully developed with respect to treatment of steroid refractory/resistant cGVHD. PTAB said that given the poor understanding of cGVHD, the lack of animal models and standardized measurement criteria, and the unpredictability in the field, it is not surprising that many potential treatments have proven unsuccessful. Therefore, POSA would not have reasonable expectation of success in treating steroid resistant/refractory cGVHD. Other prior arts also do not cure this deficiency. Thus, claims 4, 13, 15, 28–31, 43–46, 50–53 are not shown to be unpatentable.

 

 

Weekly Patent Litigation Round-Up

 

Delaware judge deals Biogen another blow in Tecfidera patent fight

A federal judge in Delaware on Wednesday dealt another setback to drug company Biogen Inc in its effort to keep generic versions of its multiple sclerosis treatment Tecfidera off the market through patent litigation. Handing a win to Novartis AG unit Sandoz and other generic drug companies, U.S. District Judge Maryellen Noreika said a Biogen patent on a Tecfidera dosing regimen was invalid because it did not sufficiently describe the claimed invention...

https://in.reuters.com/article/ip-patent-biogen/delaware-judge-deals-biogen-another-blow-in-tecfidera-patent-fight-idUSL1N2GD2OJ

 

Mylan and Development Partner, Synthon, Win Significant European Patent Office Ruling Related to Copaxone® 40mg/mL

HERTFORDSHIRE, England and PITTSBURGH, Sept. 15, 2020 /PRNewswire/ --Mylan N.V. (NASDAQ: MYL) today announced that the Technical Board of Appeal of the European Patent Office (EPO) has held that Yeda Research and Development Company, Ltd.'s European Patent no. 2 949 335 related to Teva's Copaxone® 40 mg/mL three times weekly product is invalid and revoked across Europe. With the EPO's decision, Mylan has once again overcome Teva's attempts to restrict MS patients' access to safe and affordable alternatives. Over the course of the last eleven years, Mylan has successfully defeated Teva's four waves of U.S. patent litigation, eight Citizen Petitions, injunction proceedings in India, and more than 15 regulatory challenges, patent litigations or commercial actions across Europe. The EPO's positive ruling will allow Mylan to immediately return to the market and accelerate commercialization in other markets across Europe...

https://www.biospace.com/article/releases/mylan-and-development-partner-synthon-win-significant-european-patent-office-ruling-related-to-copaxone-40mg-ml/

 

Fresenius Faces French Damages Over Alimta

Fresenius Kabi must pay Eli Lilly €28m in damages after a French court of first instance found that the generics firm’s pemetrexed infringed intellectual property protecting the Alimta chemotherapy brand. The German firm has commented on possible next steps..

https://generics.pharmaintelligence.informa.com/GB150263/Fresenius-Faces-French-Damages-Over-Alimta

 

IPAB allowed an appeal and granted a patent to pfizer for tofacitinib and its salts

The IPAB  allowed  an appeal and granted a patent to Pfizer for Tofacitinib and its salts (application 991/MUMNP/2003. This application claimed the compound 3-{(3R, 4R)-4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile and pharmaceutically acceptable salts thereof (Tofacitinib and its salts) and was refused by the patent office on various grounds, including anticipation by prior claiming and section 3(d). The main prior art cited by the controller for novelty was Document WO 0142246(D1) that claimed and disclosed the compound 3-(4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl)-3-oxo- propionitrile. The ground of anticipation by prior claiming was not raised in the hearing notice and for section 3(d) no known substance was identified.

http://updates.anandandanand.com/ipab-allowed-appeal-granted-patent-pfizer-tofacitinib-salts/

 

Ibrutinib Patent Revocation: IPAB Says the Stay is Here to Stay

Latest in the Ibrutinib patent saga is IPAB’s order maintaining the interim stay over the revocation of the anti-cancer drug patent. This comes at an interesting time, as a recent report by I-MAK suggests that US-based Biopharma Company AbbVie might be attempting to build a patent wall around Imbruvica (Ibrutinib’s market brand), having secured 88 patents out of 165 applications filed. Imbruvica currently generates a whopping $4.5 billion a year for AbbVie. In India, Pharmacyclics LLC (owned by AbbVie) had been granted the patent in 2014 (IN 262968), against which Laurus Labs had filed a post-grant opposition under Section 25(2) of the Patents Act, 1970 the next year. The hearing was scheduled in November 2017, but was adjourned and rescheduled to 25th September 2019, before being ultimately held on 22nd November. Consequently, the patent was revoked on grounds of lack of inventive step in March 2020.…

https://spicyip.com/2020/09/ibrutinib-patent-revocation-ipab-says-the-stay-is-here-to-stay.html

 

Dr Reddy’s announces settlement of Revlimid capsules patent litigation with Celgene in US

Dr Reddy’s Laboratories announced the settlement of their litigation with Celgene, a wholly-owned subsidiary of Bristol Myers Squibb relating to patents for REVLIMID (lenalidomide) capsules. In settlement of all outstanding claims in the litigation, Celgene has agreed to provide Dr Reddy’s with a license to sell volume-limited amounts of generic lenalidomide capsules in the US beginning on a confidential date after March 2022 subject to regulatory approval. The agreed-upon percentages are confidential. Dr Reddy’s is also licensed to sell generic lenalidomide capsules in the US without volume limitation beginning on January 31, 2026.…

https://www.expresspharma.in/latest-updates/dr-reddys-announces-settlement-of-revlimid-capsules-patent-litigation-with-celgene-in-us/

Dimethyl fumarate - USA

On Sep. 16, 2020, Delaware Court found multiple sclerosis method of use patent invalid for lack of written description support under principles of collateral estoppel.

Plaintiffs (Biogen) sued many generic companies based on their filing of ANDAs seeking to market generic versions of Tecfidera®. This product is indicated for relapsing forms of Multiple Sclerosis (MS). The patent at issue here is U.S. Patent No. 8,399,514, relates to method of treatment of MS with 480 mg dose. Plaintiff sued all ANDA filers in Delaware court, except Mylan - sued in district court of West Virginia. Both the proceedings carried out on almost similar timelines.  On June 18, 2020, West Virginia court found that Mylan had proven by clear and convincing evidence that the Asserted Claims of the ’514 Patent are invalid for lack of written description. You can read the decision summary “here on this blog”.

The issue now before Delaware court was whether the judgment of invalidity rendered in the Mylan case should apply here under the principles of collateral estoppel. Delaware Court evaluated the collateral estoppel factors under Third Circuit law: (1) the identical issue was previously adjudicated, (2) that issue was actually litigated, (3) the previous determination was necessary to the decision and (4) the party being precluded from relitigating the issue was fully represented in the prior action.

Delaware court heard all the parties and weighing these factors ultimately found that collateral estoppel applies here. Thus, claims are invalid for lack of written description support.

Estradiol - USA

 

On Sep 02, 2020, Delaware Court found estrogen transdermal patents invalid under lack of enablement & lack of written description support.

Noven pharmaceuticals (Plaintiff) sued Amneal pharmaceuticals (Defendant) under Hatch-Waxman Act as Defendant filed ANDA to market generic version of Minivelle®. Noven markets Minivelle® transdermal film in USA for the treatment of moderate to severe vasomotor symptoms due to menopause.  Noven sued Amneal for the infringement of US 9,833,419; US 9,730,900 and US 9,724,310 patents which are expiring in July 2028. Amneal countered with non-infringement, invalidity based on enablement, written description support & on-sale bar defenses. Court held bench trial in Nov. 2019 & Jan. 2020.

Claim 1 of US’419 is representative:

1. A monolithic transdermal drug delivery system for estradiol, consisting of (i) a backing layer, (ii) a single adhesive polymer matrix layer defining an active surface area and, optionally, (iii) a release liner, wherein the single adhesive polymer matrix layer comprises an adhesive polymer matrix comprising estradiol as the only drug, wherein the adhesive polymer matrix layer has a coat weight of greater than 10 mg/cm² and includes greater than 0.156 mg/cm² estradiol, and the system achieves an estradiol flux of from 0.0125 to about 0.05 mg/cm²/day, based on the active surface area.

Claim 1 of US’900 is representative for US’900 & US’310 evaluation :

1. A method for administering estradiol, comprising applying to the skin or mucosa of a subject in need thereof a monolithic transdermal drug delivery system consisting of (i) a backing layer and (ii) a single adhesive polymer matrix layer defining an active surface area and comprising an adhesive polymer matrix comprising estradiol as the only drug, wherein the polymer matrix has a coat weight of greater than about 10 mg/ cm² and includes greater than 0.156 mg/ cm² estradiol, and the system achieves an estradiol flux of from about 0.0125 to about 0.05 mg/ cm² /day, based on the active surface area.

 

Infringement:

Infringement of US’419 patent:

Noven contented that Amneal infringed claims of US’419 patent under literal infringement. Specifically Noven argued that Amneal’s ANDA product meet the limitation of “coat weight of greater than 10 mg/cm^2".” During claim construction court construed this limitation as having plain & ordinary meaning. Amneal ANDA product have inprocess coat weights above 10 mg/cm². Specifically, the upper limits of the coat weight in the tentatively-approved product are 10.75 mg/cm² for any individual coat weight value and 10.5 mg/cm² for the average coat weight value. Similarly, the upper limits under Anmeal's proposed amended ANDA for individual and average coat weights are 10.45 and 10.40 mg/cm2, respectively (Amneal amended its ANDA after tentative approval to tighten the limits). Court, thus held that Anmeal's product infringes the asserted claims of the '419 patent.

Infringement of US’900 & US’310 patents:

Noven contented that Amneal infringed claims of US’900 & US’310 patents under Doctrine of Equivalents (DOE). Specifically Noven argued that Amneal’s ANDA product meet the limitation of “coat weight of greater than about 10 mg/cm^2".” During claim construction court construed this limitation as - "having a coat weight which weighs more than 110% of 10 mg/cm²"; that is, a coat weight of more than 11 mg/cm². Because the claim mentions “about” term which is defined in the specification as plus or minus 10%. Court sided with Amneal during claim construction which proposed claim construction as - 9 mg/cm² to 11 mg/cm^2.  Amneal argued that lower limit is excluded since specification mentions this lower limit with respect to the prior formulation of Noven, Vivelle-Dot®. Therefore, infringement would be found only if Amneal’s ANDA contains coat weight of greater than 11 mg/cm². As seen in infringement of US’419 patent, Amneal product contains coat weight less than 11 mg/cm². Thus, Amneal does not infringe under literal infringement.

Noven argued that Amneal product infringes claims under DOE. Amneal counterargued that DOE theory is barred because of prosecution history estoppel (PHE). Specifically, Amneal argued that during prosecution Noven added this coat weight limitation & thus there is an estoppel. The Court agreed with Amneal & said that the amendments to add the coat weight limitations were narrowing. Secondly, the reason for the amendment is "a substantial one relating to patentability ." The purpose of the amendment was to avoid an obviousness rejection based on prior arts and highlight the "unexpected results based on the coat weight of the polymer to achieve the claimed flux of drug delivery." Third, Noven has not rebutted the presumption that estoppel applies, because it has failed to show that the coat weight amendment is "tangential to the asserted equivalent in the Amneal ANDA Product." Court did not find Noven’s argument persuasive. Noven argued that prior art references disclosed a coat weight range of 9 to 11 mg/cm² , so the Examiner could not have relied on the coat weight amendment to overcome rejection. Noven further argued that the Examiner had initially rejected all claims, including claim 27, which included the limitation "a coat weight of greater than about 10 mg/cm²”. Noven said that it later added this limitation into claim 1 & thus this limitation is not distinguishing feature that is responsible for allowance of claims. But court agreed with Amneal instead & said that without the coat weight limitation in the claims, Noven "would not have been able to argue that the claimed invention embodied the 'unexpected result' of higher coat weight causing higher flux rates, to overcome the obviousness rejection."

Court, therefore held that, Noven failed to prove that Amneal's ANDA product infringes the asserted claims of the '900 or '310 patents under the doctrine of equivalents.

 

Invalidity:

Specification defines “transdermal” as delivery, administration or application of a drug by means of direct contact with skin or mucosa. As used herein, "dermal" includes skin and mucosa, which includes oral, buccal, nasal, rectal and vaginal mucosa.

Lack of enablement:

With respect to Lack of enablement, Amneal argued that asserted patents fail to enable the claimed transmucosal estradiol patch systems. The specification only teaches about transdermal system containing skin & not mucosa. The asserted claims are broad; they cover not just estradiol patch systems for application to the skin but also estradiol patches to be applied to any mucosal tissue, including oral, buccal, nasal, rectal, and vaginal tissue. Specification fails as to how to make or use an estradiol patch system on any mucosa (let alone all mucosae ). The specification is silent as to how much estradiol to include, or what coat weight should be used. The specification fails to identify which excipients or ingredients would be useful for making any (let alone all) of the claimed transmucosal systems. Moreover, there is no mention in the specification of whether or how the central discovery of the patents - increasing coat weight to increase flux - would apply to the various mucosae. This is perhaps not surprising, since the relationship was discovered by testing flux across skin, not mucosa! tissue. The specification's example with respect to the flux achieved with various formulations pertained only to skin, not mucosae. A POSA seeking to make a claimed transmucosal embodiment would have faced the added challenge of obtaining the claimed flux values while keeping the estradiol concentration in the claimed range and the coat weight in the claimed range above 10 or 11 mg/cm².

Dr. Lobo (Defendant expert) explained that the physiology and drug release characteristics of oral, buccal, nasal, rectal, and vaginal mucosa could vary greatly - not only from skin, but from one another. This is primarily because the skin has an impervious barrier due to a protective outer layer, known as the "stratum comeum," which is lacking in mucosae. Drug delivery across the skin is, therefore, constant and prolonged over days, while estradiol delivery across the mucosae was known to be rapid, sometimes exhibiting a burst effect. The patents provide a POSA no guidance about how to achieve the claimed daily flux when the drug is so rapidly absorbed over mucosa.

Court said that the patents and publications Noven relied on in an effort to show that the state of the art was sufficiently advanced that a POSA would somehow have found in the specification of the Patents-in-Suit sufficient guidance to make and use a transmucosal embodiment of the claims (let alone embodiments with respect to each mucosa covered by the claims) do not suffice. Turning to the quantity of experimentation, the "nature and predictability of the field," and the level of ordinary skill, the Court found that the development and use of transmucosal patch systems constituted novel, highly unpredictable endeavors at the pertinent time. Noven's remaining arguments for enablement are unavailing. Court therefore concluded that the Asserted Claims of the Patents-inSuit are invalid for lack of enablement.

Lack of written description support:

As argued above for enablement, Court said that the specification lacks any description or example of a transmucosal estradiol system, including any description or example of any oral, buccal, nasal, rectal, or vaginal patch systems, even though such systems are within the scope of the claims. Aside from the specification's definition of"flux" and "transdermal" the words "oral," "buccal," "nasal," "rectal," or "vaginal" mucosa do not appear in the specification. The specification fails to convey to a POSA the inventor's possession or invention of the claimed transmucosal estradiol patch systems. Transmucosal delivery and formulation is a separate and distinct scientific field from transdermal formulation, each with separate bodies of specialized knowledge and separate technical literature and treatises. Court thus held that a POSA reading the specification would not have understood the inventor of the patents-in-suit to be in possession of the transmucosal embodiments. Therefore, the Asserted Claims are invalid under lack of written description support.

Vascepa® – USA

On Sep. 03, 2020, Federal Circuit affirmed (Rule-36 judgment) Nevada district court decision finding method of treating hypertriglyceridemia patents invalid as obvious.

This appeal was filed by Amarin (Plaintiff) against the decision of Nevada district court which held claims of US 8,293,728; US 8,318,715; US 8,357,677; US 8,367,652; US 8,431,560 and US 8,518,929 invalid in Hatch-Waxman litigation. District court found that defendants (Hikma & DRL) established by clear and convincing evidence at trial that all asserted claims are prima facie obvious. You can read the district court decision summary “reported here” on this blog.