Watson Infringes Bayer’s Natazia Patent; Bayer Pharma v. Watson Laboratories

On December 28, 2016, Leonard P. Stark Judge of United states district court For the district of Delaware has ordered in favor of Bayer Pharma AG, Bayer Intellectual Property GmbH, and Bayer HealthCare Pharmaceuticals Inc. (collectively “Plaintiffs”) and against Defendant Watson Laboratories, Inc. (“Watson”) on the claim in Plaintiffs’ Complaint dated December 18, 2012, that the commercial manufacture, use, offer for sale, sale, and/or importation into the United States of the proposed generic version of Bayer HealthCare’s Natazia® combined oral contraceptive that is the subject of Watson’s Abbreviated New Drug Application (“ANDA”) No. 202349 would infringe Claims 1-3 of U.S. Patent No. 8,071,577 (“the ‘5 77 patent”).

Further, the judge also ordered in favor of Plaintiffs and against Watson on the counterclaim of invalidity in Watson’s Answer and Counterclaim dated January 9, 2013. Specifically, that Claims 1-3 of the ‘577 patent are not invalid under any provision of 35 U.S.C. §§ 101, 102, 103, or 112, or any other judicially-created bases for invalidation.

Background:

FDA approved Natazia which contains Dienogest; Estradiol Valerate as active ingredients to prevent pregnancy in women who elect to use an oral contraceptive, and to treat heavy menstrual bleeding in women without organic pathology who choose to use an oral contraceptive as their method of contraception.

The following patents were listed in OB for Natazia

U.S. Patent Number Expiration Date
6,133,251 (the ‘251 patent) Expired (October 25, 2016)
6,884,793 (the ‘793 patent) Expired (October 25, 2016)
8,071,577 (the ‘577 patent) May 13, 2026
8,153,616 (the ‘616 patent) January 30, 2028

Watson has filed an ANDA  contains paragraph IV certifications under section 505(j)(2)(A)(vii)(IV) with respect to US ‘251, ‘793, and ‘577 patents, stating that each patent is invalid, unenforceable, or will not be infringed by your manufacture, use, or sale of Estradiol Valerate Tablets, 1 mg and 3 mg, Estradiol Valerate and Dienogest Tablets, 2 mg/2 mg and 2 mg/3 mg, under this ANDA.

Bayer has not initiated any action for infringement of the US ‘251 and ‘793 against Watson within the statutory 45- day period. Bayer only brought the lawsuit under the infringment of US ‘577 patent.

Watson ANDA  contains a statement under section 505(j)(2)(A)(viii)  with respect to US ‘616 patent which claims MOT and it is irrelevant to Watson ANDA.

As per the final judgment given by judge P. Stark the Food and Drug Administration(“FDA”) shall reset the effective date of the approval of Watson’s ANDA No. 202349 to be a date that is not earlier than the date of expiration of the ‘577 patent inclusive of the patent term adjustment awarded to Plaintiffs under 35 U.S.C. § 154(b) (May 13, 2026).

Pfizer sued Indian companies@Bosutinib Monohydrate

Wyeth LLC, Wyeth Pharmaceuticals Inc. (“Wyeth Inc.”) and PF PRISM C.V., (collectively, “Plaintiffs” or “Pfizer”), lodged a complaint against Alembic Pharmaceuticals, Ltd., Alembic Pharmaceuticals, Inc. (collectively “Alembic”), and Sun Pharmaceutical Industries, Inc. (“Sun”), for infringement of United States Patent No. 7,417,148 (the “’148 patent”) and United States Patent No. 7,767,678 (the “’678 patent”), and against Sun for infringement of the ’678 patent. Case 1:16-cv-01305-UNA

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Bosutinib monohydrate 

Background :

Alembic Pharmaceuticals, Ltd.’s filed an Abbreviated New Drug Application (“ANDA”) No. 209543 seeking approval by the United States Food and Drug Administration (“FDA”) to sell generic copies of Pfizer’s drug Bosulif® prior to the expiration of the ’678 and ’148 patents, and Sun’s filing of ANDA No. 209577 seeking approval by the FDA to sell generic copies of Bosulif prior to the expiration of the ’678 patent.

US ‘148 claims :

MOT  chronic myelogenous leukemia (CML) using Bosutinib. US ‘148 covers and approved indication. US ‘148 is set to expire on Jan 23, 2026

US ‘678 claims :

Crystalline forms of Bosutinib monohydrate and methods of preparing the same. US ‘678 is set to expire on Nov 23, 2026.

There are total 5 patents listed in OB for Bosulif, which includes US 6,002,008 (expiring March 27, 2018); US 7,919,625 (expiring December 11, 2025); and US RE42376 (expiring September 24, 2019; reissued of US 6,297,258).

In December 2016, U.S. Reissue Patent No. RE42376 received a patent term extension of 1,663 days, which extends its expiration date until April 13, 2024. The paragraph IV notices of Alembic and Sun do not address these three patents. Alembic owns DMF 30552 for Bosutinib.

FDA grants accelerated approval to Rubraca (rucaparib)

On December 19, 2016 the U.S. Food and Drug Administration granted accelerated approval to Rubraca (rucaparib) to treat women with a certain type of ovarian cancer. Rubraca is approved for women with advanced ovarian cancer who have been treated with two or more chemotherapies and whose tumors have a specific gene mutation (deleterious BRCA) as identified by an FDA-approved companion diagnostic test.

The structure of Rucaparib is given below:

Rucaparib.svg

Rubraca is marketed by Clovis Oncology, Inc. based in Boulder, Colorado. The FoundationFocus CDxBRCA companion diagnostic is marketed by Foundation Medicine, Inc. of Cambridge, Massachusetts.

Rucaparib is claimed as a product in US 6,495,541 B1 which is set to expire in January 2020. However, the patent may get patent term extension.

US ‘541 issued to Agouron Pharmaceuticals which was acquired by Warner-Lambert. Later, in June 2000, Warner-Lambert merged with Pfizer.

Clovis Oncology entered into an agreement with Pfizer for the development and commercialisation of Rucaparib. Under the terms of the agreement, Clovis is responsible for global development and commercialisation of Rucaparib.

Federal Jury Awards $2.5B of Royalty to Merck: Gilead Sciences Inc. v. Merck & Co@Sofosbuvir

On December 15, 2016 federal jury finds patent infringement of Merck’s US 7,608,597 B2 and awarded $2.54 billion royalty to Merck against Gilead for using patented invention as the basis for its blockbuster drug Sofosbuvir. The jury said that Gilead owed 10 percent royalties on $25.4 billion in total sales for the two drugs.

Sofosbuvir is chemically known as 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-triphosphate and structurally represented as

Sofosbuvir.svg

US 7,608,597 B2 (issued to Idenix) claims a method for the treatment of a hepatitis C virus infection, comprising administering an effective amount of a purine or pyrimidine β-D-2′-methyl-ribofuranosyl nucleoside or a phosphate thereof, or a pharmaceutically acceptable salt or ester thereof.

US ‘597 filed as a continuation application from US 6,914,054 which claims priority of May 23, 2000. Sofosbuvir claimed as a product in US 7,964,580 B2 which claims priority of 30 Mar 2007.

The claims of US ‘597 are broad, any pyrimidine β-D-2′-methyl-ribofuranosyl nucleoside or a phosphate compounds for the treatment of HCV infection falls within the scope of US ‘597. US ‘597 neither discloses nor enables Sofosbuvir specifically.

Gilead Arguments for invalidity of US ‘597

Gilead’s argued that Merck patent is invalid as the specification of the US ‘597 patent does not enable the asserted claims (or) as the specification of the US ‘597 patent does not contain an adequate written description of the asserted claims (or) as the for anticipation based on prior invention (or) the claimed subject matter would have been obvious to a person of ordinary skill in the art at the time of the claimed invention. The jury rejected Gilead’s arguments that Merck’s patent is invalid.

The verdict  doesn’t affect Gilead to sell its products. The sales of Gilead’s Sovaldi and Harvoni (developed by pharmasset; later acquired by Gilead) accounts for more than half the Gilead’s revenue.

This is the second trial between the two companies. The first, over different patents, ended in a disaster for Merck. A jury in California said that Gilead should pay $200 million in royalties, but that was thrown out because the judge said a key Merck witness lied. In that case, Merck may have to pay Gilead’s legal fees.

Paragraph IV Patent Certifications

On December 16, 2016 FDA has announced that it received Abbreviated New Drug Application’s (ANDA; U.S.C. § 355(j)(2)(A)(vii)(IV)) containing a “Paragraph IV” patent certification for the following drugs.

Drug Name  Dosage Form  Strength  RLD  Date of Submission
Aspirin and Omeprazole Delayed-release Tablets 81 mg/40 mg and 325 mg/40 mg Yosprala 10/13/2016
Buprenorphine Hydrochloride Buccal Film 75 mcg and 150 mcg Belbuca 10/24/2016
Difluprednate Ophthalmic Emulsion 0.05% Durezol 5/1/2014
Treprostinil Extended-release Tablets 0.25 mg and 1 mg Orenitram 5/19/2016

FDA Approves Anacor Pharmaceuticals Eucrisa (Crisaborole)

On December 14, 2016, the U.S. Food and Drug Administration approved Eucrisa (Crisaborole) ointment to treat mild to moderate eczema (atopic dermatitis) in patients two years of age and older. The structure of Crisaborole is given below:

crisa1

Anacor Pharmaceuticals (acquired by Pfizer) is a biopharmaceutical company focused on discovering, developing and commercializing novel small-molecule therapeutics.

Anacor’s first approved product, KERYDIN® (tavaborole) topical solution, 5%, is an oxaborole antifungal approved by the U.S. Food and Drug Administration in July 2014 for the topical treatment of onychomycosis of the toenails. Tavaborole and Crisaborole are structural analogs.

Crisaborole (AN2728) is patented in US 8,039,451 B2 which is set to expire on June 11, 2026 (including PTA). However, the term may extended due to Patent term extension.

BMS bags a patent for its HCV trial drug

BRISTOL-MYERS SQUIBB COMPANY has filed an Indian patent application IN 9336/DELNP/2008 claiming cyclopropyl fused indolobenzazepine compounds which covers Beclabuvir (BMS-791325) an antiviral drug for the treatment of hepatitis C virus (HCV) infection currently in clinical trials. Beclabuvir acts as a NS5B inhibitor.

india drug

IN ‘9336 was entered in India through PCT/US2007/068209 (published as WO 2007/136982), a hearing was offered to applicant on January 22, 2016 regarding the objections raised by the examiner.

Applicant has made his observations / arguments and filed amended set of claims, the examiner was satisfied with respect to all the objections raised previously and allowed the application for grant containing 16 claims, as of now there is no patent number assigned for this application. The decision can be find here.

Allergan v. Valeant pharmaceuticals @XIFAXAN 550 mg ANDA

As days goes on, the problems for Valeant Pharms were keep on increasing, wherein the company, already had a major down fall at stock market and now the company stated that it has received a Paragraph IV Notification for Xifaxan.

Drug-dollars_crop-219x300

On February 23, 2016, FDA has announced that it has received an Abbreviated New Drug Application (ANDA) containing a “Paragraph IV” patent certification to market a generic copy of XIFAXAN 550mg.

Allergan announced that the Company has received an Acceptable for Filing letter from the U.S. Food and Drug Administration (FDA) for its Abbreviated New Drug Application (ANDA) seeking approval to market Rifaximin Tablets, 550 mg, which is indicated for the treatment of irritable bowel syndrome with diarrhea (IBS-D) in adults and the reduction in risk of overt hepatic encephalopathy (HE) recurrence in adults.

Valeant Pharma’s Patent portfolio

As it is already known that Valeant has adopted a policy of aggressive acquisitions, which have resulted in its sales growth. The company got complete rights over Salix Xifaxan after it acquired Salix Pharms.

On Mar 24, 2010 Salix received FDA approval for its XIFAXAN 550 mg, several exclusivities such as NP and ODE were granted by FDA for this product.

Currently , there are several patents listed in Orange Book for XIFAXAN 550 mg which are all set to expire in between 2019-2029.

Valeant have several key products in its product portfolio such as Jublia (efinaconazole) and Xifaxan (rifaximin) etc.,

As of date there are no patent infringement filed by Valeant under 35 USC § 271(e)(2) against the Allergan (Actavis), the due date for initiating patent infringement seems to be end by April 13, 2016.

In 2014 Valeant failed to acquire Allergan, which was later acquired by Actavis.

For the 12 months ending December 31, 2015, XIFAXAN® 550 mg had total U.S. sales of approximately $975 million.

A specification is not required to describe each and every embodiment of a claim; Opinion In Merck v. Watson

On Aug 31, 2015 Judge Andrews stated that Watson was failed to prove by clear and convincing evidence that claim 4 of the U.S. Patent No. 6,441,168 (“the ‘168 patent”) is invalid. C.A. Nos. 13-978 – RGA & 13-1272-RGA

US dol

Background:
Watson filed two Abbreviated New Drug Applications seeking approval to engage in the commercial manufacture, importation, use, or sale of generic versions of Safyral® and Beyaz® (Drospirenone; Ethinyl Estradiol; Levomefolate Calcium). Merck and Bayer (Plaintiff) filed a suit against Watson Laboratories (Defendant) alleging infringement of US ‘168 patent. The infringement action centers on one ingredient of the proposed drugs (Levomefolate Calcium), the Type I crystal form of calcium 5-methyl-(6S)-tetrahydrofolate (“MTHF”).

US ‘168 claims Type I crystalline form of calcium salt of 5-methyl-(6S)-tetrahydrofolic acid, having a water of crystallization of at least one equivalent per equivalent of 5-methyltetrahydrofolic acid. Further, this patent also claims a process for the conversion of type I to type II, III & IV crystals.

The above lawsuit was mainly brought on the infringment of claim 4 of US ‘168, wherein the claim 4 of the patent recites: A crystalline calcium salt of 5-methyl-(6S)-tetrahydrofolic acid with 2 theta values of 6.5, 13.3, 16.8, and 20.1 (Type I) said crystalline salt having a water of crystallization of at least one equivalent per equivalent of 5-methyltetrahydrofolic acid.

Watson Arguments & the Final Decision:
Watson argued that claim 4 is invalid under the following grounds:
i) 35 U.S.C. § 102(b)-Disclosures made 1 year or less before the effective filing date of the claimed invention;
ii) 35 U.S.C. § 102(a)-lack of novelty;
iii) 35 U.S.C. § 103(a)-obviousness; and
iv) 35 U.S.C. § 112-lack of written description.

Ground I:
The ‘168 patent was filed in Apr 2000 claiming the priority from Apr 1999 and the patent was issued on August 27, 2002. Watson argues that Merck and Weider Nutrition International were exploring a strategic partnership to introduce dietary supplements with Merck ingredients into the United States, IN Sep 1998 Merck wrote to Weider saying that the MTHF to be delivered would be from Lot ESF-118. Merck stipulated that

1) Lot ESF-118 is within the scope of claim 4 of the ‘168 patent;
2) the x-ray diffraction pattern of Lot ESF-118 is disclosed in Figure 1 of the patent; and
3) the x-ray diffraction pattern of Lot ESF-118 was obtained by Merck at least as of August 25, 1998.

By showing the above statements Watson argued that the MTHF was actually ready for patenting by September 1998, and it also argued that the September 9, 1998 and September 16, 1998 communications constitute a commercial sale.

Merck argued that there was no commercial sale or offer for sale in light of§ 5.2 of the CDA was maintained.

Ground II:
Watson argued that claim 4 of the ‘168 patent is anticipated by the US 5,350,850 (‘850 patent). Watson maintains that Example 3 of the ‘850 patent details a method of obtaining a crystalline pentahydrate of MTHF. Watson further argued that the ‘850 product had a moisture content of 15.27%, which corresponds to a pentahydrate, wherein the Type I crystal is the only currently known pentahydrate polymorph of MTHF.

Merck argues that the ‘850 product and the claim 4 crystals have different solubilities, and it further argued that Watson did not followed the ‘850 process to produce the final API.

Ground III & IV:
Watson argues that claim 4 is obvious in light of the ‘850 patent alone or in combination with U.S. Patent No. 5,006,655 (the ‘655 patent). The ‘655 patent discloses the pentahydrate calcium MTHF. Watson argues that a person of skill in the art would have a reasonable expectation of producing Type I crystals by combining the pentahydrate calcium MTHF with the recrystallization process taught in the ‘850 patent. Watson maintains that crystalline MTHF was known and preferred, and there was motivation in the industry to find and characterize crystalline forms.

However, Watson has not demonstrated that a person of skill in the art would have a reasonable expectation of success of producing Type I crystals in light of the prior art.

Further, Watson argues that claim 4 lacks written description because the specification does not disclose any information from which a person of skill could conclude that the inventors possessed an MTHF polymorph with one water of crystallization.

Merck responds that the patent states, “the Type I modification typically contains ≥3 equivalents of water.” “Typically” is not limiting, meaning that sometimes Type I crystals have fewer than three waters of crystallization.

After considering the hearings from both the parties the Judge stated that Watson did not prove by clear and convincing evidence that claim 4 of the ‘168 patent is invalid. Merck is directed to submit an agreed upon final judgment within two weeks.