Paragraph IV Patent Certifications

FDA has updated Paragraph IV patent certifications which includes P-IV for  BristolMyers Squibb’s anticoagulant drug Apixaban

Drug Name Dosage Form Strength RLD Date of Submission
Apixaban Tablets 2.5 mg and 5 mg Eliquis 12/28/2016
Ivermectin Cream 1% Soolantra 12/30/2016

Apixaban product info

Apixaban is a Factor Xa inhibitor developed by BMS which received FDA approval in December 2012, marketed under the brand name ELIQUIS. The drug is patented generically and specifically. The following table represents the OB status for Apixaban. NCE is set to expire on Dec 28, 2017.

Patent No Patent Expiration Remarks Remarks
US 6,413,980

Priority: Dec 23, 1998

Publication date: Jul 6, 2000 (PCT of US ‘980)

Dec 22, 2019 Claims Apixaban generically Must be P-III with respect to this patent, as this patent is expiring in 2019.
US 6,967,208

Priority: Sep 21, 2001

December 28, 2026 (including PTE request) Claims Apixaban Specifically Coalition For Affordable Drugs has challenged this patent at PTAB via an IPR, the trial got denied by PTAB.
US 9,326,945 Feb 24, 2031 Claims pharmaceutical composition

There are total 24 DMF’s available for Apixaban.


AstraZeneca’s ONGLYZA product patent is not invalid due to obviousness

United States District Court For The District Of Delaware has issued a memorandum opinion in favour of Astrazeneca, which states that Saxagliptin product patent is not invalid due to obviousness.

Saxagliptin product description:
Saxagliptin(BMS-477118) is a once-daily, oral CD26 antigen (dipeptidyl peptidase IV, DPP IV) inhibitor discovered by Bristol-Myers Squibb and patented through USRE44186 E1 (reissue of 6,395,767).

Saxagliptin was developed by Bristol-Myers Squibb in collaboration with AstraZeneca for the treatment of type 2 diabetes mellitus (T2DM). However, AstraZeneca subsequently acquired all rights to the drug from Bristol-Meyers Squibb.

Saxagliptin FDA approval information:
FDA approved Saxagliptin hydrochloride (N022350)tablets 2.5mg and 5mg on Jul 31, 2009, which is marketed by Astrazeneca under the trade name ONGLYZA.

FDA also approved Saxagliptin hydrochloride and Metformin hydrochloride combination (N200678) on November 5, 2010, which is also marketed by Astrazeneca under the trade name KOMBIGLYZE XR.

US RE44186 is listed in Orange Book for ONGLYZA and KOMBIGLYZE, US ‘186 claims Saxagliptin and its salts including hydrochloride salt, US ‘186 is set to expire in July 2023 including PTE.

ANDA litigations:
On July 31, 2013 ANDA with a paragraph IV certification has been filed to market generic version of ONGLYZA and KOMBIGLYZE XR.

In 2014 Astrazeneca sued several generic companies such as Aurobindo, Wockhardt, Watson, Actavis, Sun Pharma, Mylan, Amneal under the patent infringment of US ‘186, US 7,951,400 and US 8,628,799. Stipulations were filed and all the claims concerning the ‘400 and ‘799 patents (formulation patents) were dismissed.

All the lawsuits were consolidated and a three-day bench trial in this matter has been held on September 19 through September 21, 2016. Defendants stipulated to infringement of all asserted claims. Thus, the sole issue is defendants obviousness defense with respect to the RE’186 patent.

The structure of Saxagliptin is given below:


The defendants has argued that the RE’186 patent is obvious in light of the prior art and the asserted claims of the RE’186 patent are valid under 35 U.S.C.§ 103.

35 U.S.C.§ 103 states that a patent may not be obtained thought the invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which said subject matter pertains.

The defendants argued that the asserted claims were obvious for three reasons:

1) a person of ordinary skill in the art would have been motivated to select Vildagliptin as a lead compound;

2) a person of ordinary skill in the art would have been motivated to move the hydroxy admantyl group; and

3) a person of ordinary skill in the art would have added a cyclopropyl ring.
Vildagliptin is claimed as a product in US 6,166,063 B2 which claims the priority date as December 10, 1998, the publication date of its PCT equivalent WO 2000/034241 A1 is June 15, 2000, whereas the US RE’186 claims the priority date as Mar 10, 2000.
The structural difference between Saxagliptin and Vildagliptin is given below:
The major differences between the two moieties are highlighted in red colour.
The defendants argued that the POSA would have moved the hydroxyadamantyl group from the nitrogen of the glycine to the alpha-carbon of the glycine in order to improve potency. Dr. Powers testified that a person of ordinary skill would have been motivated to do so because the prior art taught that DPP4 preferred bulky groups, with a free amino group, at its P2-substrate binding pocket. (Tr.79:13-14 (Powers).)
According to defendants a POSA would have been motivated to make this modification for three reasons directed to increasing the potency of the molecule:
(1) primary  amines more closely resemble the natural substrates for DPP4,
(2) beta-branching was known to increase potency, and
(3) primary amines were generally more potent than secondary amines.
Specifically, the defendants relies on the teachings of Mentlein and Ashworth I. Mentlein disclosed that natural substrates of DPP4 enzymes are peptides with primary amines at N-terminus. Ashworth I taught that the most potent, reversible DPP4 inhibitors were primary amines.

AstraZeneca responds that there was no such motivation and no reasonable expectation of success in making this modification.

The court found that Dr. Powers failed to show a motivation to move the hydroxadamantyl group of his lead compound with any reasonable expectation of success (cited Medichem, S.A. v. Rolablo).

The court also stated that Dr. Powers failed to explain why a POSA would introduce the problem of instability into a DPP4 inhibitor by moving from N-linkage to C-linkage and then adding a cyclopropyl group to solve the newly created stability problem. The combination of “several sequential modifications” is not obvious where there is no reason in the prior art to make the subsequent modification (cited Pfizer Inc., v. Mylan Pharm. Inc) and also stated that the defendants has not shown a motivation to try cyclopropanation.

AstraZeneca highlighted that there were no data available to show the effect of cyclopropanation on the stability of a DPP4 inhibitor, because no one other than the inventors proposed cycloproponation in the context of DPP4 inhibitors.

After the above arguments of the both the parties the court has stated that the defendants failed to present a primafacie case that the asserted claims of the patent-in-suit are invalid as obvious.

The court further denies AstraZeneca’s request for an award of attorney’s fees.
Apart from ANDA litigations there are several IPR’s filed by pharma companies such as Mylan, Wockhardt, Amnea, Aurobindo and Teva challenging the validity of US RE44186. PTAB has ordered to institute the IPR’s.

Anhydrous vs Monohydrate@Mometasone furoate

The District Court Of Delaware has ordered in favour of Amneal Pharmaceuticals LLC, and stated that Amneal’s product (generic Mometasone furoate nasal spray) does not infringe Merck Sharp’s US 6,127,353 which is listed in Orange book for Nasonex.


Amneal filed ANDA 207989 to produce and market a generic Mometasone furoate nasal spray; On March 20, 2015 Merck sued Amneal alleging infringement of US 6,127,353.

US ‘353 claims Mometasone furoate monohydrate and composition comprising Mometasone furoate monohydrate.

Amneal’s ANDA contains MFA (Anhydrous Mometasone furoate) as the active pharmaceutical ingredient, wherein Merck contends that the MFA in Amneal’s product will eventually convert to MFM (Mometasone furoate monohydrate). MFA and MFM are polymorphs. MFM differs from MFA in that every molecule of MFM is associated with a molecule of water, whereas no water is present in the crystal lattice structure of MFA.

Amneal produced several samples of finished product form containing MFA and produced samples of its ANDA product to Merck (Batch 16001 Day 1 samples).

Merck’s expert, Dr. Matzger conducted a thermodynamic stability test “to establish the thermodynamic stability of the monohydrate relative to the anhydrous form.”

He added an amount of MFM equal to the amount of MFA in one of the sample bottles from the Exhibit Batches and subjected the bottle to vigorous shaking at 500 RPM. After 27 days, all of the MFA had converted to MFM.

He explained that shaking “increase[s] mass transport” to help the conversion from the “less stable form to the more stable form” and “break up the viscosity” of the suspension.

Dr. Matzger concluded that “the monohydrate is the more stable form in the environment of Amneal’s formulation.” He testified that the study established that “conversion will occur,” but not “when it will occur.” He further explained that he “intentionally added [MFM] so that the conversion could take place with both forms present, and he wouldn’t know if [MFM] would become present or when it would become present if he hadn’t added it;” a person of skill in the art would “need to know all of those things to say what the rate would be in the proposed ANDA product.”

Merck’s expert Dr. Bernhardt Trout stated that it is “very difficult to make predictions” on how mixing would affect a specific system, and “to verify in a given sample whether there was conversion, it needs to be tested empirically.

Consideration of Raman Spectroscopy to identify the presence of MFM in Amneal’s product:
Raman spectroscopy is a vibrational spectroscopy technique, which looks at the way a molecule vibrates in a crystal.

IR when performed MFM has a characteristic peak around 1709 cm-1, MFA has a characteristic peak at 1725 cm-1, and the two polymorphs share a peak in the range of 1640-1680 cm-1

Dr. Matzger tested seven slides prepared from one bottle of Batch 16001 Day 1 and the obtained spectra indicates the presence of both MFM and MFA in the said sample. Dr. Matzger testified that he could not see any other characteristic peaks for MFM “because of the signal to noise limitation.”

Amneal’s expert, Dr. Brian Marquardt disagree with Dr. Matzger conclusion about the presence of MFM in Batch 16001 Day 1, and analyzed the Dr. Matzger spectra and opined that a “shoulder peak” indicative of MFA “could be easily misinterpreted … as a peak in that space and be misrepresented as MFM”. He further explained that the spectra show that “this is primarily the MFA form, which is indicated by the secondary doublet and the primary peaks … , which are indicative of both forms and opined that Dr. Matzger misinterpreted the data as MFM.” He concluded that MFM was not present.

According to Dr. Matzger a single peak is sufficient to identify MFM in the ANDA product. As per Dr. Marquardt three peaks are generally used to identify a polymorph in an unknown sample. The court concluded (based on expert testimony) that at least three peaks on a spectra must be used to identify material based on accepted practices.

Merck offers Dr. Matzger’s testing of Batch 16001 Day 1 as persuasive evidence of MFM in Amneal’s ANDA product. Merck criticizes Dr. Marquardt’s testing, arguing that such testing is insufficient to prove a negative – that MFM is not present in the ANDA product.

After the above representation’s of both the parties the court concluded that Dr. Matzger’s testimony and Merck’s related arguments are self-serving, i.e., essentially arguing that Dr. Matzger’s testing is “more and better,” therefore, only his opinion should be believed. The court is not so convinced, and finds Dr. Marquardt’s testimony at least as consistent and credible. Weighing the evidence at bar (lack of MFM in the 16001 Batch Day 1 ), the court concludes that Merck has not carried its burden to prove, by a preponderance of the evidence, that MFM is present in Amneal’s ANDA product during its two-year shelf life.

Paragraph IV Patent Certifications

On January 30, 2017, FDA published Paragraph IV patent certifications to the following drugs.

Drug Name Dosage Form Strength RLD Date of Submission
Aprepitant for Oral Suspension 125 mg/Kit Emend 11/23/2016
Liraglutide Injection 18 mg/3 mL prefilled syringe Victoza 12/12/2016

I. The following patents are listed for Emend (Oral Suspension) in Orange Book

Patent No Patent Expiration Remarks
6,096,742 Jul 1, 2018 Relates to polymorphic Forms I and II of Aprepitant
8,258,132 Sep 26, 2027 Relates to composition comprising Aprepitant with a specific particle size diameter

II. The following patents are listed for Victoza in Orange Book

Patent No Patent Expiration Remarks
6,004,297 Jan 28, 2019 Relates to an injection syringe for apportioning set doses of a medicine from a cartridge
6,268,343 Aug 22, 2022 (inclusive of PTE) Relates to product
6,458,924 Aug 22, 2017 Relates to product
7,235,627 Aug 22, 2017  Relates to product
8,114,833 Aug 13, 2025 Relates to Formulation and MOT
8,846,618 Jun 27, 2022 Relates to Formulation and a process for its preparation
9,265,893 Sep 23, 2032  Relates to Technology
RE41956 (6,582,404) Jan 21, 2021  Relates to Technology
RE43834 Jan 28, 2019  Relates to Technology

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.


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).

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:


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.

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:


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.

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.


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

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.