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.

Background:
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:

new-picture-4

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:
image
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.

Background:

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.

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).

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.

Helsinn Healthcare v. Dr. Reddy’s Laboratories@Palonosetron HCl: Patent Trial and Appeal Board

Patent Trial and Appeal Board (PTAB) accepted Dr.Reddy’s Laboratories Inter Partes Review petitions IPR2015-01550, IPR2015-01551, IPR2015-01553 and IPR2015-01554 against claims 22-27 and 30 of US  patent no. 8,729,094 which is owned by Helsinn Healthcare.

dollar

Palonosetron HCl and its patent litigations:
Palonosetron is a serotonin-3 (5-HT3) receptor antagonist indicated in adults for:
i) Moderately emetogenic cancer chemotherapy prevention of acute and delayed nausea and vomiting associated with initial and repeat courses (1.1);
ii) Highly emetogenic cancer chemotherapy prevention of acute nausea and vomiting associated with initial and repeat courses (1.1);
iii) Prevention of postoperative nausea and vomiting (PONV) for up to 24 hours following surgery.

Helsinn Healthcare received FDA approval on Jul 25, 2003 to market Palonosetron HCl injectable; intravenous (EQ 0.075mg base/1.5ml (EQ 0.05mg base/ml) EQ 0.25mg base/5ml (EQ 0.05mg base/ml)) under the brand name Aloxi.

Palonosetron is patented in US through US 5,202,333 A which is set to expire on Oct 13, 2015 (including PED) which is listed in orange book. Further, there are other patents which claims formulations are also listed in orange book.

ANDA litigations:
Several ANDA’s has been received by FDA which were filed by generic companies for seeking approval to market the generic version of Aloxi. Helsinn sued the ANDA filers. However, Teva, Dr.Reddys and Sandoz has received Tentative Approvals for generic version of Palonosetron HCl.

Helsinn Healthcare v. Dr.Reddy’s labs:
Reddy’s labs filed an ANDA (201533 & 203050) under § 505(j)(2)(A)(vii)(IV). ANDA No. 201533 seeks the FDA approval necessary to engage in the commercial manufacture, use, sale, offer for sale, and/or importation of generic 0.25mg/5mL and 0.075mg/1.5mL Palonosetron HCl intravenous solutions prior to the expiration of the US 7,947,724, US 7,947,725, US 7,960,424, US 8,518,981, US 8,598,218, US 8,598,219, and US 8,729,094 patents. Helsinn sued Reddy’s labs (and also sued other generics like Sandoz and Teva with the same patents) under the infringement of the ’US ‘724, US’725 (3:11-cv-03962), US ‘424 (3:11-cv-05579), US ‘094 (3:14-cv-04274), US ‘218, US ‘219 and US ‘981 (3:13-cv-05815) under 35 U.S.C.§ 271(e)(2)(A). All of these cases are before The Honorable Judge Cooper in the U.S. District Court for the District of New Jersey.

Before PTAB:
The present IPR petitions has been filed against the claims 22-27 and 30 of the US ‘094 patent on the grounds of obviousness.

Claim 22 comprises a method for reducing the likelihood of cancer chemotherapy-induced nausea and vomiting, comprising intravenously administering to a human in need thereof a pharmaceutical single-use, unit-dose formulation comprising a 5 mL sterile aqueous isotonic solution buffered at a pH of about 5.0+0.5, said solution comprising: about 0.05 mg/mL Palonosetron HCl based on the weight of its free base; and a tonicifying effective amount of mannitol; wherein said solution optionally comprises one or a combination of a citrate buffer and a chelating agent, wherein said formulation is stable at 24 months when stored at room temperature, and wherein said intravenous administration to said human occurs before the start of the cancer chemotherapy.

Claims 23-27 and 30 are dependent on claim 22.

Reddy’s argued that the above claims of US ‘094 Patent are taught, either expressly or inherently, in the prior art, or are obvious in view of the prior art.

The following documents have been opted as a prior art in the present case (imp considered):
i) Berger’s U.S. Patent No. 5,202,333 which claims Palonosetron and described the synthesis of the molecule, and various analogs, and it provided some basic information about how Palonosetron could be formulated and used;

ii) Chelly’s Abstracts of Scientific Papers 1996 Annual Meeting, 85 Anesthesiology, No. 34, A21 (Sept. 1996) which discloses results of a completed Phase II clinical study in humans where Palonosetron was administered orally to 351 patients to prevent postoperative nausea and vomiting (“PONV”) following laparoscopic surgery, dosed at 0.3, 1.0, 3.0, 10.0, and 30μg/kg [0.021mg, 0.07mg, 0.21mg, 0.7mg, and 2.1mg] or placebo;

iii) Tang’s The Efficacy of RS-25259, a Long-Acting Selective 5-HT3 Receptor Antagonist, for Preventing Postoperative Nausea and Vomiting After Hysterectomy Procedures, which discloses preliminary efficacy of Palonosetron in a second Phase II clinical study;

iv) Zofran’s In Physician’s Desk Reference 1503-07 (55th ed.);

v) Avis et al., Parental Drug Administration: Routes, Precautions, Problems, complications, and Drug Delivery Systems and etc.,

Reddy’s argued that the invention claimed in claim 22-27 and claim 30 are obvious to a person skilled in the art in view of the combination of the teachings disclosed in the above prior art.

FDA: Recent Paragraph IV Patent Certifications

August 5, 2015, FDA announced that it received Abbreviated New Drug Application’s (ANDA) containing a “Paragraph IV” patent certification for the following drugs.

Drug Name Dosage Form Strength RLD Date of Submission
Carbidopa and Levodopa Extended-release Capsules 61.25 mg/245 mg Rytary 6/10/2015
Doxycycline Hyclate Delayed-release Tablets 80 mg Doryx 7/1/2015
Fidaxomicin Tablets 200 mg Dificid 5/27/2015
Oseltamivir phosphate Oral Suspension 6 mg/mL Tamiflu 6/18/2015
Phenylephrine and Ketorolac Injection 1%/0.3% Omidria 5/29/2015

para

Brief Description of the above Drugs:

i) Carbidopa and Levodopa:
Carbidopa is an aromatic amino acid decarboxylation inhibitor and Levodopa is an aromatic amino acid.

Rytary is a combination of Carbidopa and Levodopa which are approved for the treatment of Parkinson’s disease, post-encephalitic parkinsonism, and parkinsonism that may follow carbon monoxide intoxication or manganese intoxication. Impax Labs Inc is the NDA (N203312) owner for Rytary (23.75MG; 95MG, 36.25MG; 145MG, 48.75MG; 195MG, 61.25MG; 245MG capsule, extended release; oral) which was approved on Jan 7, 2015, and it also received NDF exclusivity which is going to expire on Jan 7, 2018. There are several patents listed for the above combination which are set to expire on Dec 26, 2028.

ii) Doxycycline Hyclate (80 mg):
Doxycycline belongs to tetracycline class of compounds. It is a broad-spectrum antibiotic of the tetracycline class that is useful for the treatment of a number of infections, including bacterial, protozoal and helminth. Doxycycline was developed by Pfizer which first received FDA approval in 1967, pfizer marketed Doxycycline under the brand name Vibramycin.

Doryx Capsules contain specially coated pellets of Doxycycline Hyclate in a delayed-release formulation for oral administration. Mayne Pharma Intl received FDA approval for its NDA 050582 (capsule, delayed release;oral EQ 75MG and 100MG of Doxycycline Hyclate base), in July 22, 1985 which was discontinued later. Further, on May 6, 2005 Mayne Pharma received FDA approval for its NDA 050795 (tablet, delayed release;oral EQ 50, 75, 80, 100, 150, 200mg of Doxycycline Hyclate base). There are 2 patent listed in orange book for DORYX, which are US 6,958,161 (Dec 15, 2022) and US 8,715,724 (Feb 3, 2028).

iii) Fidaxomicin:
Fidaxomicin is a narrow spectrum macrocyclic antibiotic drug. Cubist Pharmaceuticals received FDA approval on May 27, 2011 for its NDA 201699, which is currently marketing Fidaxomicin under the brand name Dificid. There are several patents listed in OB for Dificid which claims polymorphic forms and compositions and etc., NCE is going to expire on May 27, 2016.

iv) Oseltamivir Phosphate:
Oseltamivir Phosphate is an influenza neuraminidase inhibitor indicated for:
a) Treatment of acute, uncomplicated influenza in patients 2 weeks of age and older who have been symptomatic for no more than 2 days. (1.1)
b) Prophylaxis of influenza in patients 1 year and older. (1.2)

Roche received FDA approval to market Oseltamivir Phosphate as capsules containing 30 mg, 45 mg, or 75 mg Oseltamivir for oral use, in the form of Oseltamivir phosphate, and as a powder for oral suspension, which when constituted with water as directed contains 6 mg/mL Oseltamivir base. Tamiflu is the brand name of Oseltamivir Phosphate.

The related patents listed in OB for Tamiflu are going to expire in 2015-2017. Its interesting to see for which patent the paragraph iv has been filed.

v) Phenylephrine and Ketorolac:
Omidria (phenylephrine and ketorolac injection) contains is an alpha 1-adrenergic receptor agonist and nonselective cyclooxygenase inhibitor which are indicated for:
Maintaining pupil size by preventing intraoperative miosis, Reducing postoperative pain

Omidria received FDA approval on May 30, 2014 which is marketed by Omeros.

No Specific Personal Jurisdiction over Zydus in the Case of Novartis v. Zydus Novel Tech Inc

On Aug 07, 2015 The District Court Of Delaware granted Zydus novel tech inc (defendants) motion to dismiss the Novartis (plaintiff) complaint for lack of personal jurisdiction.

immage

Background:
Novartis (Plaintiff) filed a Hatch-Waxman patent infringement action against defendants Zydus Noveltech, Inc., Zydus Pharmaecuticals (USA) Inc., and Cadila Healthcare Ltd for infringing two patents for the “Exelon” transdermal system, which is used to treat dementia. Immediately after filing this case, Plaintiffs filed a parallel action in the District of New Jersey.

Exelon and its patent Litigation’s:
Exelon (Rivastigmine Tartrate) is an acetylcholinesterase inhibitor indicated for treatment of:
a)
Mild to moderate dementia of the Alzheimer’s type (1.1)
b)
Mild to moderate dementia associated with Parkinson’s disease (1.2).

Rivastigmine is chemically known as (S)-N-Ethyl-N-methyl-3-[1-(dimethyl amino)ethyl]-phenyl carbamate hydrogen-(2R,3R).

Rivastigmine was developed by Marta Weinstock-Rosin of the Department of Pharmacology at the Hebrew University of Jerusalem and sold to Novartis by Yissum for commercial development. It is a semi-synthetic derivative of physostigmine.

Novartis received FDA approval for Rivastigmine Tartrate (EQ 1.5MG, EQ 3MG, EQ 4.5MG and EQ 6MG base) on Apr 21, 2000. Further, it also received approval for its film, extended release;transdermal patch (4.6MG/24HR, 9.5MG/24HR and 13.3MG/24HR).

Several generic companies received FDA approval to sell generic version of Rivastigmine Tartrate Capsule;Oral EQ 1.5MG, EQ 3MG, EQ 4.5MG and EQ 6MG base.

From 2011 Novartis filed several ANDA suits against the generic companies in the court of Delaware:
i) 11-1077-RGA and 11-1112-RGA (Novartis v. Par pharma and Novartis v. Watson);

Present Scenario:
Zydus Noveltech sent its ANDA notice letter on July 16, 2014 to Novartis in Switzerland, Germany, and New Jersey. In return Novartis sued Zydus Noveltech in the court of Delaware for infringing two patents for the “Exelon” transdermal system, which is used to treat dementia.

The patents in suits are U.S. Patent No. 6,335,031 and US 6,316,023 which are set to expire on Jan 8, 2019.

Zydus Noveltech have moved to dismiss the complaint for lack of personal jurisdiction, as the Zydus Noveltech is a New Jersey corporation with a principal place of business in Vermont. Previously defendants Zydus Pharmaceuticals and Cadila also moved to dismiss the complaint for failure to state a claim under Federal Rule of Civil Procedure 12(b)(2), and Cadila moved to dismiss for insufficient service of process under Rule 12(b)(5). The Court granted a stipulation to dismiss the complaint against defendants Zydus Pharmaceuticals and Cadila.

Zydus Pharmaceuticals and Zydus Noveltech are sister companies, and Cadila is their ultimate parent company. The majority shareholder of Zydus Noveltech is Zydus International Private Ltd., a subsidiary of Cadila.

Novartis argued that there is specific jurisdiction over Zydus Noveltech for two reasons:
i) Zydus Noveltech directed its notice of ANDA filing to Novartis Pharmaceuticals, a Delaware corporation; and
ii) Zydus Noveltech will eventually, if authorized by the FDA, sell its generic product in Delaware.

Judge Andrews referred AstraZeneca AB v. Mylan Pharmaceuticals, Acorda Therapeutics, Inc. v. Mylan Pharmaceuticals which are similar type of cases.

After hearing the arguments the judge stated that the submission of the ANDA letter triggered an injury against Plaintiff. It does not follow that that injury should be where the Plaintiff is incorporated, Delaware, rather than where the letter was directed, New Jersey. Defendant directed activity to New Jersey, not Delaware.

Further, the court also stated that the act of filing the ANDA and the paragraph IV notification constitute an injury, neither was directed at Delaware because defendant sent its letter to plaintiffs abroad and in New Jersey. Therefore, this court cannot exercise specific personal jurisdiction over Defendant.

Continuation In Part (or) Divisional: Role of Section 121 Safe Harbor in G.D. Searle LLC v. Lupin Pharmaceuticals, Inc.,

The safe harbor provision of section 121 didn’t help Pfizer to save its reissued U.S. Patent No. RE44,048.

Recently the U.S. Court of Appeals for the Federal Circuit upheld a district court ruling that a reissue patent was invalid for obviousness-type double patenting. Case No. 14-1476.

Background:

Pfizer filed a patent infringement action against Teva Pharmaceuticals in the District Court for the District of New Jersey, wherein the district court held that Teva infringed three patents owned by Pfizer specifically,
i) claims 1-3, 7-9, 11, and 13 of U.S. Patent No. 5,466,823 (“the `823 patent”);
ii) claims 1-5 and 15-18 of U.S. Patent No. 5,563,165 (“the 165 patent”); and
iii) claims 1-4 and 11-17 of U.S. Patent No. 5,760,068 (“the `068 patent”).

The claims of the above patents related to Celecoxib (Celebrex®).

The district court also held that the asserted claims of the three patents were not invalid for a best mode violation and that the asserted claims of the `068 patent were not invalid for obviousness-type double patenting.

Further, Teva appeals the decision to the Federal Circuit which concluded that
i) the asserted claims of the US `068 patent are invalid for double patenting and reverse the district court on that aspect of its judgment;
ii) that claim 9 of the US `823 patent and claim 17 of the US `165 patent are not invalid for a best mode violation;
Finally, it affirm the district court’s judgment of infringement with respect to claim 9 of the `823 patent and claim 17 of the `165 patent.

In the above case Pfizer invoked the so called “safe harbor” provision of section 121 which in certain circumstances protects a patent that issues on a divisional application from invalidation based on a related patent that issued on an application as to which a restriction requirement was made, or on an application filed as a result of such a requirement.

In 2008 Pfizer filed U.S. Patent Application No. 12/205,319 (“the ’319 application”), seeking reissue of the ’068 patent, which sought to correct that alleged error by reissue. Pfizer has made the following changes to the US ‘068 patent (imp are given).
a) it deleted portions of the ’068 patent specification that were not present in the US 5,466,823 patent;
b) it designated the US ‘068 patent as a divisional of the US ‘823 patent and removed the priority claim to the US 5,521,207 patent.

Finally the examiner has allowed some technical errors; and also allowed to make additional changes, including designating the US ’068 patent issued as a divisional of the US ‘823 and removing subject matter not present in the US ‘823 patent. Finally in 2013 USPTO issued reissued patent RE44,048 for US ‘068.

On the day the RE ’048 patent issued, Pfizer filed the instant case against five generic drug manufacturers, alleging infringement of the RE ’048 patent. However, the court found that the RE ’048 patent was not a valid reissue patent, because Pfizer’s asserted error of prosecuting a prior patent application as a continuation-in-part, rather than as a divisional, was not correctable by reissue under section 251. The court further found that the safe harbor provision of 35 U.S.C. § 121 did not apply to the RE ’048 patent, and that the relevant claims of the RE ’048 patent were invalid for obviousness-type double patenting in light of the ’165 patent. A final judgment of invalidity was entered against Pfizer. This appeal followed.

In the Federal Circuit, the parties submitted their arguments. Finally the Federal Circuit concluded that the section 121 safe harbor provision does not apply to the RE ’048 patent, and AFFIRMED the district courts decision.

The following diagram can help to understand the above case.

image 3

Allergan v. Sandoz@Bimatoprost: CAFC

On August 04, 2015 before Circuit Judges LOURIE, LINN, and HUGHES, United States Court of Appeals for the Federal Circuit Affirm the decision of District Court of Eastern District of Texas, which held that the asserted claims of Allergan’s US ’504, ’605, and ’479 are not invalid for obviousness or for lack of an adequate written description and enablement. The decision can be find here.

Background:

Sandoz, Lupin, Hi-Tech, and Watson each submitted an Abbreviated New Drug Application (“ANDA”) to the FDA, seeking approval to engage in the commercial manufacture, use, importation, sale, or offer for sale of generic versions of Lumigan (Bimatoprost) 0.01% prior to the expiration of the US 7,851,504, 8,278,353, 8,299,118, 8,309,605, and 8,338,479 patents. In response, Allergan sued each of the ANDA applicants in the United States District Court for the Eastern District of Texas, asserting that their ANDA filings infringed those patents. The district court consolidated those actions into one case.

About Lumigan:
In 2001, the FDA approved Lumigan® 0.03%, a once daily topical solution developed by Allergan, for treating open angle glaucoma and ocular hypertension. Lumigan 0.03% contains 0.03% by weight of Bimatoprost and 50 parts per million (“ppm”) benzalkonium chloride (“BAK”), among other ingredients.

Although Lumigan 0.03% was effective at lowering IOP, it also caused frequent and severe hyperemia. Many patients thus stopped using it without consulting their physicians, which led to gradual vision loss. To address that problem, Allergan explored a number of alternative formulations of Bimatoprost and surprisingly discovered that increasing the concentration of BAK from 50 ppm to 200 ppm significantly increased the corneal permeability of Bimatoprost. After further research, Allergan developed Lumigan® 0.01% (“Lumigan 0.01%”).

Lumigan® 0.01% contains 0.1 mg/mL of Bimatoprost and benzalkonium chloride 0.2 mg/mL with other excipients. Lumigan is a prostaglandin analog indicated for the reduction of elevated intraocular pressure in patients with open angle glaucoma or ocular hypertension. Lumigan 0.01% is approved (NDA: N022184) to Allergan on Aug 31, 2010. Allergan expects net sales of Lumigan between $590 million and $620 million.

There are several patents listed in Orange Book for Bimatoprost. The patents in lawsuit are US 7,851,504 (Jun 13, 2027), US 8,278,353, US 8,299,118, US 8,309,605 and US 8,338,479 which all are OB listed for Bimatoprost. The above said patents claims various compositions of Bimatoprost.

Allergan (plaintiff) v. Sandoz, Lupin, Hi-Tech Pharmacal CO (Defendants) @Texas:
After Allergan sued Sandoz and others in the district court, the  district court held a five-day bench trial in July 2013 on the issues of obviousness and infringement. The defendants argued that the claims were invalid for lack of written description and enablement in pre- and post-trial briefings.

The defendants argued that Woodward disclosed a formulation comprising 0.001%–1% Bimatoprost and 0–1000 ppm BAK for treating glaucoma, and that the amounts of Bimatoprost and BAK in the claimed formulation fall within those prior art ranges, thus rendering the claims obvious.

The cited prior art is:

1) Woodward’s US 5,688,819; and
2) Lyons’s US 6,933,289.

After going through the factual findings, the district court concluded that the asserted claims would not have been obvious. In reaching that conclusion, the court emphasized that the prior art taught away from the claimed invention because it taught:

1) that Bimatoprost lost efficacy as its concentration decreased;
2) that BAK had no impact on Bimatoprost’s permeability; and
3) that BAK was cytotoxic and could cause corneal disorders.

The district court also rejected the defendants’ invalidity challenges based on the written description and enablement requirements and it states that each of the ANDA products infringed each of the asserted claims.

Further, the defendants timely appealed (2014-1275) the decision to Federal Circuit and Hi-Tech also challenges the district court’s finding that it infringed the claims of the ’504, ’605, and ’479 patents literally and under the doctrine of equivalents.

Hi-Tech argued that it’s ANDA specifies that the proposed product has a pH of 6.8–7.2 during the product’s shelf life. And it also argues that the district court erred in construing a “pH of about 7.3 and also erred in finding that Hi-Tech literally infringed the Group I claims and that prosecution history estoppel did not bar Allergan from relying on the doctrine of equivalents to prove infringement.

Finally, the judges of CAFC reviewed the district court’s decision and its findings, after considering the arguments the Federal Circuit made the following points:

i) Rejected the Appellants’ argument that the unexpected results do not support nonobviousness because they are merely the inherent properties of an otherwise obvious formulation;
ii) The specifications of the asserted patents provide an adequate written description of the invention;
iii) The asserted claims are not invalid for lack of enablement;
iv) The district court did not clearly err in finding that Hi-Tech literally infringed the Group I claims and that Hi-Tech infringed the claims of the US ’504, ’605, and ’479 patents.

FDA: Paragraph IV Patent Certifications

On July 21, 2015 FDA announced that it received Abbreviated New Drug Application’s (ANDA) with a “Paragraph IV” patent certification for the following drugs.

Drug Name Dosage Form Strength RLD Date of Submission
Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate Tablets 200 mg/25 mg/300 mg Complera 5/20/2015
Memantine HCl Extended-release and Donepezil HCl Capsules 14 mg/10 mg and 28 mg/10 mg Namzaric 5/18/2015

About Complera:

Complera is a combination of two nucleoside analog HIV-1 reverse transcriptase inhibitors (Emtricitabine and Tenofovir Disoproxil Fumarate) and one non-nucleoside reverse transcriptase inhibitor (Rilpivirine), which was approved to Gilead Sciences INC on Aug 10, 2011. The product was approved to treat HIV-1 infection in adult patients with no antiretroviral treatment history and with HIV-1 RNA less than or equal to 100,000 copies/mL at the start of therapy. The combination is protected by related patents which are listed in the OB, NCE is going to expire on May 20, 2016 and NPP is going to expire on Dec 13, 2016.

About Namzaric:

Namzaric is a combination of Memantine HCl extended-release, a NMDA receptor antagonist, and Donepezil HCl, an acetylcholinesterase inhibitor, indicated for the treatment of moderate to severe dementia of the Alzheimer’s type in patients. The combo was approved to Forest Labs LLC on Dec 23, 2014.