Litigating Infringement of Different Types of Pharmaceutical Claims

Workshop on litigation strategies in Pharmaceutical Patents by Linda Liu &

Partners , Beijing China.18- 20 May, 2012.

Pravin Shejul, M.Sc., Ph.D. (LL.B.)

Types of Claims•Compound•Composition•Method of Treatment•Process of Manufacture•Method of [mediating a biological

pathway]•Kit claims

Types of Infringement• Statutory § 271(e)(2)(a)

▫ Filing of an ANDA• Direct § 271(a)

▫ Make, use, sell, offer to sell, import• Inducement § 271(b)

▫ Aid and abet direct infringement, requiring Knowledge intent

• Contributory § 271(c)▫ offer to sell, sell, or import a material component of a

patented machine, manufacture, combination, or composition knowing the same to be especially made for use in an

infringement of such patent, and not a staple article of commerce Having no substantial noninfringing use

Types of Infringers

API manufacturersFinished drug product

manufacturersimporters

wholesalersPharmacies

DoctorsPatients

Compound Claims•A compound of Formula I, wherein . . . •Typically the broadest of the claims, but

usually ▫the earliest filed ▫the earliest to expire▫the subject of PTE ▫the most difficult to invalidate or avoid▫the basis of a product LCM strategy

Compound Claims•Frequent challenges under 102, 103, 112•Although 2006 KSR case relaxed

standards for obviousness, still difficult to invalidate compound claims as obvious

•BUT – challenging compound claims under Section 112 increasingly successful

Structural Obviousness of Compound Claims post-KSR

Consider the following case studies:•Aciphex® (rabeprazole sodium)•Actos® (pioglitazone)•Protonix® (pantoprazole)•Famvir® (famciclovir)

Aciphex® (rabeprazole sodium)•Patented compound

is rabeprazole sodium, a proton pump inhibitor that suppresses gastric acid production by inhibiting action of the enzyme H[+]K[+]ATPase

Aciphex® (rabeprazole sodium)

• Teva selected lansoprazole as the lead compound for an obviousness-based invalidity argument

• Lower court rejected lansoprazole as lead compound even though it was structurally the closest

Eisai v. Dr. Reddy’s Lab’s, Inc.,2008 U.S. App.LEXIS 15399 (Fed. Cir. July 21, 2008)

Aciphex® (rabeprazole sodium)•Lansoprazole is an ulcer-treating

compound•Because of the differences between anti-

ulcer activity and gastric acid inhibiting activity, the closest structural compound was not the starting point for an obviousness analysis

Actos® (pioglitazone)

N O

NH

S

O

O

C2H5

N O

NH

S

O

O

H3C

• thiazolidinedione used for treating diabetes

Closest prior art contained a methyl group at an adjacent ring position

Actos®Compound b

Actos® (pioglitazone)•No motivation to start with compound b

even though an adjacent homologue•Two other prior art references taught

away from the use of compound b

Takeda v. Alphapharm, et al., 492 F.3d 1350 (Fed. Cir. 2007)

Protonix® (pantoprazole)

NH

NOF

FS

O

N

O O

NH

NOF

FS

O

N

O CH3

• Pantoprazole is a proton pump inhibitor:

• Teva alleged the claimed pantoprazole would have been obvious based on the prior art disclosure of Compound 12 in USP 4,555,518:

Protonix® (pantoprazole)• At-risk launch, Altana seeks PI• District Court, following KSR, finds no likelihood

of success, denies PI motion• Compound 12 was a natural choice for a lead

compound• Other prior art references taught:

▫ The desirability of lowering the pKa of the pyridine ring to a pKa of 4 (the Sachs reference)

▫ a compound with a methoxy group at the 3-position of the pyridine ring would have a lower pKa value (namely, a pKa of 4) that a compound with a methyl group at that position (the Bryson reference)

Protonix® (pantoprazole)•KSR applied•Defendants have provided “sufficiently

persuasive evidence that pantoprazole was a predictable variation of compound 12 and thus, is evidence of obviousness, at this stage of the litigation. See KSR, 127 S. Ct. at 1740 ("If a person of ordinary skill in the art can implement a predictable variation, and would see the benefit of doing so, section 103 likely bars its patentability.").

Famvir® (famciclovir )

N

N

N

NH2N

OCOCH3

OCOCH3

Famciclovir

• Novartis sought a preliminary injunction against Teva’s at-risk launch of famciclovir

• Famciclovir is a prodrug of penciclovir, an in-vivo active compound with anti-viral activity

Famvir® (famciclovir )•Applying KSR and Takeda (Actos), court

determined that penciclovir would have been an obvious lead compound

•the 6-deoxy modification was shown in the prior art to be several times more effective than any other substitutions, therefore “skilled artisan [would] have a reasonable expectation of success based on the prior art.” citing KSR

Novartis v. Teva (D.N.J. Sept. 6, 2007)

Nexium® (magnesium esomeprazole trihydrate)

• '504 Patent claims alkaline salts of esomeprazole. Salt scope is in question.

•Patent describes and exemplifies only six salts characterized throughout the specification as "the invention"

•No description or enablement of other salts. What other salts are legitimately covered?

•broad alkaline salt scope construction → 112 challenges

• Claims are facially generic to hydrated forms of esomeprazole salts. No claim recitation of hydrate forms, no express disclosure in the specification• No disclosure for making a hydrated form• Examples to not result in production of hydrated or even

solvated form• Later patents obtained on trihydrate form with

characterization that hydrated form could not have earlier been made

Yet claims purportedly cover specific hydrate forms• Challenges under 112, lack of enablement and written

descriptionPlant Genetic Systems v. DeKalb Genetic Corp, 315

F.3d. 1335 (Fed. Cir. 2003) (claims to transformed plant cell invalid, enabling for monocots not accused dicots); compare In re Hogan (cannot use later existing technology to invalidate patent that is enabled for what it claimed at the time of filing)

Nexium® (magnesium esomeprazole trihydrate)

Composition Claims•A pharmaceutical composition comprising

▫a compound of formula X or a pharmaceutically acceptable salt thereof

▫An HPMC polymer matrix, and▫A pharmaceutically carrier

Biaxin®•Pharmaceutical composition for extended

release of erythromycin comprising erythromycin and from about 5-50% of hydrophilic water-soluble pharmaceutically acceptable polymer

•Combination of references showing:1. controlled release formulation of

azithromycin with most preferred HPMC polymer

2. controlled release formulation of clarithromycin with water soluble alginate salt release agent

Biaxin®•second reference also disclosed:

▫ particular pharmacokinetic release characteristics of composition that meet the involved claims, and

▫ composition containing azithromycin

Biaxin®Held:•Clarithromycin is sufficiently similar to

azithromycin to provide a reasonable expectation of success in substituting clarithromycin for azithromycin in a controlled release formulation

•Obvious to administer any macrolide antibiotic in sustained release matrix to reduce adverse gastrointestinal effects

Abbott Labs. v. Andrx Pharms., Inc., 452 F.3d 1331 (Fed. Cir. 2006)

Ditropan XL®•Sustained release oxybutynin obvious

over reference disclosing sustained release composition for API highly soluble in water, including oxybutynin, disclosing release of morphine at claimed rates, where reference provided motivation to use oxybutynin

Alza Corp. v. Mylan Labs., Inc., 464 F.3d 1286 (Fed. Cir. 2006)

Combination of drug with Combination of drug with drug coatingdrug coating•Patents directed to APIs with drug

coatings that impart certain properties to the drug product▫Yasmin® ▫Pepcid® Complete (a combination of

famotidine and aluminum hydroxide)

Yasmin® (oral contraceptive)•combination of drospirenone and

ethinylestradiol•drospirenone is acid sensitive and

degrades in patient’s stomach•Bayer micronizes the combination and

markets Yasmin® as an immediate release tablet

Yasmin® - post KSR analysis •The prior art taught

▫2-4 mg drospirenone; ▫in combination with 0.01 to 0.05 mg 17

[alpha]-ethinylestradiol; ▫along with pharmaceutically acceptable

carriers; ▫used as an effective oral contraceptive in

human females

Yasmin® - post KSR analysis •Issue was whether it was obvious to a

person of ordinary skill in the art to: (1) micronize drospirenone so as to increase

its bioavailability, and (2) not protect the drospirenone from the gastric environment with an enteric coating

Yasmin® - post KSR analysis Held: ‘531 patent invalid as obvious

•micronization was a conventional formulation technique to increase absorption and bioavailability at the time of invention

•certain prior art references showed that a closely related drug, spirorenone, absorbed rather than isomerized

•other prior art references which note that poorly water soluble sex steroids benefit from micronization

Bayer Schering Pharma AG v. Barr Labs., Inc., (D.N.J . March 3, 2008)

Pepcid® Complete•Patent covers a solid oral dosage of

aluminum hydroxide or magnesium hydroxide (the "antacids") and famotidine

•Famotidine is a bitter-tasting guanidinothiazole compound that inhibits acid secretion in the stomach by interfering with histamine receptors in the stomach lining

•The famotidine is separated from the antacids by an impermeable coating because the antacids would degrade the famotidine

Pepcid® Complete•The prior art showed the combination of

uncoated famotidine and magnesium or aluminum hydroxide in a solid oral dosage

•The Wolfe reference provided that compositions combining antacids and H[2] blockers may contain "one or more agents such as, for example, sweetening agents, flavoring agents, coloring agents and the like, in order to provide a pharmaceutically elegant and palatable preparation."

•The prior art ‘114 patent describes taste-mask coating of drugs used in chewable tablets.

Pepcid® CompleteHeld: ‘340 patent obvious in view of a

combination of references•the combination of famotidine and

antacids and the use of an impermeable coating all appear in the prior art

•Internal evidence shows McNeil knew of famotidine’s bitter taste

•Pepcid AC® also involved coated famotidine in the form of a chewable tablet

Pepcid® Complete•a skilled formulator would be motivated to

mask the bitter taste of famotidine even with the addition of antacids

•Because the desirability of taste-masking famotidine was established, “a person of ordinary skill would have ample reason to combine Davis and Wolfe with the '114 patent. It also would have been obvious to combine Davis and Wolfe with the '933 application.”

McNeil v. Perrigo, 516 F. Supp. 2d 238 (Fed. Cir. 2007)

Pepcid® CompleteSecondary Considerations

▫Commercial success, but no nexus to the claimed invention Pepcid brand successfully marketed Expensive promotional campaign cannibalization of Pepcid AC Coverage by at least 3 patents

McNeil v. Perrigo, 516 F. Supp. 2d 238 (Fed. Cir. 2007)

Method Claims

Lack of Enablement: Strattera®•Lilly’s ‘590 patent is directed to the use of

atomoxetine HCl in treating ADHD•Independent Claim 1:

“A method of treating attention-deficit/hyperactivity disorder comprising administering to a patient in need of such treatment an effective amount of tomoxetine”

Eli Lilly and Company, v. Actavis, et al., 2010 U.S. Dist. LEXIS 83292 (D.N.J. August 12, 2010)

Lack of Enablement: Strattera®•Court finds claims nonobvious•Court finds no inequitable conduct•Full scope of claims enabled•What about utility requirement of

enablement?

Lack of Enablement: Strattera®The '590 patent discloses: • how to diagnose ADHD the disease to be treated, • how to use tomoxetine to treat ADHD• the preferred route of administration• the preferred dosage form, and the dosage range for

children and adults• that tomoxetine requires only once-a-day

administration• that the effective dose range of tomoxetine for

ADHD • that the use of tomoxetine to treat ADHD is effective

Lack of Enablement: Strattera®•The '590 patent does not disclose any

data or testing regarding the efficacy of atomoxetine to treat ADHD

•Def’s argued that the patentee did not establish that the claimed method of treating ADHD had utility at the time of filing

•Because no test results were provided at the time of filing, a POSA would not have recognized the claimed utility based on the ‘590 specification

Lack of Enablement: Strattera®•Lilly argued:

▫ POSA would understand from the patent that atomoxetine could be used to treat ADHD

▫In addition, Lilly obtained positive clinical data during the pendency of the patent

▫Post-filing date evidence can be used to establish utility

Lack of Enablement: Strattera®

December 1, 1994December 1, 1994 IND submitted to FDAIND submitted to FDA

January 3, 1995January 3, 1995 FDA approves Lilly’s proposed FDA approves Lilly’s proposed clinical investigationclinical investigation

January 11, 1995January 11, 1995 ‘‘590 patent filing date590 patent filing date

May, 1995May, 1995 Positive clinical results reported Positive clinical results reported to Lillyto Lilly

October, 1995October, 1995 Positive clinical results published Positive clinical results published by Lillyby Lilly

Lack of Enablement: Strattera®Would a POSA have recognized that the claimed method had utility as of the filing date?• Existence of effective ADHD drugs • Safety profile of atomoxetine • Initiation of clinical trials

Lack of Enablement: Strattera®Court says:• Post-filing test results cannot be used to

establish utility at an earlier filing date: “the utility requirement prevents a party from

patenting a mere research proposal or an invention that is simply an object of research. . . the enablement/utility case law instructs that patent applicants must demonstrate utility (as well as other enablement-related requirements) at the time of filing the patent application.”

Eli Lilly and Company, v. Actavis, et al., 2010 U.S. Dist. LEXIS 83292 (D.N.J. August 12, 2010)

Lack of Enablement: Strattera®• Patent held non-enabled• No test data• POSA would not have recognized utility

“The fact that testing had begun does not convince this Court otherwise, as "usefulness" in the context of a clinical study--which could include achieving the open-ended goal of gaining additional knowledge to assist in further research--is not the same as "utility" for the purposes of patentability.”

Eli Lilly and Company, v. Actavis, et al., 2010 U.S. Dist. LEXIS 83292 (D.N.J. August 12, 2010)

Inherent anticipation: Nexium®1. A method for treatment of gastric acid related diseases by inhibition of gastric acid secretion comprising:administering to a mammal in need of treatment a therapeutically effective amount of a proton pump inhibitor… or a pharmaceutically acceptable salt thereof,so as to effect decreased interindividual variation in plasma levels (AUC) during treatment of gastric acid related diseases.

Recited proton pump inhibitor was patented years before

"so as to effect decreased interindividual variation in plasma levels (AUC) during treatment of gastric acid related diseases." construed as

"a smaller addition to the amount of any of the hormones secreted in the pyloricantral mucosa of the stomach that stimulate secretion of stomach acid by the parietal cells as compared to the addition produced by omeprazole.”

patentee says not a mere inherent result but there is no need to carry out a comparison step recitation of a result inherent in the the administration of known compound

Mayo v. Prometheus (“While it takes ….administration … to trigger a manifestation of this relation… the relationship itself exists in principle apart form any human action… natural processes.”)

patent eligibility: Nexium®

Method Claims•What about divided Infringement?•Generic mfr. submits proposed label to

FDA•FDA includes package insert to

pharmacies•Physician writes Rx for patient•Patient fills prescription at pharmacy of

choice

Method Claims

Does a generic drug manufacturer infringe method of treatment claims?

•NO under 271(a) “Defendants do not diagnose patients and do not

administer drugs. Moreover, Lilly has made no allegation that Defendants will employ physicians to prescribe tomoxetine to treat patients with ADHD. . . . Defendants will not infringe Plaintiff's patent. Even if Defendants manufacture, market, and sell tomoxetine products, they would not be "using" tomoxetine to treat ADHD.”

Lilly v. Actavis,2009 U.S. Dist. LEXIS 43003, (D.N.J. May 20, 2009)

Does a generic drug manufacturer infringe method of treatment claims?• NO under 271(b)

“there is no evidence in the record that Apotex has directly practiced or will ever practice any of the methods claimed in the neurodegenerative method patent, all of which are directed to a method for treating neurodegenerative diseases by administering gabapentin or another cyclic amino acid compound to a mammal. . . That is hardly surprising -- pharmaceutical companies do not generally treat diseases; rather, they sell drugs to wholesalers or pharmacists, who in turn sell the drugs to patients possessing prescriptions from physicians. Pharmaceutical companies also occasionally give samples of drugs to doctors and hospitals. In none of these cases, however, does the company itself treat the disease.”

Warner-Lambert Co. v. Apotex Corp., 316 F. 3d 1348, 1363 (Fed. Cir. 2003)

Does a generic drug manufacturer infringe method of treatment claims?• YES

“Navinta's Labeling instructs clinicians to use the ANDA Products in a manner that would practice the method of claim 6, and therefore instructs physicians to infringe claim 6. [ ] Navinta reasonably knows or should know that practitioners will use its ANDA Products to practice the method of claim 6 of the '086 Patent.”

Abraxis v. Navinta (D.N.J. August 3, 2009)

• Statements in a package insert that encourage infringing use of a drug product are alone sufficient to establish intent to encourage direct infringement.

AstraZeneca LP v. Apotex, Inc., 2009 U.S. Dist. LEXIS 43677 (D.N.J. May 22, 2009)

Kit Claims• “A kit for treating respiratory diseases, the kit

comprising (a) a budesonide composition in a sealed container, the composition containing 0.05 mg to 15 mg budesonide and a solvent, and (b) a label indicating administration by nebulization in a continuing regimen at a frequency of not more than once per day.”

• Held: kit claims invalid because the claimed budesonide composition and suspension were known in the prior art and the recited label could not render a known product patentable.

AstraZeneca LP v. Apotex, Inc.,633 F.3d 1042 (Fed. Cir. 2010)

Thank You!