skgf_presentation_the role of formulations in biologics patent protection_08

Timothy J. Shea, Jr. � DirectorElizabeth Haanes - DirectorSterne, Kessler, Goldstein & Fox P.L.L.C.

IBC�s 8th Annual Conference on Formulation Strategies for Protein Therapeutics

Anaheim, CASeptember 24, 2008

The Role of Formulations in Biologics Patent Protection

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Introduction

� Introduction of the concept of patent life cycle management

� Insights from the pharma industry

� Key patentability issues in patent life cycle management

� The role of formulations in biologics patent protection� Case Studies

� Erythropoietin

� Growth hormone

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The Dilemma

� The cost to develop a drug or biologic and bring to market is hundreds of millions of $$$

� Patent protection for the basic NCE or protein is generally sought very early in the R&D process

� Due to the extensive regulatory review period, significant patent term has been lost by the time the product goes to market

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Patent Life-Cycle Management

� Strategic use of patents to maintain product exclusivity and revenue stream over life of blockbuster drug or biologic

� Involves obtaining additional patents that extend protection beyond the original patents covering the NCE or biologic per se

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Insights from the Pharma Industry

� Patent life-cycle management is a familiar concept for big pharma

� Hatch-Waxman Act

� Recognizes regulatory delay

� Allows innovator to extend patent term of single patent up to 5 years

� BUT, provides for generic entry immediatelyupon expiration of patent coverage

� Generics often seek to market upon expiration of original patent to NCE

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Insights from Pharma Industry

� Pharma companies have countered generics by increasing the breadth and complexity of the patent �fence� around their crown jewels� �traditional� protection covered NCE, method of

making, method of using (treating), and a pharmaceutical formulation

� Today, patents are typically also filed on:� New indications

� Polymorphs

� Mechanisms of action

� Combination products/therapies

� Dosing regimens

� Dissolution/bio profiles

� NEW FORMULATIONS 0 very important

� Methods of stabilizing

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Insights from Pharma Industry

� Novel formulations are extremely valuable to patent life cycle management

� Example: individual isomers are generally more potent than racemic mixtures

� Currently no formal legal/regulatory framework for approving generic biologics @ but it�s coming� pending legislation stalled pending election,

but demand for formal framework is great

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Patentability Issues

� Term of a U.S. patent now extends 20 years from the earliest effective filing date

� Issue date is irrelevant

� To extend patent coverage on the drug or biologic, the second (improvement) patent must have a later filing date than the original patent to the product

� Thus, the original patent is often prior art to the later filed application

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� To obtain an improvement patent, applicant must show claimed subject matter is novel, nonobvious, etc. over earlier patent to drug or biologic per se� Generally not difficult to show novelty

� But must be careful regarding inherent anticipation

� Focus is generally on obviousness

� KSR Int�l Co. v. Teleflex Inc., 550 U.S. ___(2007)� Supreme Court �clarified� obviousness

� Now easier for USPTO to establish prima facie case of obviousness and shift burden to applicant to prove otherwise

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� KSR v. Teleflex

� Improvement must be more than predictable use of prior art elements

� Not limited to references dealing with precise problem addressed

� Any need or problem known in the field and addressed by patent can provide reason for combining elements

� �Obvious to try� could be enough in some instances

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� In response to KSR case, USPTO established training guidelines for examiners

� Identified acceptable �rationales� to support prima facie case of obviousness:

A. Combining prior art elements according to known methods to yield predictable results

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� USPTO �Rationales� for Obviousness� B. Simple substitution of one known, equivalent

element for another to obtain predictable results� E.g. one known excipient for another?

� C. Use of known technique to improve similar products in the same way

� Application of technique to similar product must be within ordinary skill in art

� D. Applying a known technique to a known product ready for improvement to yield predictable results

� E.g. lyophilization?

� E. �Obvious to try� � choosing from a finite number of predictable solutions

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� Rebutting Obviousness Rejections� Submit technical evidence showing that subject

matter claimed in later (improvement) patent could not have been predicted to work

� Show that claimed subject matter (e.g. new formulation) has unexpected advantages (e.g., increased efficacy, stability, etc.)

� Clinical studies provide good opportunities for patenting improvements, since in vivo effect are difficult to predict

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The Role of Formulations in Biologics

Patent Protection

� Although no formal legal/regulatory framework for approving generic biologics exists, biologic innovators are already applying patent life cycle management strategies to extend patent protection on blockbuster biologics

� As in the pharma industry, formulation patents are essential components of a patent life cycle management strategy for biologics

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Case Study I � Erythropoietin (Amgen)

� U.S. Pat. No. 4,703,008� Effective filing date 12/13/83 (but 17-year term

from grant since pre-GATT)

� Claim 2: A purified and isolated DNA sequence consisting essentially of a DNA sequence

encoding human erythropoietin.

� U.S. Pat. No. 5,547,933� Effective filing date = 12/13/83 (17 year term)

� Claim 3. A non-naturally occurring erythropoietin glycoprotein product . . . having glycosylation

which differs from that of human urinary

erythropoietin.

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� U.S. Pat. No. 5,597,562 � Effective filing date = 6/3/91 (17-year

term)

� Claim 1: An oral dosage form

comprising the components:

(a) GCSF or erythropoietin;

(b) Surfactant(s)

(c) Fatty acid(s); and

(d) Enteric material,

wherein said components (a), (b) and (c) are mixed in liquid phase and lyophilized prior to combination with component (d).

Case Study I: Erythropoietin (Amgen)

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� U.S. Pat. No. 5,856,298� Effective filing date = 10/13/89 (17-year

term)

� Claim 1: An isolated biologically active

erythropoietin isoform having a single isoelectric point and having a specific number of sialic acids per molecule, said number selected from the group consisting of 1-14 . . . .

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� U.S. Pat. No. 7,217,689� Effective filing date = 10/13/89 (17 year

term)

� Claim 1: An analog of human

erythropoietin . . . comprising an amino acid sequence which differs from the amino acid sequence of human erythropoietin . . . by having one or more

additional glycosylation site(s) as compared to human erythropoietin.

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� U.S. Pat. No. 5,661,125� Effective filing date = 08/06/92 (almost 9

years after first patent) (17-year term)

� Claim 1: A stable pharmaceutical

composition comprising a solution of a therapeutically effective amount of erythropoietin and a preservative selected from the group consisting of benzyl alcohol, a paraben and phenol or a mixture thereof.

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� U.S. Pat. Pub. No. 2006/0264377� Effective filing date = 4/7/00 � If issues will expire 4/7/2020� Claim 1: A pharmaceutical composition

comprising:(a) A substantially homogenous preparation of mono-

PEGylated NESP, said mono-PEGylated NESP consisting of a polyethylene glycol moiety connected to a NESP moiety solely at the N-terminus thereof;

(b) Fewer than 5% non-pegylated NESP molecules; and

(c) A pharmaceutically acceptable diluent, adjuvant or carrier.

(NESP is a hyperglycosylated EPO analog having five changes in the amino acid sequence of rHuEPO which provide for two additional carbohydrate chains)

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Case Study II: Growth Hormone (Novo)

� U.S. Pat. No. 5,633,352� Effective filing date = 12/9/83 (17-year term)

� Claim 1: Biosynthetic ripe human growth

hormone from pituitary derived human growth hormone.

� U.S. Pat. No. 5,547,696� Effective filing date = 10/13/94 (17-year term)

� Claim 1: A pharmaceutical formulation comprising

a growth hormone in the amount of about 0.1 mg/ml to about 40 mg/ml and valine at a concentration up to about 100 mM.

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� U.S. Pat. No. 5,552,385� Effective filing date = 6/5/95

� Claim 1: A pharmaceutical formulation comprising a growth hormone and Lys-

Gly-Asp-Ser (SEQ ID No: 1).


� Claim 1: Divalent cation crystals of human

growth hormone (hGH) or derivatives thereof.

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� Claim 1: A pharmaceutical composition in the form of a lyophilized powder comprising a growth hormone or a derivative thereof and histidine or histidine derivative . . . .


� Claim 1: A pharmaceutical formulation comprising a human growth hormone pretreated with zinc salt

for at least one hour before addition of other components to the formulation and optionally containing lysine or calcium ion.

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� U.S. Pat. No. 6,566,329� Effective filing date = 06/28/99� Claim 1: A method for preparing a soluble freeze-

dried solid preparation of hGH . . . .

� U.S. Pat. Pub. No. 2006/0257479� Effective filing date = 10/8/04� If issues, patent will expire in 2024

� Claim 1: A sustained release formulationcomprising a protein modified so as to provide a reduced clearance, wherein said protein does not comprise a methionine in which the side chain sulphur has been modified.

� Claim 2: The formulation according to claim 1, wherein said protein is a growth hormone compound.

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Conclusions

� Patent life-cycle management is the strategic use of patents to maintain product exclusivity and revenue stream over the life of a commercially valuable drug or biologic

� Successful companies will have fully integrated patent life-cycle and product life cycle programs

� Companies should consider strategic patenting both before and after marketing approval

� Formulation patents are particularly effective at extending exclusivity

� Effective patent life-cycle management requires careful attention to the timing of filings and the content of the application

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The Role of Formulations in Biologics Patent Protection

Thank You

Timothy J. Shea, Jr.

Elizabeth Haanes

Sterne, Kessler, Goldstein & Fox, P.L.L.C.

(202) 772-8679

skgf_presentation_the role of formulations in biologics patent protection_08

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