The Role of Formulations in

Biologics Patent Protection

Timothy J. Shea, Jr. – Director

Elizabeth Haanes - Director
Sterne, Kessler, Goldstein & Fox P.L.L.C.

IBC’s 8th Annual Conference on

Formulation Strategies for Protein
Therapeutics

Anaheim, CA
September 24, 2008
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 immediately
upon 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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Patentability Issues
• 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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Patentability Issues

• 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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Patentability Issues

• 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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Patentability Issues
• 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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Patentability Issues

• 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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Case Study I: Erythropoietin (Amgen)

• 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).

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Case Study I: Erythropoietin (Amgen)

• 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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Case Study I: Erythropoietin (Amgen)

• 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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Case Study I: Erythropoietin (Amgen)

• 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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Case Study I: Erythropoietin (Amgen)

• 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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Case Study II: Growth Hormone (Novo)

• 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).
• U.S. Pat. No. 6,117,984
• Effective filing date = 7/12/91
• Claim 1: Divalent cation crystals of human
growth hormone (hGH) or derivatives
thereof.

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Case Study II: Growth Hormone (Novo)

• U.S. Pat. No. 5,849,704

• Effective filing date = 12/16/92
• 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 . . . .
• U.S. Pat. No. 6,022,858
• Effective filing date = 1/28/92
• 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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Case Study II: Growth Hormone (Novo)

• 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 formulation
comprising 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

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