Download Strategic Development of Pharmaceutical Solid Form Patents

Strategic Development of
Pharmaceutical Solid Form Patents
Dr. Gaby L. Longsworth, Esq.
2008 IQPC Improving Solubility Conference
October 28, 2008
Introduction
1.
2.
3.
4.
Pharmaceutical Solid Forms
Detecting Pharmaceutical Solid Forms
Strategic Development of Pharmaceutical Solid Form
Patents
Optimization of Solid Form Intellectual Property Rights
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What are Pharmaceutical Solid Forms?
Single component forms
Polymorphs
Amorphous
Multi component forms
Salt
Solvate
Hydrate
Co-crystal
= Counter-ion
= Solvent
= Water
= Co-former
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Detection of Pharmaceutical Solid Forms
© eurostar-science Newsletter 01, issued May 21, 2001 by katiniko
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Identifying Optimum Solid Forms
• From the pharmaceutical point of view, bioavailability
(through solubility profile), processability and stability
may be influenced by the existence of different solid
forms
• To avoid undesired changes during the production
process or during the product lifetime, it is therefore
extremely important to know the thermodynamic and
kinetic stability of all forms as a function of temperature
and other environmental variables
• Advantages of Identifying Optimum Solid Forms
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Clearing Regulatory Hurdles
Establishing IP portfolios
Increased Exclusivity Periods
Staving-Off Generic Competition
Risk Management
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Case Study – Norvir®
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Ritonavir, or Norvir®, was
patented in 1993 and marketed
in 1996 by Abbott Laboratories.
The drug was on the market for
18 months before a serious
problem emerged: the drug
began precipitating out of
formulation in large quantities
The new form was dubbed
Form 2, and was found to be
less soluble, greatly reducing
bioavailability
Abbott was forced to remove
Ritonavir from the market until
they solved the problem,
resulting in extreme losses:
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$250 million in sales
Estimated hundreds of millions
of dollars in R&D trying to
recover the original Form I
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Strategic Development of Pharmaceutical
Solid Form Patents
• Why?
– Drug companies usually file patents on all the different solid
forms during development
– When initial patents on the compound itself expire, they can
conceivably extend a product’s life by moving to another
form
– Generic companies may also target unprotected forms to
avoid patent infringement
• When?
– Solid form patents should be filed as soon as new forms are
discovered
• How?
– Establishing the legal requirements for patentability
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Drug Patent Life-Cycle
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Patent Term Restoration
• In 1984, Congress enacted a law to
extend the patent life of pharmaceutical
products to compensate patent holders
for marketing time lost while developing
the product and awaiting FDA approval
• A maximum of 5 years can be restored
to the patent
– In all cases, the patent life (including
extensions) cannot exceed 14 years from
the date of approval
– Any product that has 14 years left of patent
term at the date of approval is ineligible for
PTR
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Patent Term Restoration
•
The regulatory review period
is the basis for patent
extension, and is composed
of two parts:
– Testing phase: the period
between the effective date
of an INDA and the initial
submission of the NDA
– Approval phase: the
period between the
submission and approval of
the marketing application
•
•
The FDA determines the
regulatory review period and
notifies the PTO and the
applicant
The PTO is responsible for
determining the period of
extension.
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Patent Application Examination
Application Examined
Application Examined
0
0
Provisional
Application
Provisional
Application
12 mo.
12 mo.
18 mo.
18 mo.
Non-Provisional
Application
Application
Non-Provisional
Application
Publication
Application
Publication
~48 mo.
~48 mo.
Issuance
Issuance
Foreign
Filing
Foreign
Filing
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Patent Law Fundamentals
• Pharmaceutical solid forms must
meet the same standards for
patentability as other inventions
– 35 U.S.C. § 101 Utility
– 35 U.S.C. § 102 Novelty
– 35 U.S.C. § 103 Obviousness
– 35 U.S.C. § 112 Specification
• Written Description
• Enablement
• Best Mode
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35 U.S.C. § 101 Utility
“Whoever invents or discovers any new and
useful process, machine, manufacture, or
composition of matter, or any new and useful
improvement thereof, may obtain a patent
therefor, subject to the conditions and
requirements of this title.”
– [P]harmacological or therapeutic inventions
that provide any “immediate benefit to the
public” satisfy 35 U.S.C. § 101 (MPEP
2107.01)
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35 U.S.C. § 102 Novelty
• Novelty requires that the invention was not
published, known or used by the public
• What was known before is referred to as “prior
art”
• Prior art created by anyone, including inventor
– Only matters if occurred > 1 year before patent
application filed
– Includes:
• Patent (US or Foreign)
• Printed Publication, e.g., article, abstract or poster,
published patent application, in US or foreign country
• Sale or Offer for Sale of the Invention in US
• Public use in US
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35 U.S.C. § 103 Obviousness
• A patent cannot be
obtained if the
differences between
the subject matter
sought to be patented
and the prior art are
such that the subject
matter as a whole
would have been
obvious at the time the
invention was made to
a person having
ordinary skill in the art
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35 U.S.C. § 112 Specification
– Written Description:
the invention is
described with certain specificity (serves as
notice to others; fixes patent rights)
– Enablement:
the patent application
must enable someone skilled in the relevant
art, how to make and use the solid form
– Best Mode:
the patent application must
describe the best mode for practicing the
invention; known to the inventor at the time
of filing; no duty to update
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Strategic Development of Pharmaceutical
Solid Form Patents
• Legal Issues in Solid Form Patents
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Utility
Anticipation (Novelty)
Obviousness
Enablement
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35 U.S.C. § 101 Utility
• For composition of matter API
polymorph patent – utility can be
based on underlying API
• In Europe, best to show a benefit of
the new polymorph (e.g., better
solubility properties, handling
properties, etc.)
• More tests/data will be needed for a
European filing than for a U.S. filing
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35 U.S.C. § 102: Anticipation
• An invention is anticipated only
if each and every element in the
claim is found, expressly or
inherently, in the prior art
• Two important cases describing
inherent anticipation
– SmithKline Beecham v. Apotex, 403
F.3d 1331 (Fed. Cir. 2005)
– Abbot v. Baxter, 471 F.3d 1363 (Fed.
Cir. 2006)
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SmithKline Beecham v. Apotex
403 F.3d 1331 (Fed. Cir. 2005)
• Crystalline paroxetine hemihydrate is claimed in
U.S. Pat. No. 4,721,723
• Paroxetine is disclosed in U.S. Pat. No.
4,007,196 (prior art)
• Court said that by practicing the ‘196, one
would inherently get CPHH
– “The ‘196 patent discloses a method of
manufacturing CP anhydrate that naturally
results in the production of CP hemihydrate.
Consequently, applying the facts as found by
the district court to the correct standard, this
court holds that claim 1 of the ‘723 patent is
invalid for anticipation by the ‘196 patent.”
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Abbott v. Baxter
471 F.3d 1363 (Fed. Cir. 2006)
• Abbott got a second-generation patent
on a stable composition of sevoflurane
• Baxter argued that the Abbott patent was
invalid based on prior art (anticipation)
• Abbott argued that the prior art did not
anticipate their invention because the
effects were not known at the time of the
prior art.
• Court held the Abbott patent to be invalid
– “[I]nherent anticipation does not require that
a person of ordinary skill in the art at the time
would have recognized the inherent
disclosure.”
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35 U.S.C. § 103: Obviousness
• “the presumption of obviousness based
on a reference disclosing structurally
similar compounds may be overcome
where there is evidence showing there is
no reasonable expectation of similar
properties in structurally similar
compounds.” (MPEP 2144.09)
• Novel solid forms may be patented
without showing unexpected results if
one of ordinary skill cannot predict the
structures, properties, or how to make a
novel solid form
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Pfizer, Inc. v. Apotex, Inc.
480 F.3d 1348 (Fed. Cir. 2007)
• In Pfizer v. Apotex, Pfizer got a second
generation patent on a salt form of
amlodipine (Norvasc ®)
• Apotex challenged the validity of the
solid form patent, claiming the particular
salt form (maleate) was obvious over the
prior art (besylate).
• The Ct. agreed with Apotex, stating:
– “[W]e hold that the [claimed salt] would have
been obvious where as here the [claimed
salt] has no effect on the therapeutic
effectiveness of the active ingredient and the
prior art heavily suggests the particular anion
used to form the salt.” (emphasis added)
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35 U.S.C. § 112: Specification
Enablement
•
In re Wands (Fed. Cir. 1988)
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•
The claimed invention must be enabled so that any
person skilled in the art can make and use the
invention without undue experimentation
Wands factors: look at (1) quantity of
experimentation, (2) amount of direction or
guidance, (3) working examples, (4) nature of
invention, (5) state of art, (6) relative skill in art, (7)
predictability of art, and (8) breadth of claims
In re Wright (Fed. Cir. 1993)
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A court will not grant broad claim scope in an
unpredictable art, when there is no reasonable
expectation of success for such an extrapolation
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35 U.S.C. § 112: Specification
Enablement
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Final Rejection of 10/26/2005 for U.S. Patent No. 7,078,526 (assigned to
TransForm Pharmaceuticals, Inc.)
Examiner’s Arguments: Specification was enabling as to a process for making
two species of co-crystals; however, the specification did not enable one skilled in
the art to make the genus of these co-crystals
Applicant’s Arguments: the specification provides the level of skill necessary to
practice the invention. The formation of itraconazole HCl tartaric acid co-crystals
can be achieved without undue experimentation by following the methods provided
Result:
•
Applicant cancelled all genus claims in order for the patent to issue
•
•
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Solid Form Patents:
Polymorph
•
Granted Claim (Detrol® Polymorph, Pat. No. 7393874, Issued Jul. 1, 2008, assigned to
Hetero Drugs Ltd.):
•
Got around prior art by distinguishing the process (XRPD, temperatures, solvents,
seeding, etc.)
•
Pitfall: Narrow Claim Construction
– “It is elementary patent law that all limitations are material. The single-peak analysis
was thus insufficient because . . . in order to prove infringement Glaxo was required to
establish the presence of each limitation of the asserted claims.” Glaxo v. Novopharm,
110 F.3d 1562 (Fed. Cir. 1997)
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Solid Form Patents:
Amorphous
• Glaxo Group Ltd. v. Ranbaxy Pharmaceuticals,
Inc., 262 F.3d 1333 (Fed. Cir. 2001); Glaxo’s
claim:
• Court interpreted “essentially free” to mean
<10% crystalline, based on an example
• Product that was 10-15% crystalline was found
not to infringe
• Technological advancements may increase the
ability to identify amorphous forms (i.e.
nanocrystalline)
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Solid Form Patents:
Salts & Solvates
• Granted Claim (SmithKline, Paxil ®: issued Jan 1988)
• SmithKline developed a more stable hemihydrate form of
their original anhydrate Paroxetine HCl
• Generic producers of the anhydrate form were held to
infringe the hemihydrate form because small quantities of
the hemihydrate were detectable when producing the
anhydrate form (SmithKline Beecham Corp.v. Apotex
Corp., 403 F.3d 1331 (Fed. Cir. 2005))
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Solid Form Patents:
Co-Crystals
•Cocrystals:
•A crystalline entity in which more than one molecular
substance is incorporated into the unit cell
•A new form of matter derived via synthetic pathway
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Solid Form Patents: Co-Crystals
• Modafinil co-crystal (potential second generation patent of
Provigil ®?; Cephalon Inc. Appl. No. 10/570,405)
*Claim 9 continues to list XRPD data through (ix)
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Solid Form Patents: Co-Crystals
• Initially the Examiner rejected these claims as
indefinite under 35 U.S.C 112, for using the
term “comprising” in the claims.
• Cephalon’s response:
• This argument was successful, as the claims
were allowed on 9/19/08
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What’s At Stake?
• Total Drug Market of about $250B
• 51% of prescriptions are generic drugs
• Reported that sales of $80B will be exposed to
generic competition through 2008 by patent
expirations (only $5-7B in 2005)
• Earnings of some of the top drug makers are
depressed due to generic competition
– BMS: -16%
– GSK: -9%
– Merck: -28%
• Drug pipelines are said to be “anemic”
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Strategies for Developing
Solid Form Patents
• Focus on the form’s properties and
advantages
– Manufacturing
• Hygroscopicity
• Filtering, flow,
caking, and drying
• Stability
– Pharmaceuticals
• Solubility
• Purity
• Bioavailability/Predictability
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Strategies for Developing
Solid Form Patents
• Typical crystalline form characterization:
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Raman/IR
XRPD
Thermal analysis
Solid state NMR
Hygroscopicity
Water Solubility
• Compare data results of API and co-former with that of
the co-crystal
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Optimizing Intellectual Property Rights
• Solid form patents are a reality
– Detrol®
(polymorph, issued 7.1.08)
– Provigil®
(co-crystal, notice of
allowance sent 9.19.08)
• Only one piece in a
comprehensive patent portfolio
• Detect, Protect, Enforce
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Questions?
Thank you!
[email protected]
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