United States Patent Law and Polymorphs

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United States Patent Law and Polymorphs
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Overview of Presentation

• Overview of U.S. Patent Law
• What is a patent?
• What is required to get a patent?
• Why are polymorphs patentable?
• Infringement of Patents
• Cases relating to polymorphs
• District courts decision in SB v. Apotex
• The Appellate decision in SB v. Apotex

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What is a Patent?

• A Patent Is a Contract Between the Patent Holder
  and the Government.
• A patent provides the government, and thus the
  general public, with a detailed disclosure of the
  invention.
• In return for this disclosure, the patent holder
  receives a 20 year monopoly.

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What is a Patent?

• A Patent Does Not Give Anyone (even the Patent
  Owner!) the Right to Practice the Invention.

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What is a Patent?

• Rather, a Patent Gives the Right to Exclude
  Others from
• making
• using
• offering for sale
• selling, or
• importing
• the patented invention

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What is a Patent?

• Patents are provided for in the U.S.
  Constitution.
• The Congress shall have power.to promote the
  progress ofthe useful arts, by securing for
  limited times toinventors the exclusive right to
  theirdiscoveries.
• Laws governing the issuance of patents are in
  U.S.C. Title 35.

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What is a Patent?

• Title 35 U.S.C. Creates Rules for What is a
  Patentable Invention

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What is a Patent?
U.S. Patent 6,293,874 USER-OPERATED AMUSEMENT
APPARATUS FOR KICKING THE USERS BUTTOCKS
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What is a Patent?
U.S. Patent 3,538,508 COMBINATION PILLOW AND
CRASH HELMET
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What is a Patent?
U.S. Patent Des. 302,693 INTEGRAL HANDSET
TELEPHONE AND FLIP-TOP SHOE
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What is a Patent?
U.S. Patent 4,995,379 INSTANT FACE LIFT
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What is a Patent?
U.S. Patent 5,708,983 INFLATABLE CHEESE WEDGE HAT
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What is a Patent?
U.S. Patent 912,152 FIRE-ESCAPE
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What is a Patent?

• Requirements for patent
• Utility (35 U.S.C. 101)
• Novelty (35 U.S.C. 102)
• Nonobviousness (35 U.S.C. 103)

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Requirements for Obtaining a Patent

• 35 U.S.C. 101 (Utility)
• Whoever invents or discovers any new and useful
  process, manufacture, or composition of matter,
  or any useful improvement thereof, may obtain a
  patent thereof, subject to the conditions and
  requirements of this title.

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Requirements for Obtaining a Patent

• Utility
• Example of Inventions that are Patentable
• Processes
• Machines
• Manufacture
• Compositions of matter (Polymorphs)

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Requirements for Obtaining a Patent

• Utility
• Example of Inventions That Are Not Patentable
• Products naturally occurring in nature
• Scientific principles
• Laws of nature
• Mental processes

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Polymorphs and 101 SB v. Apotex
SmithKline Beecham v. Apotex, Nos. 03-1285, 2004
WL 868425 (Fed. Cir. April 25, 2004).

• Case Involved Different Crystalline Forms of
  Paroxetine Hydrochloride
• SB demonstrated that one crystal form converted
  to a more stable crystal form in the presence of
  seeds and sufficient water.

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Polymorphs and 101 SB v. Apotex

• Appellate judge expressed the view that the claim
  covered subject matter that was unpatentable
  under section 101, because one crystal form
  converted to a more stable crystal form, without
  human intervention.
• A naturally occurring process

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Polymorphs and 101 SB v. Apotex

• However, the majority of judges hearing the case
  dismissed this view, because the crystal compound
  was a synthetic, man-made compound, and thus a
  composition of matter eligible for patent
  protection.

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Requirements for Obtaining a Patent

• Novelty (35 U.S.C. 102)
• Seven subsections
• Focus on 102(a) and 102(b).

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Requirements for Obtaining a Patent

• 35 U.S.C. 102(a) (b)
• Control whether an event or document qualifies as
  a potentially patent-defeating activity.
• Potentially patent-defeating activities are
  described as prior art.
• For prior art to invalidate a patent, it must
  describe every element of the claimed
  invention.

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Requirements for Obtaining a Patent
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Requirements for Obtaining a Patent

• What is the difference between 35 U.S.C. 102(a)
  and 35 U.S.C. 102(b)?

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Requirements for Obtaining a Patent

• 35 U.S.C. 102(a) states
• A person shall be entitled to a patent
  unless-(a) the invention was known or used by
  others in this country, or patented or described
  in a printed publication in this or a foreign
  country, before the invention thereof by the
  applicant.

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Requirements for Obtaining a Patent

• 35 U.S.C. 102(b) states
• A person shall be entitled to a patent
  unless-(b) the invention was patented or
  described in a printed publication in this or a
  foreign country or in public use or on sale in
  this country, more than one year prior to the
  date the application for patent in the United
  States.

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Requirements for Obtaining a Patent

• 35 U.S.C. 102(a)
• Defines prior work by others that may prevent an
  inventor from obtaining a patent.
• Such prior art includes
• If the invention was used by others in the US, or
• If the invention was already patented or
  described in a printed publication in the US or
  another country.
• Use of an invention in Europe will not be prior
  art under 102(a) unless the use was described in
  a printed publication or patented.

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Requirements for Obtaining a Patent

• 35 U.S.C. 102(b)
• Defines what activities by the inventor himself
  may invalidate a patent.
• An invention cannot be
• patented or described in a printed publication in
  the United States or foreign country
• used in public or offered for sale in the United
  States
• More than one year before filing the patent
  application IN THE UNTIED STATES
• This one year period is called the critical
  period.

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Requirements for Obtaining a Patent

• 35 U.S.C. 103 (Non-obviousness)
• A patent may not be obtainedif the differences
  between 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 to
  which said subject matter pertains.
• Question is how closely the invention as a whole
  resembles the prior art.

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Requirements for Obtaining a Patent

• Non-obviousness
• Structurally similar chemical compounds held non-
  obvious if the compound has unexpected results.
• Novel polymorphs can be patented without showing
  unexpected properties
• Reason one of ordinary skill cannot predict the
  structures, properties, or how to make a novel
  crystal form.

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Polymorphs and 103 In re Irani
In re Irani, 427 F.2d 806 (C.C.P.A. 1970)

• Patent Office rejected a claim to crystalline
  anhydrous ATMP as obvious over a reference that
  disclosed amorphous ATMP.
• Patent Office no patentably significant change
  in properties or utility.
• C.C.P.A. reversed We are not convinced that
  the references . . . would lead one of ordinary
  skill . . . to expect that ATMP could exist in a
  crystalline, anhydrous form . . . ."

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Polymorphs and 103 In re Cofer
In re Cofer, 354 F.2d 664, 668 (C.C.P.A. 1966)

• "We think the board failed to address itself to
  other factors which must be given weight in
  determining whether the subject matter as a whole
  would have been obvious, namely, whether the
  prior art suggests the particular structure or
  form of the compound or composition as well as
  suitable methods of obtaining that structure or
  form."

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Polymorphs and 103 Zenith
Zenith Labs., Inc. v. Bristol-Myers Squibb Co.,
19 F.3d 1418, 1422 (Fed. Cir. 1994)

• The patentability of a claim directed to a
  chemical compound "derives from the structure of
  the claimed compound in relation to prior
  compounds.
• The relevance to patentability of the properties
  . . . exhibited by the compound is limited to
  assessing the significance of the structural
  distinctions of the claimed compound over the
  prior art."

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Requirements for Obtaining a Patent

• 35 U.S.C 112
• What must be included in the patent itself
• Specification
• Claims

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35 U.S.C. 112 Specification

• The Specification Must Contain
• a written description of the invention
• . . . in such full, clear, and exact terms as to
  enable any person skilled in the art to which it
  pertains . . . to make and use the invention,
  and
• shall set forth the best mode contemplated by the
  inventor of carrying out his invention.

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35 U.S.C. 112 Claims

• The Claims
• Applicant shall conclude with one or more claims
  particularly pointing out and distinctly claiming
  the subject matter which the applicant regards as
  his invention.

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35 U.S.C. 112 Claims

• The Claims
• Similar to a fence around a piece of property.
• Claim defines the metes and bounds of a patent
  holders property.

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35 U.S.C. 112 Claims
Intellectual Property
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35 U.S.C. 112 Claims
Intellectual Property
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35 U.S.C. 112 Claims
Intellectual Property
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35 U.S.C. 112 Claims

• Polymorphs
• Claims often Limited by Analytical Data.
• X-ray powder Diffraction Patterns,
• Infrared Spectra
• DSC
• Be Wary of How Much Data to Include in a Claim.

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35 U.S.C. 112 Claims
Zenith Labs., Inc. v. Bristol-Myers Squibb Co.,
19 F.3d 1418, 1422 (Fed. Cir. 1994)

• Claim was directed to a Monohydrate Compound
• Defined by a X-ray Powder Diffractogram, that
  incorporated into the claim 37 relative
  intensities.

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35 U.S.C. 112 Claims
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35 U.S.C. 112 Claims
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35 U.S.C. 112 Claims
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Zenith Labs. v. Bristol-Myers Squibb Co., 19 F.3d
1418 (Fed. Cir. 1994)
Infringement

• Federal Circuit found no infringement
• BMS's reference sample possessed a different
  X-ray diffraction pattern than that claimed in
  the patent.
• Only 22 lines corresponded to the lines of the
  patent claim "15 of the lines recited in the
  claim (representing about 40 of the total) were
  not considered by the district court in its
  comparison."

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Infringement

• Thus, it is Critically Important to Consider
  Issues of Infringement When Drafting Claims.
• The more detailed the claim, the less property
  your fence covers and the easier it becomes for
  other companies to avoid infringement.

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Infringement SB v. Apotex
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Infringement SB v. Apotex
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Infringement SB v. Apotex

• Crystalline Paroxetine HCl Hemihydrate
• New crystalline form of paroxetine hydrochloride
• Contains a 21 ratio of paroxetine hydrochloride
  to water bound in the crystalline structure
• We cant predict the existence of paroxetine
  hydrochloride hemihydrate . . . or even if we
  could, how to make it or what its properties
  would be. Testimony of Professor Joel
  Bernstein.

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SmithKline Beecham Corp. v. Apotex Corp., 247
F.Supp.2d 1011 (N.D.Ill. 2003)
Infringement SB v. Apotex

• Apotex filed an ANDA for approval to market
  paroxetine hydrochloride anhydrate
• SB argued that Apotexs anhydrate converts to
  paroxetine hydrochloride hemihydrate

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Factors Causing Conversion
Infringement SB v. Apotex

• Water
• Seeds of Hemihydrate
• Heat
• Force

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Infringement SB v. Apotex

• "Solid-State forms of paroxetine hydrochloride,
  Intl J. of Pharm. 42 (1988)
• . . . a batch of Form II anhydrate which was
  stable at all conditions showed rapid and
  complete conversion when 'spiked' with levels
  from 1 to 5 of Form I hemihydrate and stored
  at 37ºC / 75 RH for 7 days."
• experiments with paroxetine HCl tablets
  demonstrating conversion of anhydrate to
  hemihydrate

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Infringement SB v. Apotex
Evidence from Apotex Documents

• Anhydrate Hygroscopic
• "HYGROSCOPIC MATERIAL STORE UNDER NITROGEN IN
  SEALED CONTAINERS AND AVOID EXPOSURE TO
  MOISTURE."
• Laboratory Studies
• Samples of anhydrate converted to high
  percentages of hemihydrate overnight
• Stability Studies
• Batches of anhydrate converted to almost entirely
  hemihydrate when stored at 40ºC and 75 humidity
  within one month

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Infringement SB v. Apotex

• Polymorphic Study of batches used to make
  Defendants' ANDA tablets
• Batches stored at 25C, 605 RH

Initial 9 months
Batch 1 Anhydrate 100 Water content .96 Hemihydrate 3 Water content 3.87
Batch 2 Anhydrate 100 Water content .70 Hemihydrate 6 Water content 4.06
Batch 3 Anhydrate 100 Water content .63 Hemihydrate 28 Water content 4.26
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Apotex Arguments
Infringement SB v. Apotex

• Seeding is Junk Science
• Mechanism not understood
• Not widely accepted

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Infringement SB v. Apotex
Well, I submit that if one believes in Santa
Claus we might believe in these seed crystals . .
. .
Counsel For NovoPharm, Inc. Glaxo v. NovoPharm
Trial August 9, 1993
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Apotex Arguments (cont.)
Infringement SB v. Apotex

• Bulk Supplier improved process
• Manufacturing steps
• Improved storage bags less permeable to water
• But, tablet manufacturer . . .
• Tablets at normal humidity
• Sprays tablets with aqueous coating (88 water)

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Infringement SB v. Apotex

• District Court rejected Apotexs attacks on
  seeding
• Apotex's contention "that there is no scientific
  basis for believing that seeding occurs . . . is
  obviously wrong."
• "Many scientific phenomena are identified before
  their causal mechanism is understood."

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Infringement SB v. Apotex

• District Court finds that anhydrateconverts to
  hemihydrate
• The greater the heat . . . and the humidity,
  the likelier is conversion . . . .
• The presence of hemihydrate seeds in a batch
  of anhydrate is likely, provided normal humidity
  and temperature, to produce conversion within a
  short time"
• Greater humidity, temperature, or pressure"
  can convert anhydrate to hemihydrate in amounts
  greater than a few percent
• Given enough humidity, heat, etc., conversion
  to the hemihydrate form may continue until it
  reaches 100 percent"

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Infringement SB v. Apotex

• District Courts Conclusions
• Apotex probably will be 'making' at least some
  hemihydrate crystals and therefore infringing, at
  least prima facie, patent 723 . . . ."
• Some conversion from anhydrate to hemihydrate is
  likely to occur in a seeded facility in which the
  anhydrate is exposed to air BCI's plant is
  seeded and the anhydrate manufactured there is
  exposed to nondehumidified air before it leaves
  the plant.

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Infringement SB v. Apotex

• District Court still Ruled Against SB
• The 723 patent notes that hemihydrate is not
  hygroscopic and thus has certain manufacturing
  benefits
• District court limited claim 1 to only
  commercially significant amounts of hemihydrate
  
• High double digits to contribute any commercial
  value
• SB did not establish Apotex will make high
  double digits amounts

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Equitable Defense of Seeding?
Infringement SB v. Apotex

• District Court found that SB was responsible for
  seeds of hemihydrate
• Thus, district court found that Apotex was not
  responsible for the hemihydrate in its product

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SBs Position on Appeal
Infringement SB v. Apotex

• Claim 1 contains only four words Crystalline
  Paroxetine Hydrochloride Hemihydrate
• Claim not limited to high double digit amounts
  of hemihydrate
• District court found Apotex will likely market
  some hemihydrate
• SB should win

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Apotex Position on Appeal
Infringement SB v. Apotex

• District Courts claim construction correct
• Attacks District Courts findings concerning
  conversion as clearly erroneous
• In sum, the district courts apparent
  fascination with the seeding theory led it to a
  finding that smacks of alchemy, not chemistry.

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The Federal Circuit Agreed with SBs Claim
Construction
Infringement SB v. Apotex

• The specification discusses the superior
  handling properties of the hemihydrate form that
  improve the manufacture of PHC. Those
  references, however, do not redefine the compound
  in terms of commercial properties, but emphasize
  that the new compound exhibits favorable
  characteristics.

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The Federal Circuit Agreed with SBs Claim
Construction
Infringement SB v. Apotex

• Nothing in the 723 patent limits that
  structural compound to its commercial
  embodiments.

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The Federal Circuit Agreed with SBs Claim
Construction
Infringement SB v. Apotex

• Thus, reading claim 1 in the context of the
  intrinsic evidence, the conclusion is inescapable
  that the claim encompasses, without limitation,
  PHC hemihydrate?a crystal form of paroxetine
  hydrochloride that contains one molecule of bound
  water for every two molecules of paroxetine
  hydrochloride in the crystal structure.

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The Federal Circuit Agreed with SB that Apotex
will infringe
Infringement SB v. Apotex

• SmithKline's Experts Applied the Disappearing
  Polymorph Theory to Show that Apotexs PHC
  anhydrate tablets inevitably convert to
  hemihydrate when combined with moisture,
  pressure, and practically ubiquitous PHC seeds.

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THE END