Strategic Development of Pharmaceutical Solid Form Patents Dr. Gaby L. Longsworth, Esq. 2008 IQPC Improving Solubility Conference October 28, 2008
Introduction 1. Pharmaceutical Solid Forms 2. Detecting Pharmaceutical Solid Forms 3. Strategic Development of Pharmaceutical Solid Form Patents 4. Optimization of Solid Form Intellectual Property Rights 2
What are Pharmaceutical Solid Forms? Single component forms Polymorphs Amorphous Multi component forms Salt Solvate Hydrate Co-crystal = Counter-ion = Solvent = Water = Co-former 3
Detection of Pharmaceutical Solid Forms eurostar-science Newsletter 01, issued May 21, 2001 by katiniko 4
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 Clearing Regulatory Hurdles Establishing IP portfolios Increased Exclusivity Periods Staving-Off Generic Competition Risk Management 5
Case Study Norvir 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: $250 million in sales Estimated hundreds of millions of dollars in R&D trying to recover the original Form I 6
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 7
Drug Patent Life-Cycle 8
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 9
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. 10
Patent Application Examination 0 12 mo. 18 mo. ~48 mo. 0 12 mo. 18 mo. ~48 mo. Provisional Application Provisional Application Non-Provisional Application Non-Provisional Application Application Examined Application Examined Application Publication Application Publication Issuance Issuance Foreign Filing Foreign Filing 11
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 12
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) 13
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 14
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 15
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 16
Strategic Development of Pharmaceutical Solid Form Patents Legal Issues in Solid Form Patents Utility Anticipation (Novelty) Obviousness Enablement 17
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 18
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) 19
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. 20
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. 21
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 22
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) 23
35 U.S.C. 112: Specification Enablement In re Wands (Fed. Cir. 1988) 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) A court will not grant broad claim scope in an unpredictable art, when there is no reasonable expectation of success for such an extrapolation 24
35 U.S.C. 112: Specification Enablement 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 25
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) 26
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) 27
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)) 28
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 29
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) 30
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 31
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 32
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 33
Strategies for Developing Solid Form Patents Typical crystalline form characterization: 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 34
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 35
Questions? Thank you! glongs@skgf.com 36