Should a company be permitted to patent a mutated human gene that can be targeted for therapy or an endogenous protein that they would like to produce as a therapeutic?
1. The landscape of clinical trials has changed drastically over the last decade. The protocols are becoming more complex, leading to increased workload, burden on patients, and longer treatment times. Additionally, there has been an increase in the number of Phase 3 projects terminated, resulting in increasing costs of drug development – which is an accumulation from preclinical studies, failures, salaries, and the profit that could have been earned if the drug was approved. 2. The launch of ClinicalTrials.gov in 2000 provided key insight into the evolution of clinical trials. With the requirement by ICMJE to report prospective registration of clinical trials as a precondition for publication, this ensured that not only “successful” trials are published. The details required on ClinicalTrials.gov have expanded overtime, such as reporting results and adverse events. As of 2016, over 200,000 trials are listed and conducted in 191 countries. 3. Phases of clinical drug development are categorized as I, II, III, and IV. Phase I studies typically involve healthy volunteers or patients and conducted to determine responses to drug in humans and animals. The goal is to assess safety, efficacy, tolerability, and PK/PD of the drug. In Phase II trials, the drug is being studied in patients with the target disease for the first time to assess dosing requirements and study efficacy. When the drug development process fails, it typically happens in Phase II. Phase III studies are done in a much larger scale to further establish safety and efficacy. Phase IV trials are also known as Post Marketing Surveillance Trial, which may be required by regulatory authorities or sponsors to monitor the safety of the new drug in large number of patients. 4. A good protocol is designed to answer research questions. A good research question is constructed with three key points in mind: feasibility, relevance, and justifiable costs. Regarding feasibility, one must consider whether there is sufficient patient population that can enroll in the study as well as whether the trial is manageable in scope. For relevance, one must determine if the trial will advance scientific knowledge, guide further research, or affect public policies. Lastly, is the study aligned with the therapeutic focus of the sponsor to justify the costs it will take the conduct the study? 5. There are three ethical principles in clinical research that must be taken into consideration. First, it is the principle of Respect for the Person. This principle has two moral requirements – acknowledging that individuals should be treated as autonomous beings capable of representing their own goals and interests and acknowledging that people who are not capable of self-determination must be protected. Second, beneficence notes that scientists must refrain from knowingly harming their research subjects. Lastly, justice refers to the principle that the benefits and burdens of research must be fairly distributed. Principles of Drug Discovery: Patent Law in the Pharmaceutical Industry Paul A. Calvo, Ph.D., J.D. Director Sterne, Kessler, Goldstein & Fox Washington, DC 1 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. What is a patent? • A property right specified in Article I of the U.S. Constitution • Purpose: to promote the progress of science and useful arts by securing for limited times to authors and inventors the exclusive right to their respective writings and discoveries. 2 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. What is a patent – con’t • Term of a patent is 20 years from earliest filing date. • The rights are exclusionary • Is a right to exclude others AND NOT a right to make and use invention • Not an automatic right to practice invention – may need to obtain license for dominant patent 3 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Types of patents • Utility patent – Issued for the invention of a new and useful process, machine, manufacture, or composition of matter, or a new and useful improvement thereof 4 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Types of patents • Plant patent – for asexually reproduced distinct and new variety of plant Brunnera macrophylla Brunnera macrophylla ‘Sea Heart’ US PP24684 5 Brunnera macrophylla ‘Looking Glass’ US PP17829 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Types of patents • Design patent – legal protection granted to the ornamental design of a functional item 6 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. What is the value of patents? • • • • • • • 7 Used to raise capital Protects profitability and market share Ensures return on R&D dollars Aids access to competitors innovations Offensive uses (the sword) Defensive uses (the shield) Protects right to use (i.e., freedom to operate) • Stifles infringement charges by 3rd parties • Encourages cross-licensing arrangements to settle disputes S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Parts of a patent Face page 8 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Parts of a patent Written description 9 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Parts of a patent Figures 10 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Parts of a patent Claims 11 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Who is an inventor? • “The threshold question in determining inventorship is who conceived the invention. Unless a person contributes to the conception of the invention, he is not an inventor.” • Is a legal determination • Must be a person, not a corporation • Inventorship is determined on a claim-by-claim basis • Inventor not required to perform the work directly • Conception and reduction to practice • But performing work does not guarantee inventorship • Incorrect inventorship can be corrected 12 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Authorship vs. inventorship • Merely being an author does not satisfy the requirements of inventorship. • In the scientific world, authors of journal articles may be involved in designing or performing the experiments or in writing the resulting manuscripts. • Authorship is sometimes granted for the recognition of hard work or even for financial support. This is NOT to be confused with inventorship. 13 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Non-inventors • A person who: • Contributes an obvious element to the invention • Merely suggests an idea • Simply follows instructions • Explains how or why an invention works • Adopts derived information from another • Actually did the experiment, but did not conceive of the invention is NOT an inventor 14 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Conception and Reduction to Practice • An invention is conceived when a definite and permanent idea of an operative invention is known. Conception is complete when one of ordinary skill in the art could make the invention without undue research or experimentation. • Two kinds of reduction to practice • Actual reduction to practice requires making a working model of the invention that demonstrates that the invention will work to fulfill its intended purpose. • Constructive reduction to practice is accomplished by the filing of a patent application that enables one of ordinary skill in the art to make and use the invention without undue research or experimentation. 15 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Laboratory Notebooks • The Lab Notebook is the initial Record of the Invention • It is used to: • establish the date of the invention • overcome prior art • priority in a contest to determine who invented first • determine actual inventorship 16 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Laboratory Notebooks • Laboratory Notebooks should: • Be evidence of conception of the invention • Demonstrate diligence in reducing the invention to practice • Establish basis for corroboration by a non-inventor • Record discussions with collaborators • Every entry should be signed and dated by the Inventor, and • Be countersigned by a non-inventor 17 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Laboratory Notebooks • Notebooks are preferably: • Bound and written in ink • On sequentially numbered pages • Few or no eraser marks • Have an index • Be a coherent record of the experiments and their results • If using electronic notebooks: • Use software that permanently records dates of entries and an unalterable electronic signature • Print hard copies for corroboration • Adopt a standard procedure followed by all lab members 18 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. How to avoid inventorship issues? • Keep good records • Know your inventors • Know where they live, where they invented and what they invented • Know your invention • If you determine an error in inventorship – fix it! 19 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Federal Funding • Under the Bayh Dole Act, the US government encourages patenting of inventions made using government funds • Funding source MUST be disclosed in the patent application and in a separate form to the US government • The US Government has rights in the invention – they rarely take up these rights, but they do have them 20 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Types of applications • Provisional Application • Secures a priority date for the subject matter which is disclosed therein, but no more than this • No claims are required • Is not examined by the Patent Office • Expires after one year from the filing date unless it is converted to a non-provisional application • Small filing fee • May be used as a priority document for foreign filed application 21 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Types of applications • Non-provisional Application • Filed for all types of inventions • May claim priority date of prior provisional application • Published 18 months after earliest priority date • Must include claims • Is examined by the Patent Office • Proceeds through the process of prosecution until issue or abandonment • Filing fee depends on the number and type of claims filed 22 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Types of applications • Divisional application • Required by USPTO when 2 or more inventions are present in 1 application • Priority dates retained • Continuation in Part (CIP) application • Filed for improvements on existing applications • New material given priority of CIP filing • Old material retains original priority date • At least one common inventor 23 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Types of applications • Patent Cooperation Treaty (PCT) Application • International application • Single application designates selected member countries • Same filing date for selected countries • World Intellectual Property Organization (WIPO) • There is no such thing as a worldwide patent 24 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Patent claims • Composition versus Method claims • 1. A pharmaceutical composition comprising a tyrosine kinase inhibitor having the formula… • 1. A method of killing and/or inhibiting the growth of the blood stream form of a kinetoplastid protozoan of the species Trypanosoma brucei in a subject, the method comprising administering to the subject an effective amount of a tyrosine kinase inhibitor; wherein the tyrosine kinase inhibitor is a 4-anilinoquinazoline selected from the group consisting of AG1478, erlotinib, and lapatinib. 25 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Patent claims, continued • Dependent claims • The pharmaceutical composition of claim 1, wherein the tyrosinse kinase inhibitor is present at a concentration of 1-10 mM. • The method of claim 1, wherein the 4-anilinoquinazoline is administered at a dose of 10 ug/kg. 26 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Composition of matter claims • You cannot patent a composition that is already known • But… • You can get a composition claim to: • A new formulation of the composition • Combination of the composition to a delivery device 27 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Method claims • New use for an old drug is PATENTABLE • In fact, patents to multiple new uses can be obtained by several third parties provided that the new uses are novel and nonobvious variants 28 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Patent application timeline Priority Application PCT or Nonprovisional Application National/ Regional Phases Europe US Japan India China Etc. Grant Publication Start 1 year 18 months Additional data can be added to application 29 30 months 3-5 years Enforceable rights S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Requirements for patentability • • • • • • Utility Novelty (cannot have been described elsewhere) Non-obvious Enable a person of skill in the art to make and use invention Adequately described (Adequate written description) Best mode for carrying out invention – US Patent offices examine all of these requirements in view of what is CLAIMED. 30 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Utility • Likely the easiest of the patentability requirements • The invention must be useful 31 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Patentable Subject Matter: 35 U.S.C § 101 • Patentable Subject Matter: • Compounds/compositions of matter • Processes or methods of use • Machines (combination of elements that function together) • Non-patentable Subject matter • Products of nature • Printed materials (books, journals, etc.) • Abstract formulas/algorithms • Use of nuclear material or atomic energy 32 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Novelty • The invention was not known, described, or offered for sale prior to filing the patent application. 33 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Novelty: 35 U.S.C. § 102 • Publications or patents anywhere in the world • Journal articles as of the date of publication • Oral presentations • Public use in the United States • Experimental use • Clinical trials are exempt • Prior sale or offer for sale in the United States • Prior invention in the United States • Reference MUST TEACH ALL aspects of claimed invention – arranged as claimed 34 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Grace Period – U.S. • Time period prior to filing in which applicant’s own work cannot be used against them as prior art • Provides a limited time period to file after an intentional or accidental disclosure of the invention • Balances applicant needs with desire for early filing • NO GRACE PERIOD IN MOST COUNTRIES – ABSOLUTE NOVELTY REQUIREMENT! 35 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Obviousness • Inventions must be non-obvious • Cannot be simple modifications of an old invention • Obviousness is determined using Person of Ordinary Skill in the Art (POSA) standard 36 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Obviousness: 35 U.S.C. § 103 • Obviousness can be predicated on multiple references and/or general knowledge in the field • Must be reason to combine references however • Reference(s) must teach or suggest all of the claimed limitations • A POSA must have a reasonable expectation of success • VERY SUBJECTIVE TEST 37 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Obviousness – But wait! • Objective indicia of non-obviousness • Commercial success • Long felt but unmet need • Failure of others • Skepticism by experts • Praise by others • Copying of the invention by competitors 38 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Written Description • Patent specification must adequately describe the claimed invention in a manner as to enable a POSA to make and use the invention • Goal of written description is to show possession of invention • When claims encompass a genus – must describe a representative number of species or a structure common to members of genus 39 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Enablement • Experimentation is acceptable – just not UNDUE experimenation • Breadth of the claims; • Nature of the invention; • State of the prior art; • Level of ordinary skill in the art; • Predictability of the art; • Amount of direction provided in the specification; • Any working examples; and • Quantity of experimentation needed relative to the disclosure. 40 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Duty of disclosure in US • File Information Disclosure Statement • Duty on applicants, attorneys and anyone substantively involved in the patent application process to disclose all “material” information that they are aware of to the Patent Office • No duty to search • Duty continues until issuance • Failure to comply may render patent unenforceable 41 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Examination process in US 36 months US Examination Routine formalities Power of Attorney Reporting Events Official Filing Receipt Publication Information Disclosure Statement RCE Office Action Reply Notice of Allowability Final Office Action Reply Advisory Action Patent Granted 42 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Patent Application Process (3-5 Years on Average?) 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 43 Conceive the invention Write the application File the application Meet the application formalities – e.g., declaration, formal drawings Examination process begins Restriction requirement issued – sometimes Substantive Office Action issued Reply filed (usually there will be multiple iterations of this and the above step before an allowance is obtained) Appeal filed Application Allowed Pay necessary fees – file continuations? Patent issues Pay Maintenance Fees S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Patent term • 20 years from initial United States filing date • 17 years from issue date, if longer (older patents) • One patent per drug product can be extended up to 5 years due to FDA delay – Patent Term Extension (PTE) • Extensions may be possible for Patent and Trademark Office delay – Patent Term Adjustment (PTA) 44 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. America Invents Act (AIA) • Brings US in line with ROW – first to file system • Inventor will still have a personal grace-period, which is not available to inventors outside the US. • However, disclosures of third-parties who independently arrive at the invention information will be used against the inventor. • No grace-period relative to third party disclosures. 45 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. AIA proceedings Proceeding 46 Threshold Prior Art Estoppel? Third party pre-issuance submissions N/A Patents/printed publications N/A Post-grant review (PGR) More likely than not at least 1 claim unpatentable Any ground Raised or could have raised Inter partes review (after PGR) Reasonable likelihood that petitioner would prevail on at least 1 claim Patents/printed publications Raised or could have raised Ex parte reexam (unchanged) Substantial new question of patentability Patents/printed publications None Supplemental examination Substantial new question of patentability Any information N/A Derivation proceedings Claimed invention derived from another N/A N/A S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. AIA – Prior User Rights Defense • What happens when you are using a process that someone else later comes along and patents? Are you guilty of patent infringement even though you used the process before they filed? • NO! • The act provides a broader “prior use” defense when a business is using a process or machine as part of a process, and has been doing so for more than one year prior to the effective filing date of a patent that would cover the process or machine. • The defense is personal to the user, and can only be transferred with the business to which the process or machine relates. 47 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Should you always file for a patent? What about trade secrets?? 48 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. What is a trade secret? • Broadly speaking, any confidential business information which provides an enterprise a competitive edge may be considered a trade secret. • Trade secrets encompass manufacturing or industrial secrets and commercial secrets. • Unauthorized use of such information is regarded as an unfair practice and a violation of the trade secret. 49 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Advantages of Trade Secrets • • • • 50 Trade secret can cover abstract ideas Trade secret can last indefinitely Trade secret protection is comparatively cheap Trade secrets can create aura of mystique S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Patent versus Trade Secret • • 51 Advantages • Market exclusivity • Revenue opportunities – license • Leverage in negotiations and litigation • Deter/disrupt competitors Disadvantages • Disclosure is required • Cost (relative to maintaining know-how as trade secret) • Difficult to determine what to file on • Difficult to spot infringement • • S K G F. C O M Advantages • Maintain private competitive edge • Ability to protect know-how, embryonic ideas • No prosecution costs Disadvantages • Hard to police unathorized disclosure • No protection against reverse engineering • Employee turnover • Desire for inventors to publish © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Balance of issues Increased risk of unauthorized disclosure Increased harm of unauthorized disclosure 52 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Process patents can block marketing of product made • Process Patent Act – 35 U.S.C § 271(g) • Whoever without authority imports into the United States or sells or uses within the United States a product which is made by a process patented in the United States shall be liable as an infringer, if the importation, sale, or use of the product occurs during the term of such process patent. ….. A product which is made by a patented process will, for purposes of this title, not be considered to be so made after-• (1) it is materially changed by subsequent processes; or • (2) it becomes a trivial and nonessential component of another product. A+B→C 53 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Patenting and Commercializing Inventions: Is It Worth It? • Yes, and it is likely part of your job • The public benefits from innovation • IP is the only protection during development that provides cover for financial risks. • Patent prosecution can always be (and often is) abandoned – but cannot be started when it is too late (e.g., disclosures) • It will not interfere with the free exchange of information and reagents • Patenting does not preclude publishing 54 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Research Commercialization Provides Many Benefits • Provides means getting innovative products to the market for public benefit • Commercial & public recognition of important technologies • Attracts new R&D resources & partnerships for the University • Obtains return on investment • Stimulates economic development 55 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Research Commercialization: An Interdisciplinary Field Intellectual Property Discovery 56 Commercialization S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Product Commercialization: From Lab Bench to Customer TECHNOLOGY TRANSFER Discovery Intellectual Technology Property Transfer BUSINESS DEVELOPMENT ATTORNEYS Financial Corporate R&D Sales & Capital Partnership Clinical trials Marketing Regulatory Manufacturing 57 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. The Researcher’s Basic Obligations for Successful Commercialization • Keep accurate lab notebooks • Remember all disclosures can count against you so safeguard your rights • Work with tech transfer office staff, law firm and commercial partners. • CDAs/MTAs (Confidential Disclosure Agreements / Material Transfer Agreements) – are essential for the transfer of information and reagents 58 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Research Commercialization at Universities • University evaluate inventions for patenting • University work closely with inventors • Work with law firms and management of patents • Identify and negotiate with a commercial partner for license or collaboration agreements • Managing relationship with commercial partners 59 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Useful links and resources • Manual of Patent Examiners and Practitioners – MPEP • https://mpep.uspto.gov/RDMS/MPEP/current • US Patent and Trademark Office – USPTO • https://www.uspto.gov/ • World Intellectual Property Organization – WIPO • http://www.wipo.int/portal/en/index.html • Patent Law Blogs • http://patentlyo.com/ • http://www.patentdocs.org/ 60 S K G F. C O M © 2017 Sterne, Kessler, Goldstein & Fox P.L.L.C. All Rights Reserved. Biosimilars: Development and Approval Rita Raddatz Drexel 06 Mar17 1 Career Path BS in Pharmacy Student Co-op at Merrell Dow Pharmaceuticals Pharmacology Licensed Pharmacist and Research Associate at Merrell Dow Pharmaceuticals PhD Neuroscience with Molecular Pharmacology (Wash U) Post – Doc in Pharmacology Dept. (MUSC) Synaptic Pharmaceuticals Astra Zeneca Cephalon Teva Branded Pharmaceutical Products R&D Director, Protein and Cell Sciences Global Bioassays and Technology 2 Outline 1 Introduction to Biosimilars 2 Approval Pathway Requirements 3 Case Studies 4 Future of Biosimilars in US 3 What is a Biosimilar? The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) part of the Affordable Care Act was signed into law on March 23, 2010. BPCI Act creates an abbreviated licensure pathway, 351(k) of the Public Health Service Act (PHS Act), for biological products shown to be biosimilar to or interchangeable with an FDA-licensed reference product. Product is “highly similar” to an FDA-licensed biological product (the reference product), and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product. 4 Why Biosimilars? Annual cost of Prolia: ~ $1,650 per year TNF blockers: $15, 000 – $25,000 per year* Medical costs rising in many countries Boom in biologics sales (ex: Humira highest selling drug at $16 billion world-wide in 2016+) Blockbuster biologics set to go off patent Cost reduction by biosimilars expected to be small in %, but still $$ Generics small molecule drugs common 5 *(Bonafede et al, Adv Ther 2012) +(AbbVie Jan 27, 2017 press release) How is biosimilar different from generic drug? mAb Aspirin Much higher R&D, legal and manufacturing costs Adapted from: Developing the Nation’s Biosimilars Program, NEJM 2011 6 Steven Kozlowski, M.D., Janet Woodcock, M.D., Karen Midthun, M.D., and Rachel Behrman Sherman, M.D., M.P.H. Current Status of Biosimilars in US March, 2015 first approval of 351(k) biosimilar application, Sandoz Inc’s Zarxio, biosimilar to Amgen’s Neupogen (filgrastim, metG-CSF) Celltrion and Pfizer’s Inflectra, biosimilar of Janssen Biotech’s Remicade (infliximab, anti-TNFα) approved April 2016 Approval of Sandoz’s Erelzi, biosimilar of Amgen’s Enbrel (etanercept, TNF blocker) Aug 2016 Amgen’s Amjevita approved as biosimilar of AbbVie’s Humira (adalimumab, anti-TNF α) Sept 2016 Biosimilar Sponsor must provide at least 180 day notice to reference product sponsor after approval before marketing, ongoing litigation Several announced to be under review 7 Earlier Biosimilars in Europe– Why? Starting in 2006, EC has authorized 23 biosimilars for sale 3 infliximabs (2013-2016) and one etanercept (2016), others less complex proteins Some biologics that are off patent in US produced by others– but used full BLA pathway for approval EMA guidelines available as early as 2005 In the absence of a well defined path, risk was on industry to bring 351(k) application to FDA 8 Presented at DIA Biosimilars meeting 2012 Niklas Ekman, Ph.D. Senior Researcher, Quality/CMC Assessor Finnish Medicine Agency (FIMEA) 9 FDA Biosimilars Guidances Drafts ~ 2012; Finalized 2014 – ……. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Quality Considerations in Demonstrating Biosimilarity to a Reference Protein Product Biosimilars: Questions and Answers Regarding Implementation of the Biologics Price Competition and Innovation Act of 2009 Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants Clinical Pharmacology Data to Support a Demonstration of Biosimilarity to a Reference Product (Dec 2016) Nonproprietary Naming of Biological Products (Jan 2017) Interchangeability Draft Jan 2017, 60 days to comment, revisions likely 10 Outline 1 Introduction to Biosimilars 2 Approval Pathway Requirements 3 Case Studies 4 Future of Biosimilars in US 11 Basics of Demonstrating Biosimilarity Different than demonstrating a new drug is safe and effective. Totality-of-the-evidence approach consistent throughout The more evidence generated through the characterization process, the less clinical data a sponsor will be required to obtain Faster time to market Significantly less cost Ethical considerations of clinical trials 12 Comparative Studies Clinical Safety and Efficacy “residual uncertainty” Clinical Immunogenicity, PK/PD Animal studies, toxicity Extensive structural and functional characterization Adapted from: FDA’s Overview of the Regulatory Guidance for the Development and Approval of Biosimilar Products in the US Leah Christl, Ph.D. Associate Director for Therapeutic Biologics 13 Practical Considerations to Biosimilarity Biologics are complex products of cell lines or biological systems Biosimilar development must begin with identical protein sequence, where applicable. Similar concept to generic drugs that have the same chemical structure as the reference product. Expression system as close as reasonable to reference product (ex: CHO cell or bacteria) Originator company owns the actual clonal cell line expressing their protein (reference product) Manufacturing process, purification, formulation, product characterization and control key to achieving biosimilarity Iterative processes 14 Biologics Characterization Biologics are too complex to completely characterize by traditional analytical methods “The process is the product” Aspects that may alter product: Host cell line (CHO, yeast, …..) Growth medium composition Culture conditions (pH, temperature, aeration) Production type (batch, fed batch, perfusion) Growth regimen (duration, fed type, perfusion rate) Culture history (genetic stability) Hold times Purification Formulations Storage (buffer, container, stoppers, temperature) 15 EBG Biosimilars Satellite Symposium European Association of Hospital Pharmacists Congress 17 March 2016 16 Biosimilars Development in Practice Analytical Similarity Data Extensive structural and functional characterization of reference product Quality Target Product Profile (QTPP) should be defined early in product development. Understand the relationship between quality attributes and the clinical safety / efficacy profile QTPP should be based on analytical data from several batches of the reference medicinal product Includes impurities and product stability Characterize proposed biosimilar product quality profile Determine how proposed biosimilar lots compare to originator lots Identify and evaluate impact of any differences 17 Comparison to Reference Products Reference Product : the single biological product, licensed under section 351(a) of the PHS Act, against which a biological product is evaluated in an application submitted under section 351(k) of the PHS Act. Many lots of originator drug must be tested over several years Quality attributes of product on the marker may shift with manufacturing changes Example- comparison of glycans on lots of Enbrel before (light blue) and after (dark blue) change M Schiestl et al., Nat Biotech 2011 18 Animal Studies From FDA Guidances: Animal toxicity data are useful when uncertainties remain about the safety of the proposed product prior to initiating clinical studies. A comparison of PK/PD in an animal model may be useful. Not all biologics interact with target in relevant toxicology species Some biologics highly immunogenic in animals Sponsors should consult with FDA prior to the pre-IND/IND stage to ensure that they do not conduct unnecessary animal studies. Immunogenicity in pre-clinical species not predictive of humans 19 Clinical Studies The nature and scope of clinical studies will depend on the extent of residual uncertainty about the biosimilarity of the two products after conducting extensive structural and functional characterization and, where relevant, animal studies. Type of Clinical Data PK (pharmacokinetcs) and PD (pharmacodynamics) if relevant At least 1 clinical study that includes a comparison of the immunogenicity of the proposed and reference product Comparative clinical study if there are residual uncertainties about whether there are clinically meaningful differences . Extrapolation to indications not tested in clinical trial(s) For example, Amjevita was approved for 6 of the 10 indications approved for Humira Inflectra approved for all indications of Remicade, only rheumatoid arthritis and ankylosing spondylitis tested in comparative trials. 20 Sandoz Development Stages Strategy Sandoz advisory committee briefing document – public release 21 Outline 1 Introduction to Biosimilars 2 Approval Pathway Requirements 3 Case Studies 4 Future of Biosimilars in US 22 Sandoz/Novarits Zarxio Biosimilar to Amgen Neupogen Amgen seeing ~ $1.2 B (billion!) a year in sales Sandoz filgrastim (Zarzio) biosimilar approval from EMA in 2009 Filgrastim (GCSF; 18.8 kDa protein) High homology across mammalian species Treatment for neutropenia in cancer patients mostly Stimulates leukocyte proliferation Produced in bacterial cells, not glycosylated 23 Analytical Comparison: Zarxio to Neupogen 3- 16 lots compared in orthogonal tests covering: Sequence and disulfide bond formation N-terminal Edman sequencing LC/MS/MS Tryptic peptide map by HPLC Folding Circular dichroism NMR Functional assays Target Binding Cell -based potency Size Variants Size Exclusion chromatography Sub visible particles (microflow imaging) Sandoz advisory committee briefing document – public release 24 Analytical Comparison: Zarxio to Neupogen Highly Similar but not identical Variants profile Deamidation Truncated and norleucine variants Oxidation (below) Sandoz advisory committee briefing document – public release 25 Zarxio : Neupogen in Animal Studies Zarxio compared with Neupogen in five, GLP compliant, animal studies (rats and rabbits) Pharmacodynamics (neutrophil count) Toxicity (observations including blood chemistry, histopath) Toxicokinetics (drug levels at different time points) Local tolerance (hypersensitivity reactions) Different buffering systems Immunogenicity differences were investigated Sandoz advisory committee briefing document – public release 26 Zarxio : Neupogen Clinical Studies Studies previously conducted comparing with EU Neupogen as reference product Two pivotal trials specifically performed to compare Zarxio with US-licensed Neupogen PK/PD in 174 healthy volunteers Comparative safety and efficacy in 388 breast cancer patients. 90% confidence intervals AUC 27 Outline 1 Introduction to Biosimilars 2 Approval Pathway Requirements 3 Case Studies 4 Future of Biosimilars in US 28 CT-P13 (infliximab) Biosimilar to Remicade Celltrion’s infliximab was first biosimilar monoclonal antibody in the world (EC approval 2013) Biosimilar licensed in 67 countries (Inflectra /Remsima) Remicade ~ $4 billion a year in US sales (J&J) Anti-TNFα monoclonal antibody Human/ mouse antibody chimera More complex protein (~ 144 kDa) produced in mammalian cells Remicade approved for use in Crohn’s disease (adult and pediatric) Ulcerative Colitis (adult and pediatric) Psoriasis Psoriatic Arthritis Ankylosing Spondylitis Rheumatoid Arthritis 29 Analytical Comparison: CT-P13 to Remicade 3-way Comparison to Bridge US to EU Remicade (infliximab) Highly similar in key Quality Attributes Differences characterized and impact assessed Intact IgG (95.1% vs 98.2%, 98.3%) – cell potency results Glycation – not in TNF binding regions, no potency differences, immunogenicity assessed in clinical trails G0 content – 24 different ex vivo studies for function and binding comparisons Celltrion advisory committee briefing document – public release 30 Analytical Comparison of CT-P13 to Remicade (infliximab) Celltrion advisory committee briefing document – public release 31 Analytical Comparison of CT-P13 to Remicade (infliximab) Celltrion advisory committee briefing document – public release 32 CT-P13:Remicade in Animals and Clinical Trials Infliximab does not bind non-human TNFα Performed rat TK and immunogenicity assessment Remaining uncertainties addressed in clinical studies Charge variants High molecular weight forms Initially EU biosimilar approval based on 2 trials in AS and RA patients Post marketing safety and extension studies Pharmacodynamics, pharmacokinetics and safety compared Immunogenicity key clinical comparison (CT-P13, US, EU groups, resp) 15%, 12% and 33% positive (109 CD patients) 27%, 11%, 25% positive (211 healthy volunteers) Celltrion advisory committee briefing document – public release 33 Comparison of CT-P13 to Remicade (infliximab) 3-way clinical PK study to bridge EU and US Remicade Celltrion advisory committee briefing document – public release 34 Summary of CT-P13 Biosimilarity to Remicade Celltrion advisory committee briefing document – public release 35 Outline 1 Introduction to Biosimilars 2 Approval Pathway Requirements 3 Case Studies 4 Future of Biosimilars in US 36 Remaining Questions Extend indications (ex: Remicade licensed for 8 indications) The potential exists for a biosimilar product to be approved for one or more conditions of use for which the US-licensed reference product is licensed based on extrapolation of data intended to demonstrate biosimilarity in one condition of use. * Sufficient scientific justification for extrapolating data is necessary. * Pricing (Zarxio 15% less than Neupogen) Jan 2017 FDA Guidance on Naming – xxxx added to end to identify manufacturer for originator and biosimilar products Sandoz’s Zarxio (filgrastim-sndz) and Erelzi (etanercept-szzs), Amgen’s Amjevita (adalimumab-atto), Celltrion’s Inflectra (infliximab-dyyb) *FDA’s Overview of the Regulatory Guidance for the Development and Approval of Biosimilar Products in the US Leah Christl, Ph.D. 37 Associate Director for Therapeutic Biologics Remaining Question of Interchangeability Could be substituted at the pharmacy level FDA draft guidance just published Jan 2017 Clinical trials may require multiple switches between proposed biosimilar and marketed drug Subject to sate laws on substitution (18 states so far) Tennessee : a prescriber must allow substitution unless the prescriber determines “the medical necessity” New Jersey : the pharmacist must inform the prescriber of any substitution In the EU, member states regulate interchangeability (GaBI Online, Thimmaraju et al, 2015) 38 Future of Biosimilars in US Advisory Committees at least for first applicants with each new biosimilar target. Acceptance by doctors and patients FDA Continuing Medical Education Engagement of patient advocacy groups Patent protection strategies by originators: Constitutionality of Act Manufacture processes Formulations Delivery systems Uses FDA inspections of manufacturers? 39 Which Biologics to Make as Biosimilars? 40 Which Biologics to Make as Biosimilars? Market / patient needs Patent timing Complexity / manufacturability Fit with company’s portfolio and sales force Investment: 9-12 years start to market 41 Udpa and Million, Nat Rev Drug Discov 2016 Main Points Highly Similar – Not Identical Heavy reliance on analytical comparison data No clinically meaningful differences Totality of Evidence 42