Pharma Session 1: Sufficiently plausible?

Pharma Session 1: Sufficiently plausible? Monday, October 16 2017 09:00-10:30 www.aippi.orgg

Jürgen Meier, Vossius & Partner (Moderator) Dominic Adair, Bristows Charles Boulakia, Ridout & Maybee LLP Judge Xia Luo, No.3 Civil Division of the Supreme People's Court of China Michele Wales, InHouse Patent Counsel Logo 1 Logo 2 Logo 4 Logo 5 2

Jürgen Meier Vossius & Partner

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Clear? Unambiguous? Credible? Plausible? Complete? Sufficient? 5

Quid Pro Quo Purpose of the patent system: Support innovation by granting a monopoly in exchange for an enabling technical teaching (an invention). Technical Board 3.3.08 in T 1452/06: "A basic principle of the patent system is that exclusive rights can only be granted in exchange for a full disclosure of the invention, which includes the need to indicate how to exploit the invention." AGAIN (at least in the EPO): performable is enough, performed not required! A "deposit" facilitates or (in some case) even guarantees "performability and/or a plausible disclosure 6

A. 84 EPC: Clarity A. 84 EPC: Claims The claims shall define the matter for which protection is sought. They shall be clear and concise and be supported by the description. The claims, which define the matter for which protection is sought, must be clear, meaning not only that a claim must be comprehensible from a technical point of view, but also that it must define clearly all the essential features of the invention (Guidelines for Examination, F-IV, 4.5.1; T32/82). T 133/85 A claim which does not include a feature which is described in the application (on the proper interpretation of the description) as an essential feature of the invention, and which is therefore inconsistent with the description, is not supported by the description for the purpose of Article 84 EPC. (headnote I). 8

"Inventive Step" vs "Clarity" T 2001/12 Hence, if the claims do not comprise a feature which is described in the application as essential, or which is disclosed in the description as being indispensable for solving the problem defined in the application, then an objection under Article 84 EPC may properly arise. By contrast, the determination of the objective contribution of the claimed invention, i.e. having regard to the totality of the prior art, and in particular the objectively identified closest prior art, forms part of the examination for inventive step. (point 4.3) [ ], having regard to the prior art, and irrespective of what may be asserted in the description, it does not appear credible that the invention as claimed would actually be capable of solving the problem, then an objection under Article 56 EPC 1973 may be raised (point 4.4) Technical effect is not expressed in the claim vs. claimed subject-matter does not credibly solve the technical problem: - lack of essential feature(s) in the claim (but comprised in the description) A. 84 EPC (not clear) - in light of the prior art, solution is not credible/a not-disclosed essential feature is missing A. 56 EPC (no IS) A MEDICAL USE may be the essential technical effect! www.aippi.org 9

T 1329/04, "Factor-9/JOHN HOPKINS" Technical Board 3.3.8 coined the plausibility test and refused the application for lack of inventive step: The definition of an invention as being a contribution to the art, i.e. as solving a technical problem and not merely putting forward one, requires that it is at least made plausible by the disclosure in the application that its teaching solves indeed the problem it purports to solve. Therefore, even if supplementary post-published evidence may in the proper circumstances also be taken into consideration, it may not serve as the sole basis to establish that the application solves indeed the problem it purports to solve. Natural compound : per se patentable, but in this particular case: Unconventional structure and low homology in the absence of experimental evidence was not enough! 10

A. 83 EPC: Sufficiency Sufficiency of disclosure within the meaning of Art. 83 EPC must be assessed on the basis of the application as a whole including description and claims and not of the claims alone ("White Book", II.C.2; T 14/83) Substantially any embodiment of the invention, as defined in the broadest claim must be capable of being realized on the basis of the disclosure and the common general knowledge. The person skilled in the art even recognizes and rectifies errors on the basis of such knowledge. ("White Book", II.C.2; T 226/85, T 206/83, T 772/89,...) This also holds true for embodiments which are defined as optional or preferred (T 206/13) 11

T 2094/13 on "broad subject matter" "While it is established case law that claims can validly cover broad subjectmatter, the question of the allowability of a broad claim versus the requirement of sufficiency of disclosure is one which is strictly assessed on a case-by-case basis, influenced by the extent to which the information in the patent in suit could be used to develop further embodiments without a major conceptual leap; e.g. decision T 636/97 [...]" ; Reason 22 12

How much Data for a Medical Invention? In general, there must be a plausible disclosure of the medical use. This is normally accepted if a correlation between the active ingredient and the disease (or the "effect" obtained) has been established (T 163/08). Plausibility can be generated by in vitro experiments. Clinical trials are normally not required. 13

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Dominic Adair Bristows LLP (UK)

A matter of policy Plausibility is a bar to speculative claiming (i.e. armchair inventions) Are armchair patents always bad? Not if self-evident that they will work Very little is self-evident in pharma, especially 2 nd medical use Plausibility is like a quality control assessment for patents, conducted at the filing / priority date Not mandated by legislation (absent from TRIPS, PCT, EPC, UK Patents Act) What does plausibility mean? More than "not incredible" is required there must be some real reason for supposing that the statement is true (Lord Justice Jacob in Lilly v HGS) 16

The EPO Approach First case: T939/92 Agrevo (1995) An invention requires a technical contribution Applies to inventive step and scope of claims and rules out arbitrary selections (lack technical contribution) Where there is any doubt as to whether the invention will work, the patentee must prove the contribution is plausible Post-filed evidence: if negative, can be used to attack the patent; if positive can support plausibility but not as sole basis How much proof is required to show plausibility? T609/02 Salk: it must be shown, for example by appropriate experiments, that the product has an effect on a disease process so as to make the claimed therapeutic effect plausible 17

The UK Approach First case: Prendergast s Application (1999) Jurisprudence now extends to: Inventive step (e.g. Conor v Angiotech, 2008) Industrial applicability (e.g. HGS v Lilly, 2011) Insufficiency (e.g. Regeneron v Genentech, 2013) Priority (e.g. Hospira v Genentech, 2014) Novelty (e.g. Merck v Ono, 2015) UK generally tends to follow the EPO approach but not perfect alignment (e.g. T903/05 Gemvax) Plausibility threshold very low and held to be different from the fair expectation of success standard in the was it obvious to try? test (Actavis v Lilly, 2015) 18

Unanswered Questions Does the plausibility threshold change according to the invention (and its merit)? Should an applicant s plausibility package affect claims interpretation? How does plausibility apply to embodiments within the claims scope that an applicant didn t foresee at the time of filing? How many failures are allowed before a common principle does not apply to substantially everything within the claim? If a molecular mechanism is plausible at the priority date, but later shown to be wrong, is the patent invalid if the invention still (mysteriously) works? 19

Plausibility in the UK - Summary Citation Claimant Defendant Patent Data Outcome [2016] EWHC 299 (Pat) Merck Shionogi EP 1 422 218 Yes in vitro biochemical assays Implausible [2016] EWHC 1045 (Ch) GSK Wyeth EP 2343308 Yes - serum bactericidal assays Plausible [2016] EWHC 24 (Pat) Accord Medac EP 2 046 332 No Plausible [2015] EWHC 3294 (Pat) Actavis Eli Lilly EP 0 721 777 No Plausible [2014] EWHC 3916 (Pat) Idenix Gilead EP 1 523 489 No Implausible [2015] EWHC 2973 (Pat) Merck Ono EP 1 537 878 Yes - in vivo mouse study Plausible [2016] EWCA Civ 1006 Warner Lambert Actavis EP 0 934 061 Yes - in vivo mouse study Implausible [2014] EWHC 1094 (Pat) Hospira Genentech EP 0 590 058 No Plausible [2013] EWCA Civ 925 Mylan Yeda EP 0 762 888 Yes - toxicity analyses in vivo (mice) and in vitro Plausible [2013] EWHC 1737 (Pat) Eli Lilly Janssen EP 1 994 937 Yes - in vivo mouse study Implausible [2013] EWCA Civ 93 Regeneron Bayer EP 1 238 986 Yes - in vitro studies using bovine cells Plausible [2008] EWHC 1903 (Pat) HGS Eli Lilly EP 0 939 804 No - but contains examples of 'cloning and expression of neutrokine-a' experiments undertaken in literature Plausible 20

Charles Boulakia Ridout & Maybee LLP

Canada: Sufficiency of Disclosure 27 (3) The specification of an invention must (a) correctly and fully describe the invention and its operation or use as contemplated by the inventor; (b) set out clearly the various steps in a process, or the method of constructing, making, compounding or using a machine, manufacture or composition of matter, in such full, clear, concise and exact terms as to enable any person skilled in the art or science to which it pertains, or with which it is most closely connected, to make, construct, compound or use it; (c) in the case of a machine, explain the principle of the machine and the best mode in which the inventor has contemplated the application of that principle; and (d) in the case of a process, explain the necessary sequence, if any, of the various steps, so as to distinguish the invention from other inventions....not to be conflated with utility requirement under s.2 22

Sufficiency of Disclosure (i) What is the invention (ii) How does it work? (iii) Having only the specification, can a POSITA successfully produce the invention using only the instructions contained in the disclosure 23

Sufficiency of Disclosure Disclosure needs only to describe the invention; how it works; and contain enough information to enable a skilled person successfully produce the invention using only the instructions contained in the disclosure. 24

Sufficiency of Disclosure Are prophetic examples enough? As long as a skilled person can successfully produce the invention using only the instructions contained in the disclosure. If the skilled person, without resorting to inventive means, would be able to make the claimed invention based on common general knowledge and noninventive experimentation, the specification is sufficient. But if a skilled person must undertake a minor research project to put invention into practice then the patent is insufficient. 25

Canada: Sound Prediction Utility must be demonstrated or soundly predicted Patent as filed must have: 1. Factual basis for prediction 2. Articulable [sic] and sound line of reasoning from which the desired result can be inferred from the factual basis 26

Data Obtained Post-Filing Canada: Can almost never be used. Cannot be used to support utility/sound prediction Cannot be used to bolster sufficiency of disclosure Cannot be used to support non-obviousness 27

Data Obtained Post-Filing Canada: Sometimes acceptable to show: that the invention was operable at time of filing that the spec was enabling at time of filing (if no undue experimentation or undue adaptation of methods ) commercial success to construe general knowledge at claim date or construe/clarify patent claims as at publication date to compare to cited prior art 28

Canada: Promise of the Patent Doctrine is GONE!* (*Some conditions may apply) 29

Judge Xia Luo, No.3 Civil Division of the Supreme People's Court of China

Post-filing data and sufficient disclosure in China 31

Outline Opening Remarks ------Respect On Uniqueness Of Inventions In Chemical Field 1. Post-filing Data----Attitude /Relevance of Evidence 2. Technical contribution not described in the description 3. Step For Determining Sufficiency Of Disclosure 4. Sufficient Disclosure Of A New Chemical Product----Connect experimental data with the asserted therapeutic effects/specific uses. Scenario: Applicant submits, on the basis of post-filing experimental data, that an application complies with Article 22.3 (inventive step) or Article 26.3 (sufficient disclosure) of the Chinese Patent Law. 32

Find Issues Q1. What is the prerequisite for such evidence to be adopted? Why time and subject are two main factors that should be considered in determining whether or not to be the admissible evidence? Q2. Should the technical effects demonstrated by the experimental data be disclosed in the original description? Why? Q3. Whether is there an order for examining the reproducibility of a technical solution and the technical problem to be solved by the technical solution, when assessing whether an application complies with sufficient disclosure? Q4. When the application did not disclose experimental data in connection with the asserted therapeutic effects or specific uses, would it only leads to lack of inventive step? Whether the description fulfills the requirement of sufficient disclosure? 33

Q1. Post-filing data (attitude of mind) Patent Reexamination Board and Warner Lambert vs. Beijing Jialin Supreme Court s Administrative Judgment (2014) Xing-Ti-Zi No.8 Holding of the Supreme People s Court: 1. Evidence, which can demonstrate the common knowledge in the art prior to the priority date of the subject patent, is admissible by the Court. 2. Post-filing experimental evidence should be considered, rather than not being considered only because it is filed after the filing date, if it can prove that with the knowledge level and cognitive ability of a person skilled in the art before the filing date, one can carry out the invention based on the disclosure of the description. ---- The data shall not be rejected merely because they are filed after the filing date. 34

Q1. Post-filing data (attitude of mind) Holding of the Supreme People s Court (continued): 3. When judging whether or not experimental evidence should be admissible, two factors, i.e., time and subject, should be strictly examined. (1) In terms of time, experimental conditions, process, etc. used in the experimental evidence should be directly obtainable or easily conceivable by a person skilled in the art upon reading of the description before the filing date or the priority date; (2) In terms of subject, it should be based on the knowledge level and cognitive ability of a person skilled in the art. A1.---- The prerequisite of adopt these data must be demonstrating that the technical effects recited in the original application documents can be achieved by a person skilled in the art at the filing date. 35

Q2. Post-filing Data (Relevance of Evidence) Takeda Pharmaceutical Co. Ltd. vs. PRB, Sichuan Haisco Pharmaceutical Co. Ltd., and Chongqing Pharmaceutical Research Institute Co. Ltd. Supreme Court s Administrative Ruling (2012) Zhi Xing Zi No. 41 Fact: The Patentee submitted Counter-evidence 7 to prove that combined use of pioglitazone and glimepiride has unexpected synergistic effects compared with use of either component alone and unexpected effects compared with other combined uses In this case, the description of the patent at issue only proves that the combined use of an insulin sensitivity enhancer and an insulin secretion enhancer achieved better effects in lowering blood sugar than the use of either single drug, via the experimental results achieved by the combined use of pioglitazone and voglibose or the combined use of pioglitazone and glibenclamide. However, the description does not mention the advantages or disadvantages of different combined administrations compared to one another. 36

Q2. Post-filing Data (Relevance of Evidence) Supreme Court s Administrative Ruling (2012) Zhi Xing Zi No. 41 Holding of the Supreme People s Court : The effect to be proved by the experimental data submitted by Takeda is neither described nor proved in the original application documents, so such experimental data cannot serve as a basis for assessing inventiveness of a patent. Submitting comparative experimental data to demonstrate that the claimed technical solution involves an inventive step over the prior art, the prerequisite for such data to be adopted is that the data are directed to technical effects expressly described in the original application documents. A2.------ Technical solutions, technical effects, etc. which are not disclosed in the description generally cannot serve as the basis for assessing whether the invention conforms with the requirements for granting a patent right. 37

Q2. Post-filing Data (Relevance of Evidence) Supreme Court s Administrative Ruling (2012) Zhi Xing Zi No. 41 Reasoning of the Supreme People s Court: Experimental data submitted after the filing date does not belong to the contents described and disclosed in the original application documents, and the public cannot get access to this information. If such experimental data do not belong to the prior art of the application, they are not available to a person skilled in the art before the filing date, it shouldn t be admissible. Otherwise, based on such experimental data, to acknowledge that the technical solution can achieve the technical effects would offend against the principle of first to file and depart from the essence of the patent system, namely, a patent system of disclosure in exchange for patent protection. Thus, granting a patent based on such post-filing data is unfair to the public. 38

Q3. Step For Determining Sufficiency Of Disclosure Supreme Court s Administrative Judgment (2014) Xing-Ti-Zi No.8 Fact: The subject matter of Claim 1 is crystalline form I atorvastatin hydrates having 1-8 moles of water, characterized by X-ray powder diffraction pattern (XPRD). The water content of the crystalline form I atorvastatin hydrates is a component and structural feature of the product invention. No matter based on the general disclosure of the patent description or based on the specific Examples therein, one cannot believe that the crystalline form I atorvastatin hydrate of the patent with 1 to 8 mole, preferably 3 mole, of water can be prepared. The description fails to disclose the water contained in the crystalline form I atorvastatin hydrate of the patent in a manner sufficiently clear and complete. Uncompleted?Protect experimental data? 39

Q3. Step For Determining Sufficiency Of Disclosure Supreme Court s Administrative Judgment (2014) Xing-Ti-Zi No.8 The Beijing Higher Court determined the technical problem to be solved by the invention first and then considered chemical/physical property parameters associated with the technical problem to be solved. ----reject the decision made by PRB The Supreme People s Court said it was inappropriate, without judging the reproducibility of the technical solutions defined by the claims,and should be corrected. ----uphold the decision made by PRB Q3. whether is there an order for examining the reproducibility of a technical solution and the technical problem to be solved by the technical solution when evaluating whether an application complies with sufficient disclosure? 40

Q3. Step For Determining Sufficiency Of Disclosure Holding of the Supreme People s Court: If the description sets forth a technical means, but a person skilled in the art cannot solve the technical problem as addressed in the invention by using the technical means, the description is not in line with sufficient disclosure. The technical problem to be solved by the invention shall be considered does not mean that the technical problem to be solved by the invention shall be considered firstly. If the technical solution of an invention cannot be reproduced in itself, the description, obviously, is not in line with the provisions of sufficient disclosure, then it will be meaningless to consider the technical problem to be solved by the invention. Emphasis on reproducibility of a technical solution (preparation + identification + use/effect) 41

Q3. Step For Determining Sufficiency Of Disclosure Reasoning of thesupreme People s Court: For a chemical invention, there is a logical order among the reproduction of the technical solution, the solving of the technical problem and the achievement of the technical effect, wherein whether the technical solution is reproducible according to the disclosure of the description should be determined at first, and whether the technical problem is solved and the technical effect is achieved may be determined after that. A3---- Whether an invention in chemical filed can be carried out is difficult to be predicted and needs to emphasis on reproduction of the technical solution. In the case of not confirming whether the technical solution per se can be carried out, it is meaningless to consider whether the technical solution can solve the corresponding technical problem and achieve the beneficial technical effect relative to the prior art. 42

Q4. Sufficient Disclosure Of A New Chemical Product MT Pharma v. PRB Supreme Court (2015) Zhi-Xin-Zi No. 352 The Beijing Higher Court held that, Regarding a claim directed to a novel compound product or the preparation method thereof, it cannot be concluded that the description lacks sufficient disclosure just because the description fails to sufficiently disclose experimental data on the effect or specific use of the novel compound. The fact that the description fails to prove the therapeutic effect or specific use may lead to lack of inventive step or practicability. But this is different from the issue of sufficient disclosure in the description. The Supreme People s Court said it was inappropriate, and should be corrected. Respect on the Uniqueness of Inventions in Chemical Field----Quantitative and qualitative experimental data for assessing the sufficient disclosure 43

Q4. Sufficient Disclosure Of A New Chemical Product Holding of the Supreme People s Court 1. The sufficient disclosure of a novel compound requires that the description must describe and verify at least one use or technical effect thereof. The therapeutic effect or specific use of the novel compound cannot merely be considered when assessing the inventive step and practicability. 2. The description should disclose the technical information on whether it has utilization value in industry and whether it has been substantively completed. 3. Where the claimed invention is a chemical product itself, the description shall describe the identification, preparation and use and/or its technical effect of the product. 44

Q4. Sufficient Disclosure Of A New Chemical Product MT Pharma v. PRB Supreme Court (2015) Zhi-Xin-Zi No. 352 Reason of the Supreme People s Court: In most circumstances, it is difficult to predict whether a technical solution can be carried out and what use/effect the technical solution has, which needs to be confirmed by experimental results. Issue: When shall the experimental data showing the therapeutic effect or specific use of a novel compound be considered? inventive step or sufficiently disclose. FIND YOUR ANSWER TO QUESTIONS? 45

Michele Wales InHouse Patent Counsel

Patentable Subject Matter Supreme Court Decisions Starting 2010 Abstact Ideas: Bilski and Alice Laws of Nature/Natural Principals: Mayo Natural Products: Myriad Disproportionately Impacts Biopharmaceutical Sector Diagnostic Companies (Mayo) 47% of approved drugs no longer be patentable Inconsistent with TRIPS Very Effective Tool for Defendants Federal Circuit 92% invalid District Court 62% invalid Increasing number of cases filed 47

Type of Data to Support Patent Filing Prophetic Examples Must be written in past tense. Confirmatory Post-Published/Generated Data. Deposits Satisfy Sufficiency/Enablement Required if claims recite specific clones. Deposit needed prior to allowance (after filing). Must release all restrictions on grant. Competitors can access. 48

Amgen v. Sanofi/Regeneron, Fed. Cir. 2017-1480 (Oct. 5, 2017) Cholesterol treatment - antibodies bind to PCSK9, thereby lowering high LDL levels Amgen - (Repatha TM ) FDA approval in Aug. 2015 Sanofi (Praluent TM ) FDA approval July 2015 Representative Claim An isolated monoclonal antibody, wherein, when bound to PCSK9, the monoclonal antibody binds to at least one of the following residues: [list of specific amino acids], and wherein the monoclonal antibody blocks binding of PCSK9 to LDL[-]R. 49

Amgen s Disclosure in US8,829,165 and US8,859,741 Repatha TM sequence not disclosed 22 antibody sequences binding to same antigen disclosed X-ray crystallography of 2 antibodies disclosed. Detailed methods of screening for antibodies using PCSK9 disclose 50

Post-Published Evidence Can be used to argue lack of WD/Enablement of claimed genus. Evidence of extensive experimentation after filing date to generate antibodies falling within claimed genus. Even alleged infringers evidence Used to Defeat Patentability 51

Antibody Exception Eliminated Past: Small Molecule: Specific description of structural features Antibody: Well-characterized antigen supported broad genus claim to antibody 52

Structure of Antibody Needed Patent to antibody; antigen is not invention WD for Antibodies - same as Small Molecules Claims at Risk Composition of Matter - broad antibody genus Methods of treatment using antibody genus claims USPTO will likely issue new guidance Look at licenses Increase competition in antibody therapeutics 53

Summary Issue Yes No Are Prophetic Examples in Specification Sufficient to Satisfy Enablement/Sufficiency? Ability to Rely on Post-Published Data Data Does Every Embodiment in Patent Application Need to be Enabled? Can Deposits Satisfy Enablement/Sufficiency? Ability to Patent Natural Products without something more? Ability to Patent Diagnostics without something more? United States CAN* EPO United States China EPO EPO* (claims) United States CAN* EPO EPO China EPO* China* CAN* United States* CAN China China United States CAN* United States CAN* China 54

Thank you for your attention! Questions?