6 - Coehn and Lavoie

Small molecules, big differences?
Comparing patentability of small molecule pharmaceu:cals in the US to Europe Teresa Lavoie Markus Coehn Overview •  Inven2ve Step in EP and Obviousness in US •  Double Paten2ng •  Polymorphs •  Nega2ve Claim Limita2ons and Disclaimers •  Express •  Prosecu2on History-­‐based Inven:ve Step Analysis for Small Molecules •  EPO follows the problem-­‐solu2on approach (p-­‐s-­‐a) •  p-­‐s-­‐a aimed at avoiding a hindsight analysis of the prior art •  p-­‐s-­‐a makes it rela2vely easy to obtain protec2on for an individual compound 3 Double paten:ng before the EPO: •  No express legal provisions in the EPC •  Sanc2oned in G 1/05 and G 1/06 for divisional applica2ons •  Claims in two applica2ons for the same applicant have to be „quite dis2nct in scope and directed to different inven2ons” (Guidelines G-­‐IV-­‐5.4) •  No generally accepted standard for determining „dis2nct subject-­‐maYer“ •  EPO generally follows an applicant-­‐friendly approach •  Ques2on of obviousness expressly rejected in T 587/98, Reasons 3.4 Obviousness of Small Molecules in the US Otsuka Pharma v. Sandoz, 678 F.3d 1280 (Fed. Cir. May 7, 2012) •  Case addresses small molecule “lead compound analysis” and differences in applying the same in obviousness vs. obviousness-­‐type double paten2ng. •  Affirmed non-­‐obviousness ruling because there was no clear and convincing evidence showing that one of ordinary skill would have chosen the asserted prior art compound as the lead compound for further development, or that one of ordinary skill would have been mo2vated to modify the alleged lead compound to make the patented chemical compound at issue with a reasonable expecta2on of success. •  Claimed compound – aripiprazole (Abilify®) for trea2ng schizophrenia, bipolar disorder, and depression 5 Compound at issue -­‐ aripiprazole State of the art •  Schizophrenia •  Posi2ve symptoms -­‐ hallucina2ons and delusions •  Nega2ve symptoms -­‐ flat affect, poverty of speech, inability to experience pleasure, lack of desire to form rela2onships, and lack of mo2va2on •  An2psycho2cs “typical” “atypical” Three “lead” compounds -­‐ 1 •  U.S. Patent No. 4,734,416 (“the ‘416 patent”) •  Broad genus disclosed covering “approximately nine trillion compounds.” •  Compound claimed specifically and as the ac2ve ingredients in a claim to “A method of producing an an2histaminic effect in a mammal…” Three “lead” compounds -­‐ 1 Compound No. ED50 5 2.1 6 9.3 16 15.1 39 2.5 41 (Unsub. botoxy) 5.5 42 10.7 43 3.4 44 0.53 45 8.1 Three “lead” compounds -­‐ 2 •  Disclosed in two foreign counterparts to ‘416 patent (SE and DE) •  SE “discloses dozens of carbostyril compounds” •  2,3-­‐dichloro propoxy is 1 of 96 compounds disclosed in Example 134 alone •  DE disclosure is substan2ally the same as the SE Three “lead” compounds -­‐ 3 •  Otsuka development compound that was tested in humans as a poten2al an2psycho2c •  “the an2-­‐psycho2c ac2on was not strong but the strength of the ac2va2ng ac2on stood out” •  “expected to have fewer side effects than conven2onal drugs of the same class” •  “experienced sleeplessness, stagger, weakness, fa2gability, heavy headedness, lack of mo2va2on and disturbed concentra2on, which were so severe that they were not able to perform daily rou2ne work.” Obviousness – Lead Compound •  “prima facie obviousness under the third Graham factor generally turns on the structural similari2es and differences between the claimed compound and the prior art compounds. Daiichi Sankyo Co. v. Matrix Labs., Ltd. 619 F.3d 1346, 1352 (Fed. Cir. 2010) •  Two-­‐part inquiry 1.  Selec2ng a lead compound 2.  Reason or mo2va2on for modifying a lead with a reasonable expecta2on of success Obviousness – selec:ng a lead compound •  Relevant Inquiry: Whether a chemist of ordinary skill would have selected the asserted prior art compounds as lead compounds, or star2ng points, for further development efforts •  “a compound in the prior art that would be most promising to modify in order to improve upon its … ac2vity and obtain a compound with beYer ac2vity” •  Takeda Chem. Indus., Ltd. v. Alphapharm Pty., Ltd. (Fed. Cir. 2007) •  “a natural choice for further development efforts” •  Altana Pharma AG v. Teva Pharm. USA, Inc. (Fed. Cir. 2009) Obviousness – reason or mo:va:on to modify •  Relevant inquiry: Whether the prior art would have supplied a PHOSITA with a reason or mo2va2on to modify a lead compound to make the claimed compound with a reasonable expecta2on of success •  As with any obviousness inquiry, mo2va2on can come from any number of sources •  “it is sufficient to show that the claimed and prior art compounds possess a ‘sufficiently close rela2onship…to create an expecta2on’…that the new compound will have ‘similar proper2es’ to the old” AvenKs Pharma v. Lupin (Fed. Cir. 2007) District Court’s “lead compounds” •  DC iden2fied two viable lead compounds: •  clozapine and risperidone were the only two marketed an2psycho2c compounds at the 2me •  No carbostyril compounds were marketed or known to have good an2psycho2c ac2vity Review of three “leads” -­‐ 1 •  ‘416 patent explicitly discloses an2histaminic effect for the “lead” compound •  Nakagawa declara2on did not support selec2on of the compound Review of three “leads” -­‐ 2 •  SE patent listed 2,3-­‐dichloro propoxy as one of hundreds compounds poten2ally useful for an extensive list of central nervous system controlling ac2vi2es •  Defendants tried to analogize to Pfizer (Fed. Cir. 2007) alleging that generic disclosure is all that is required for obviousness Review of three “leads” -­‐ 3 •  Taken as a whole, prior art taught away from using OPC-­‐4392 as a lead compound •  Necessary modifica2ons: 1.  Conver2ng carbostyril core into a dihydrocarbostyril 2.  Changing propoxy linker to butoxy 3.  Replacing 2,3-­‐dimethyl subs2tuents to 2,3-­‐dichloro Obviousness of Small Molecules in the US •  Generic drug companies do not like the Lead Compound test •  Lead compound inquiry is contrary to KSR-­‐mandated flexible approach to obviousness •  Have consistently lost in Hatch-­‐Waxman li2ga2on on NCEs •  Contrast formula2on cases •  Examiners open do not apply the lead compound analysis, and instead apply a flexible obviousness analysis •  Typically pluck structurally closest molecule from the prior art and argue (hindsight?) that PHOSITA would have been mo2vated to make the modifica2ons to result in the claimed molecule. •  Can s2ll rely on surprising and unexpected results to rebut obviousness 19 Obviousness-­‐Type Double Paten:ng in the US •  Non-­‐statutory, grounded in public policy – prevent unjus2fied extension of patent term and possible harassment of an infringer by mul2ple unrelated patentees •  Two or more patents or applica2ons must have at least one common inventor and/or be commonly assigned or subject to a joint research agreement •  Focus necessarily is on the claims •  For small-­‐molecules, do the claims serng forth generic and/or species claims in the reference patent/applica2on an2cipate and/or render obvious the claims in the case at issue? 20 Otsuka -­‐-­‐ OTDP Analysis is different from obviousness analysis •  The patent principally underlying the double paten2ng rejec2on need not be prior art. •  Lead compound status is presumed for a claimed compound •  “[T]he issue is not whether a skilled ar2san would have selected the earlier compound as a lead compound. That is so because the analysis must necessarily focus on the earlier claimed compound over which double paten2ng has been alleged, lead compound or not.” •  Implica2ons for follow-­‐on applica2ons for patentee vs. third party OTDP – clarifying Geneva Pharm v. GlaxoSmithKline PLC •  Judge Rader’s footnote: The dis2nc2ons between obviousness under 35 U.S.C. § 103 and nonstatutory double paten2ng include: 1. 
2. 
3. 
The objects of comparison are very different: Obviousness compares claimed subject maYer to the prior art; nonstatutory double paten2ng compares claims in an earlier patent to claims in a later patent or applica2on; Obviousness requires inquiry into a mo;va;on to modify the prior art; nonstatutory double paten;ng does not; Obviousness requires inquiry into objec2ve criteria sugges2ng non-­‐
obviousness; nonstatutory double paten2ng does not. 349 F.3d 1373, 1378 (Fed. Cir. 2003) Limita:ons of Geneva •  Geneva involved nonstatutory double paten2ng based on an2cipa2on, not obviousness. •  Geneva does not stand for the proposi2on that, in considering whether one compound is an obvious variant of another for OTDP, analyzing the compound of the prior claim for a reason or mo2va2on to modify is irrelevant. Claims not obvious under ODTP analysis – no mo:va:on to modify •  None of the prior art references provided sufficient mo2va2on to modify the “lead” compounds to result in aripiprazole •  Field was thought to be “very unpredictable” and an2psycho2c research at that 2me was “notoriously unsuccessful” Polymorphs in Europe: T 777/08 •  Claim directed to the novel polymorph IV of atorvasta2n •  Closest prior art: amorphous form •  Demonstrated advantages: shorter filtra2on and drying 2mes for form IV compared to the amorphous form •  Ques2on: Obviousness? T 777/08 – 1st Headnote At the priority date of the patent in suit, the skilled person in the field of pharmaceu2cal drug development would have been aware of the fact that instances of polymorphism were commonplace in molecules of interest to the pharmaceu2cal industry, and have known it to be advisable to screen for polymorphs early on in the drug development process. Moreover, he would be familiar with rou2ne methods of screening. Consequently, in the absence of any technical prejudice and in the absence of any unexpected property, the mere provision of a crystalline form of a known pharmaceu;cally ac;ve compound cannot be regarded as involving an inven;ve step. T 777/08 – 2nd Headnote When star2ng from the amorphous form of a pharmaceu2cally ac2ve compound as closest prior art, the skilled person would have a clear expecta2on that a crystalline form thereof would provide a solu2on to the problem of providing a product having improved filterability and drying characteris2cs. The arbitrary selec;on of a specific polymorph from a group of equally suitable candidates cannot be viewed as involving an inven;ve step. T 777/08 – 3rd Headnote The skilled person in the field of drug development would not be dissuaded from aYemp2ng to obtain a crystalline form by the prospect of a poten;al loss of solubility and bioavailability when compared to the amorphous form, but would rather regard this as being a maIer of trade-­‐off between the expected advantages and disadvantages of these two classes of solid-­‐state forms. T 777/08 – Outlook for Europe •  no follow-­‐up case law to clarify T 777/08 •  presumably few unexpected proper2es in comparison to the amorphous form •  Comparison of various polymorphs necessary to avoid arbitrary selec2on from a group of equally suitable candidates •  Hurdle substan2ally increased in Europe Polymorphs in the US Claims to polymorphs need to be: •  Clear – no accepted nomenclature for claiming •  typically need to include physico-­‐chemical parameters in the claims •  XRDP peaks, DSC, IR, NMR, density, solubility profiles •  Supported – sufficient disclosure re: synthesis and characteriza2on to support wriYen descrip2on, enablement 30 Polymorphs in the US •  Novel •  Compara2ve data to previously known amorphous or x-­‐al forms •  Inherency concerns •  Non-­‐obvious •  Note typically considered unpredictable to prepare in US •  Rou2ne rejec2ons in base composi2on of maYer case for limita2on such as “or a polymorph thereof” •  Need to adequately describe prepara2on and characteriza2on •  May need some sort of beneficial feature – physical/formula2on benefit, not yet clinical superiority over amorphous or other x-­‐al form 31 Polymorphs in the US •  Need to face global and commercial exclusivity reality •  Contrast EP and other jurisdic2ons (IN, CN, KR) with US •  Orange Book prac2ce of lis2ng polymorph patents •  Bioequivalent (if listed polymorph not the form in the marketed drug) •  Barrier to generic entry? •  If no substan2al formula2on or clinical efficacy difference? •  Language on drug label as to safety or efficacy difference? 32 Disclaimers before the EPO: Disclaimers and Nega:ve Claim Limita:ons in the US Santarus, Inc. v. Par Pharmaceu:cal, Inc., 694 F.3d 1344 (Fed. Cir. 2012) •  Patent claim included limita2on to a composi2on for trea2ng an acid-­‐caused gastrointes2nal disorder: “wherein the composi2on contains no sucralfate.” •  Specifica2on indicated claimed composi2on was “advantageous” to sucralfate and noted disadvantages of sucralfate. •  District Court held that specifica2on needed to include evidence that sucralfate is “contraindicated” to meet the wriYen descrip2on requirement for the nega2ve limita2on. 34 Disclaimers and Nega:ve Claim Limita:ons in the US •  Fed. Cir. disagreed: “The claim limita2on . . . restricted the claims to this preferred use of the [claimed] formula2on. This exclusion narrowed the claims, as the patentee is en2tled to do.” •  MPEP indicates that claims may state the exclusion of alterna2ves recited in the specifica2on. •  MPEP § 2173.05(i): “If alterna2ve elements are posi2vely recited in the specifica2on, they may be explicitly excluded in the claims.” •  “Nega2ve claim limita2ons are adequately supported when the specifica2on describes a reason to exclude the relevant limita2on. Such wriYen descrip2on support need not rise to the level of a disclaimer. In fact, it is possible for the patentee to support both the inclusion and exclusion of the same material.” 35 Prosecu:on-­‐History Based Disclaimers Biogen IDEC, Inc. v. GlaxoSmithKline LLC, 2013 WL 1603360 (Fed. Cir. Apr. 16, 2013) •  Claim construc2on: heavy presump2on exists that claim terms carry their full and ordinary meaning, unless it can be shown the patentee expressly relinquished claim scope. •  If unequivocal and unambiguous disavowal of claim scope to obtain the patent, then prosecu2on history disclaimer narrows the meaning of the claim consistent with the scope of the claim surrendered. •  Promotes public no2ce func2on of the prosecu2on history and protects public reliance on same 36 Prosecu:on-­‐History Based Disclaimers •  Term at issue: “an2-­‐CD20 an2body” •  Patentee’s proposed construc2on: “an an2body that binds to a cell surface CD20 an2gen” •  Did statements in prosecu2on history overcome heavy presump2on that term carries ordinary and customary meaning? •  In response to enablement rejec2on re: scope of claim, Applicants argued that specifica2on was enabling for an2-­‐CD20 an2bodies with similar affinity and specificity as Rituxan® and noted that other an2bodies directed to same an2gen might have different affini2es and func2onal characteris2cs. •  Clear they were limi2ng inven2on to what they Examiner believed they enabled – an2bodies that have a similar specificity and affinity for specific epitope to which Rituxan® binds. 37 Thank you! 38