Lunes de Patentes Universitat de Barcelona. Mónica López - Bernabé Zea Barcelona, 23 de marzo de 2015

Transcripción

1 Materia patentable (subject matter eligibility) en los EEUU: de dónde venimos y a dónde vamos, particularmente en el sector químico-farmacéutico-biológico Lunes de Patentes Universitat de Barcelona Mónica López - Bernabé Zea Barcelona, 23 de marzo de

2 Sistemas legales en el mundo 2

3 Common Law (Derecho Anglosajón) La jurisprudencia tiene un obligado seguimiento que no existe en el sistema continental europeo Existe una estricta jerarquía en la jurisprudencia, que vincula al resto de jueces de instancias inferiores En Europa continental la jurisprudencia no tiene el mismo carácter vinculante (ni tan siquiera la del TS) Una decisión del TS estadounidense puede cambiar de forma efectiva la aplicación de una norma El tribunal US juzga un caso concreto pero su decisión se aplica de forma general 3

4 Invenciones biotechnológicas en EEUU Con la AIA no se introdujeron modificaciones en el artículo utilizado para determinar las Judicial exceptions (Eligibility). No ha habido cambios normativos sustanciales: 35 U.S.C. 101 Inventions patentable. 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. Los cambios actuales en el sector biotecnológico/biomédico son debido a decisiones de los tribunales estadounidenses, especialmente el TS 4

5 Normativa vs Jurisprudencia Normas Decisiones tribunales Decisión política tras escuchar los actores del sector Generalmente no tienen carácter retroactivo Decisión judicial tras escuchar dos partes concretas (y más) Retroactiva en la aplicación a la norma 5

6 Funcionamiento PCR 6

7 Myriad En junio del 2013, el Tribunal Supremo de los Estados Unidos decretó en relación con el caso Association for Molecular Pathology vs. Myriad Genetics Inc. que secuencias de DNA genómico son productos de la naturaleza, y como tales no son materia patentable Esto es un gran cambio, ya que la USPTO históricamente ha concedido patentes con reivindicaciones de secuencias de DNA genómico como producto per se Sin embargo se decretó que una secuencia de cdna, al carecer de los intrones (modificación introducida por el hombre), no es un producto de la naturaleza y, por tanto, sí es patentable 7

8 Polémica por la patentabilidad de genes In fact, though, the Clinton Blair statement signals no policy change, but simply reinforces existing policies that attempt to strike a balance between researchers need for access to genome data and the biotech/pharmaceutical industry s need to protect its investments in gene research. The statement has no impact on current patent law or our examination of [gene] patents, said Richard Maulsby, director of public affairs at the PTO. The two governments urged that all raw genome sequence data be made public as soon as it is available. The raw DNA code churned out by the Genome Project s and Celera s sequencing machines is not patentable, and an estimated 97% of it is not even part of any gene. In contrast to raw genome sequences, human genes are patentable in the United States. In fact, hundreds of genes are already patented, including the breast cancer genes BRCA1 and BRCA2 J Natl Cancer Inst (2000) 92(8):

9 Myriad - Extractos For the reason that follow, we hold that a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but that cdna is patent eligible because it is not naturally occurring. Judge Bryson gave no weight to the PTO s position on patentability because of the Federal Circuit s position that the PTO lacks substantive rulemaking authority as to issues such as patentability. We have long held that this provision contains an important implicit exception: Laws of nature, natural phenomena, and abstracts ideas are not patentable. Mayo, 566 U.S. 9

10 Myriad - Extractos It is undisputed that Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes. The location and order of the nucleotides existed in nature before Myriad found them. Nor did Myriad create or alter the genetic structure of DNA. Instead, Myriad s principal contribution was uncovering the precise location and genetic sequence of the BRCA1 and BRCA2 genes within chromosomes 17 and 13. The question is whether this renders the genes patentable. Myriad did not create anything. To be sure, it found an important and useful gene, but separating that gene from its surrounding genetic material is not an act of invention. 10

11 Myriad - Extractos Myriad found the location of the BRCA1 and BRCA2 genes, but that discovery, by itself, does not render the BRCA genes new composition[s] of matter, 101, that are patent eligible. Nor are Myriad's claims saved by the fact that isolating DNA from the human genome severs chemical bonds and thereby creates a nonnaturally occurring molecule. cdna does not present the same obstacles to patentability as naturally occurring, isolated DNA segments Petitioners concede that cdna differs from natural DNA the lab technician unquestionably creates something new when cdna is made As a result, cdna is not a product of nature and is patent eligible under 101, except insofar as very short series of DNA may have no intervening introns to remove when creating cdna. In that situation a short strand of cdna may be indistinguishable from natural DNA. 11

12 Myriad - Extractos Similarly, this case does not involve patents on new applications of knowledge about the BRCA1 and BRCA2 genes. Judge Bryson aptly noted that, [a]s the first party with knowledge of the [BRCA1 and BRCA2] sequences, Myriad was in an excellent position to claim applications of that knowledge. Many of its unchallenged claims are limited to such applications. 689 F.3d, at

13 Myriad DNA no es patentable pero la justificación es puramente porque se trata de un producto de la naturaleza Afecta esta decisión al resto de productos naturales? Un gen ( o un producto natural?) no conocido no puede patentarse (ineligible) pero pasa a formar parte del estado de la técnica? 13

14 Prometheus En marzo del 2012, el Tribunal Supremo de los Estados Unidos decretó en relación con el caso Mayo Collaborative Services vs. Prometheus laboratories que la asociación entre una señal biológica (nivel de un metabolito) y una conclusión de carácter clínico (adecuación de un tratamiento) es un descubrimiento de un fenómeno natural y, como tal, no patentable Este tipo de invenciones sólo son patentables si presentan características adicionales como reactivos, primers, anticuerpos, etc, que sean nuevos y no-obvios. Es decir, sólo son patentables si tienen un caracter limitado por la tecnología utilizada en la detección de la señal biológica 14

15 Prometheus - Extractos The case before us lies at the intersection of these basic principles. It concerns patent claims covering processes that help doctors who use thiopurine drugs to treat patients with autoimmune diseases determine whether a given dosage level is too low or too high. The claims purport to apply natural laws describing the relationships between the concentration in the blood of certain thiopurine metabolites and the likelihood that the drug dosage will be ineffective or induce harmful side-effects. We must determine whether the claimed processes have transformed these unpatentable natural laws into patent eligible applications of those laws. We conclude that they have not done so and that therefore the processes are not patentable. 15

16 Prometheus - Extractos We find that the process claims at issue here do not satisfy these conditions. In particular, the steps in the claimed processes (apart from the natural laws themselves) involve well-understood, routine, conventional activity previously engaged in by researchers in the field. At the same time, upholding the patents would risk disproportionately tying up the use of the underlying natural laws, inhibiting their use in the making of further discoveries. 16

17 Prometheus - Extractos Prometheus patents set forth laws of nature namely, relationships between concentrations of certain metabolites in the blood and the likelihood that a dosage of a thiopurine drug will prove ineffective or cause harm. While it takes a human action (the administration of a thiopurine drug) to trigger a manifestation of this relation in a particular person, the relation itself exists in principle apart from any human action. The relation is a consequence of the ways in which thiopurine compounds are metabolized by the body entirely natural processes. And so a patent that simply describes that relation sets forth a natural law. The question before us is whether the claims do significantly more than simply describe these natural relations. 17

18 Prometheus - Extractos If a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself. Other cases offer further support for the view that simply appending conventional steps, specified at a high level of generality, to laws of nature, natural phenomena, and abstract ideas cannot make those laws, phenomena, and ideas patentable. The determining step too is set forth in highly general language covering all processes that make use of the correlations after measuring metabolites, including later discovered processes that measure metabolite levels in new ways. 18

19 Prometheus - Extractos What role would laws of nature, including newly discovered (and novel ) laws of nature, play in the Government s suggested novelty inquiry? Intuitively, one would suppose that a newly discovered law of nature is novel. The Government, however, suggests in effect that the novelty of a component law of nature may be disregarded when evaluating the novelty of the whole. See Brief for United States as Amicus Curiae 27. These considerations lead us to decline the Government s invitation to substitute 102, 103, and 112 inquiries for the better established inquiry under

20 Prometheus - Extractos In consequence, we must hesitate before departing from established general legal rules lest a new protective rule that seems to suit the needs of one field produce unforeseen results in another. And we must recognize the role of Congress in crafting more finely tailored rules where necessary. We need not determine here whether, from a policy perspective, increased protection for discoveries of diagnostic laws of nature is desirable. For these reasons, we conclude that the patent claims at issue here effectively claim the underlying laws of nature themselves. The claims are consequently invalid. 20

21 Alice En junio del 2014, el Tribunal Supremo de los Estados Unidos decretó en relación con el caso Alice Corporation PTY. Ltd. vs. CLS Bank International et al que las ideas abstractas no son materia patentable Indica que la simple implementación de una idea abstracta mediante un ordenador no convierte esta idea en algo patentable (Judicial Exception) Esta decisión va en la línea de la decisión Bilski vs. Kappos. (2010) relacionada con un método para la toma de decisiones en temas financieros 21

22 Alice - Extractos The patents at issue in this case disclose a computer implemented scheme for mitigating settlement risk (i.e., the risk that only one party to a financial transaction will pay what it owes) by using a third-party intermediary We hold that the claims at issue are drawn to the abstract idea of intermediated settlement, and that merely requiring generic computer implementation fails to transform that abstract idea into a patent-eligible invention. 22

23 Alice - Extractos In Mayo Collaborative Services v. Prometheus Laboratories, Inc., we set forth a framework for distinguishing patents that claim laws of nature, natural phenomena, and abstract ideas from those that claim patent-eligible applications of those concepts. First, we determine whether the claims at issue are directed to one of those patent-ineligible concepts If so, we then ask, [w]hat else is there in the claims before us?... To answer that question, we consider the elements of each claim both individually and as an ordered combination to determine whether the additional elements transform the nature of the claim into a patenteligible application We have described step two of this analysis as a search for an element or combination of elements that is sufficient to ensure that the patent in practice amounts to significantly more than a patent upon the [ineligible concept] itself. 23

24 Alice - Extractos As to its system claims, petitioner emphasizes that those claims recite specific hardware configured to perform specific computerized functions. But what petitioner characterizes as specific hardware a data processing system with a communications controller and data storage unit, for example is purely functional and generic. Nearly every computer will include a communications controller and data storage unit capable of performing the basic calculation, storage, and transmission functions required by the method claims As a result, none of the hardware recited by the system claims offers a meaningful limitation beyond generally linking the use of the [method] to a particular technological environment, that is, implementation via computers. 24

25 AMBRY El (un día después de la aparición de la segunda Guía de la USPTO, un Tribunal del Federal Circuit tomo la decisión Myriad Genetics, Ind et al vs. Ambry Genetics Corp. en relación con la invención de Myriad relacionada con los genes BRCA1 y BRCA2 Esta decisión va dirigida a reivindicaciones no analizadas en la decisión Myriad del TS: métodos consistentes en comparar secuencias de genes con las wild type y ciertos primers La decisión, basada en la decisión Myriad del TS, indica que los primers y los métodos son una Judicial Exception y, por lo tanto, las reivindicaciones son inválidas 25

26 AMBRY - Extractos The primers before us are not distinguishable from the isolated DNA found patent-ineligible in Myriad and are not similar to the cdna found to be patent-eligible. Primers necessarily contain the identical sequence of the BRCA sequence directly opposite to the strand to which they are designed to bind. They are structurally identical to the ends of DNA strands found in nature. Contrary to Myriad s argument, it makes no difference that the identified gene sequences are synthetically replicated. As the Supreme Court made clear, neither naturally occurring compositions of matter, nor synthetically created compositions that are structurally identical to the naturally occurring compositions, are patent eligible. 26

27 AMBRY - Extractos Myriad argues that primers are in fact not naturally occurring because single-stranded DNA cannot be found in the human body. But, as the Supreme Court made clear, separating [DNA] from its surrounding genetic material is not an act of invention. 27

28 AMBRY - Extractos Myriad also argues that the sequences, when extracted as primers, have a fundamentally different function than when they are part of the DNA strand. When part of the naturally occurring genetic sequence, DNA stores the biological information used in the development and functioning of all known living organisms, but when isolated as a primer serve[s] as a starting material for a DNA polymerization process. In fact, the naturally occurring genetic sequences at issue here do not perform a significantly new function. Rather, the naturally occurring material is used to form the first step in a chain reaction a function that is performed because the primer maintains the exact same nucleotide sequence as the relevant portion of the naturally occurring sequence. One of the primary functions of DNA s structure in nature is that complementary nucleotide sequences bind to each other. It is this same function that is exploited here the primer binds to its complementary nucleotide sequence. Thus, just as in nature, primers utilize the innate ability of DNA to bind to itself. 28

29 AMBRY - Extractos A DNA structure with a function similar to that found in nature can only be patent eligible as a composition of matter if it has a unique structure, different from anything found in nature. Ambry argues that Mayo is directly on point because the method claims here, as there, simply identify a law of nature (the precise sequence of the BRCA genes, and comparisons of the wild-type BRCA sequences with certain mutations of those gene sequences found in the test subject) and apply conventional techniques. We need not decide if Mayo is directly on point here because the method claims before us suffer from a separate infirmity: they recite abstract ideas. 29

30 AMBRY - Extractos Claim 1 reads as follows: A method for screening germline of a human subject for an alteration of a BRCA1 gene which comprises comparing germline sequence of a BRCA1 gene or BRCA1 RNA from a tissue sample from said subject or a sequence of BRCA1 cdna made from mrna from said sample with germline sequences of wild-type BRCA1 gene, wild-type BRCA1 RNA or wild-type BRCA1 cdna, wherein a difference in the sequence of the BRCA1 gene, BRCA1 RNA or BRCA1 cdna of the subject from wild-type indicates an alteration in the BRCA1 gene in said subject. 30

31 AMBRY - Extractos the comparisons described in the first paragraphs of claims 7 and 8 are directed to the patent-ineligible abstract idea of comparing BRCA sequences and determining the existence of alterations. The methods, directed to identification of alterations of the gene, require merely comparing the patient s gene with the wild-type and identifying any differences that arise The number of covered comparisons is unlimited. The covered comparisons are not restricted by the purpose of the comparison or the alteration being detected. Because of its breadth, the comparison step covers detection of yetundiscovered alterations, as well as comparisons for purposes other than detection of cancer. Even with respect to cancer, the comparisons are not limited to the detection of risk of breast or ovarian cancer. 31

32 AMBRY - Extractos The second paragraph of claim 7 describes the way in which the sequences are compared: they are compared by 1) hybridizing a BRCA gene probe and 2) detecting the presence of a hybridization product. Similarly, claim 8 requires 1) amplification of the BRCA1 gene and 2) sequencing of the amplified nucleic acids. The non-patent-ineligible elements of claims 7 and 8 do not add enough to make the claims as a whole patent-eligible. Myriad does not challenge the district court s finding that the claims contain no otherwise new process for designing or using probes, primers, or arrays beyond the use of BRCA1 and BRCA2 sequences in those processes. The second paragraphs of claims 7 and 8 do nothing more than spell out what practitioners already knew how to compare gene sequences using routine, ordinary techniques. 32

33 Guías de la USPTO La USPTO publicó el la Guidance for Determining Subject Matter Eligibility of Claims Reciting or Involving Laws of Nature, Natural Phenomena & Natural Products Consecuencia de las decisiones Myriad y Prometheus Establecen ciertas pautas para determinar qué puede y qué no puede protegerse por patente en relación con productos naturales y leyes de la naturaleza Según estas directrices, no pueden protegerse por patente los productos de origen natural sin modificaciones sustanciales (no se limita a los ácidos nucleicos) Posteriormente, el la USPTO publicó una nueva versión de las Guías que sustituyen a las primeras 33

34 GUÍAS DEL

35 Comentarios preliminares - Es una guía dirigida al examinador - Evidentemente es una ayuda para los agentes de patentes a la hora de redactar y defender las solicitudes de patente - No es un documento cerrado - Se han aportado nuevos ejemplos (ideas abstractas) se cerró el plazo para la presentación de comentarios al documento - Se espera opinión del Federal Circuit en el caso Ariosa Diagnostica Inc. vs Sequenom Inc. (tecnología diagnóstica) - Pero tras Ambry no hay muchas esperanzas de un cambio favorable a los titulares - No son útiles en los pleitos de nulidad 35

36 Primeras vs segundas guías 36

37 Etapa 1 Las invenciones de tipo químicofarmacéutico biotecnológico caen en al menos una de estas categorías SÍ 37

38 Etapa 2A: Is the invention directed to a Judicial Exception? 38

39 Etapa 2A: Is the invention directed to a Judicial Exception? directed to significa que la reivindicación describe específicamente la excepción como tal Se ha eliminado el término involved que aparecía en las primeras guías No se impide la patentabilidad de una determinada materia por el hecho de que ésta pueda reducirse a una ley o fenómeno natural 39

40 Ejemplos de Judicial Exception Ley de naturaleza Alto nivel de glucosa => diabetes Niveles de proteína => patología Fenómeno natural Principio activo natural SNPs Bacteria sin modificar Idea abstracta Comparación de un gen de un paciente con el gen wt e identificar diferencias 40

41 Etapa 2A: Is the invention directed to a Judicial Exception? Judicial Exception --> Estas guías se centran en el concepto nature-based product Para determinar si el nature-based product citado en la reivindicación es una Judicial Exception debe analizarse la existencia de Markedly different characteristics (MDCs) MDC aparece en Myriad referiéndose a la decisión previa Diamond vs. Chakrabarty 41

42 Markedly different characteristics (MDCs) La sustancia reivindicada debe presentar un cambio notable (markedly) en alguna de las características respecto a la versión natural El descubrimiento de una nueva característica innata o inherente al producto natural no es suficiente para justificar un cambio Sin embargo una cambio notable en su función o actividad biológica, propiedades físico-químicas, y cambios estructurales o fenotípicos, puede ayudar a defender que se trata de un producto no natural No hay una definición sobre qué significa el término markedly ( cómo de notable ha de ser el cambio!?) 42

43 Etapa 2A: Análisis de MDCs Producto (p. ej. una cepa bacteriana, una célula, un anticuerpo ) - Se consideran en esta categoría las reivindicaciones de tipo product-by-process - Es curioso comprobar que en estas guías la USPTO trata estas reivindicaciones como productos, mientras que los tribunales estadounidenses las tratan básicamente como procedimientos -Debe determinarse la existencia de alguna diferencia notable en cuanto a función, estructura y/o propiedad respecto al producto natural 43

44 Ejemplo de producto eligible The Antibiotic L of claim 1, which is expressed by recombinant yeast - Antibiotic L natural - la expresión en levadura incorpora en la posición aminoacídica 49 del antibiótico un N-glicano con alto contenido en manosa -menor inmunogenicidad y diferente vida media 44

45 Composición Etapa 2A: Análisis de MDCs i) Determinar los componentes naturales - si hay un único producto natural no modificado, la reivindicación is directed to a Judicial Exception - los componentes no-naturales no permiten defender que la composición no es una Judicial Exception ii) Si hay dos o más productos naturales combinados, determinar si la combinación de componentes presenta al menos una MDC respecto a cada uno de los productos naturales por separado iii) Cambio sustancial respecto a guías anteriores donde una combinación de productos naturales era considerada non-eligible 45

46 Ejemplo de combinación eligible 1. Gunpowder comprising: an intimate finely-ground mixture of 75% potassium nitrate, 15% charcoal and 10% sulfur. - Composición explosiva de 3 sustancias naturales - Las sustancias naturales por separado no son explosivas -Las guías admiten un MDC y considera que no es una Judicial Exception -Las guías de marzo 2014 no incluían esta reivindicación 2. A fountain-style firework comprising: (a) a sparking composition, (b) calcium chloride, (c) the gunpowder of claim 1, (d) a cardboard body having a first compartment containing the sparking composition and the calcium chloride and a second compartment containing the gunpowder, and (e) a plastic ignition fuse having one end extending into the second compartment and the other end extending out of the cardboard body. 46

47 Etapa 2A: Análisis de MDCs Procedimiento - En principio, las reivindicaciones de procedimiento (p. ej. de preparación de una sustancia) no han de someterse al análisis de MDCs - Únicamente en aquellos casos en que la reivindicación describa un proceso natural o no exista diferencia sustancial con una reivindicación de producto (p.ej. un método de producción de una manzana) -Los métodos de tratamiento no se consideran en principio una Judicial Exception - Se interpretan como reivindicaciones en las que se protege la aplicación del producto en una enfermedad concreta. y el uso de un metabolito para el tratamiento de una enfermedad mediada por la deficiencia de ese metabolito?? 47

48 Ejemplo de métodos de tratamiento eligible A method of treating breast or colon cancer, comprising: administering an effective amount of purified amazonic acid to a patient suffering from breast or colon cancer A method of treating colon cancer, comprising: administering a daily dose of purified amazonic acid to a patient suffering from colon cancer for a period of time from 10 days to 20 days, wherein said daily dose comprises about 0.75 to about 1.25 teaspoons of amazonic acid 48

49 Etapa 2B: Is there any element to ensure that the claim as a whole amounts to significantly more than the judicial exception? 49

50 Etapa 2B: Is there any element to ensure that the claim as a whole amounts to significantly more than the judicial exception? En este análisis se tienen en cuenta los elementos presentes en la reivindicación, tanto de manera individual como en combinación (tanto los de origen natural como los nonaturales) La cuestión a plantearse es si la reivindicación: include additional features to ensure that the claim describes a process or product that applies the exception in a meaningful way, such that it is more than a drafting effort designed to monopolize the exception En la práctica, intenta evitar monopolios completos 50

51 Etapa 2B: Is there any element to ensure that the claim as a whole amounts to significantly more than the judicial exception? Qué se entiende por significantly more (meaningful way, more than a drafting effort )? En las primeras guías se exigía cumplir con el criterio significantly different y se proporcionaban 6 criterios a favor y 6 en contra Como las guías actuales reemplazan a las anteriores, en principio, esos 12 criterios ya no aplicarían Estas nuevas guías no proporcionan una definición para este concepto, únicamente lista (de manera no exhaustiva) algunos ejemplos De un total de 37 reivindicaciones analizadas, sólo una ilustra un caso en que la respuesta a la Etapa 2B permite excluir la Judicial Exception 51

52 Ejemplos a favor de significantly more - Improvements to another technology or technical field; - Improvements to the functioning of the computer itself; - Applying the judicial exception with, or by use of, a particular machine; - Effecting a transformation or reduction of a particular article to a different state or thing; - Adding a specific limitation other than what is wellunderstood, routine and conventional in the field, adding unconventional steps that confine the claim to a particular useful application; or - Other meaningful limitations beyond generally linking the use of the judicial exception to a particular technological environment. 52

53 Ejemplos en contra de significantly more Adding the words apply it (or an equivalent) with the judicial exception, or mere instructions to implement an abstract idea on a computer; Simply appending well-understood, routine and conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, e.g., a claim to an abstract idea requiring no more than a generic computer to perform generic computer functions that are wellunderstood, routine and conventional activities previously known to the industry; Adding insignificant extrasolution activity to the judicial exception, e.g., mere data gathering in conjunction with a law of nature or abstract idea; or Generally linking the use of the judicial exception to a particular technological environment or field of use 53

54 Casos prácticos para análisis de etapa 2B A composition comprising a population of isolated man-made human pacemaker cells in a container 54

55 Casos prácticos para análisis de etapa 2B las células son idénticas a las naturales no se modifican al colocarlas en un container No hay MDCs no hay elementos en la reivindicación que comporten significantly more ya que el container se usa de manera rutinaria en el crecimiento de células 55

56 Casos prácticos para análisis de etapa 2B A composition comprising a population of isolated man-made human pacemaker cells in a biocompatible three-dimensional scaffold 56

57 Casos prácticos para análisis de etapa 2B a) las células y el scaffold son idénticos a los naturales b) no existen MDCs como consecuencia de la combinación al colocarlas en un scaffold aumenta la velocidad de regeneración de tejido cardíaco impacto en tecnología regenerativa 57

58 Otros ejemplos incluidos en guías A. Ácido amazónico 1. Purified amazonic acid. [idéntica a la natural]--> 2. Purified 5-methyl amazonic acid. [diferencia estructural (un H se sustituye por Me) y (b) diferencia funcional (actividad estimulante del cabello)]- 58

59 Otros ejemplos incluidos en guías Antibiotic L - conocidas cepas naturales productoras de este mismo Purified Antibiotic L - al purificar el antibiótico cambia su estructura cristalina de hexagonal-piramidal a un prisma tetrahédrico o triangular 59

60 Otros ejemplos incluidos en guías A purified antibiotic comprising an amino acid sequence that has at least 90% identity to SEQ ID NO: 2 and contains at least one substitution modification relative to SEQ ID NO: 2 - no se han descrito modificaciones para la secuencia nonnaturally occurring substitution modification - considera que esos cambios en secuencia dan lugar a cambios estructurales Cambios conservativos? > MDCs?? Con 99% de identidad, es más que probable que hayan otros organismos de cepas cercanas que produzcan de manera natural el antibiótico reivindicado 60