Viewpoint
`
`pubs.acs.org/acsmedchemlett
`
`Protecting Chemistry Inventions: The Double-Edged Sword of Being
`an Unpredictable Art
`Holger Tostmann*
`European Patent Attorney, German Patent Attorney, Wallinger, Ricker, Schlotter, Tostmann, Zweibrückenstraße 5-7, 80331
`München, Germany
`
`ABSTRACT: Recent decisions by the highest courts in the US in regard to written description and enablement as well as
`parallel restrictions previously established in Europe emphasize that applicants in the fields of chemistry/pharma/life sciences
`should strive to include as many examples, data, and guidance about how to extrapolate from the example(s) in the description.
`This holds in particular whenever a broad genus and/or functional features is/are to be protected. It is important to keep in mind
`that these data and this guidance must be disclosed in the application at the time of filing. Data collected at a later stage can only
`be used to further support data and evidence already present in the application as filed.
`
`I nventions, i.e., novel and non-obvious substances, devices, or
`
`methods, can be protected by patents, irrespective of the
`field of technology from which they originate. A gearbox or a
`battery management method is subject to the same patent-
`ability requirements and the same sequence of examination as a
`chemical substance or a synthetic method. A summary of the
`relevant material patentability requirements and the examina-
`tion sequence before the United States Patent Office (USPTO)
`and the European Patent Office (EPO), as applicable for all
`applications, can be found in Table 1.
`
`Table 1. Patentability Requirements and Examination
`Sequence before USPTO and EPOa
`
`EPO
`USPTO
`patentability requirement
`35 U.S.C. § 101
`Art. 52, 53 EPC
`patent eligible subject matter
`35 U.S.C. § 102
`Art. 54 EPC
`novelty
`35 U.S.C. § 103
`Art. 56 EPC
`inventive step/non-obviousness
`35 U.S.C. § 112 (a)
`Art. 83 EPC
`written description/enablement
`35 U.S.C. § 112 (b)
`Art. 84 EPC
`clarity
`aU.S.C.: United States Code. EPC: European Patent Convention.
`
`However, in day-to-day practice, some of these patentability
`requirements are judged differently for the so-called “predict-
`able” technology fields, such as mechanical and electrical
`engineering, than for the so-called “unpredictable” fields such as
`chemistry and biotechnology. This distinction presupposes that
`the electrical and mechanical arts lack unpredictable factors
`while the chemical arts lack predictability.
`To illustrate this distinction, we refer to a famous historical
`example: Mathematicians Leverrier and Adams predicted the
`existence of the planet Neptune, based on irregularities of
`Uranus’ orbit. When astronomer Galle found Neptune, the
`prediction of a planet “by pen” was a dramatic confirmation of
`Newton’s law of gravitation. When Newton’s law of gravitation
`failed to fully describe Mercury’s orbit, Einstein’s general theory
`of relativity resolved this discrepancy and established the reign
`of predictability in the fields of physics and engineering. By
`contrast, as we will see below, simple modifications to a
`
`modestly complex small molecule can lead to unpredictable
`changes in activity and hence may be the basis for an invention.
`The fact that a skilled person cannot predict, with any
`certainty, which function or activity a substance may possess
`has several important repercussions on how an invention in the
`areas of chemistry and life sciences is examined for patent-
`ability. As a potential advantage, whenever a hitherto unknown
`(i.e., novel) substance is synthesized, typically a non-predictable
`effect or use can be ascribed to this substance. Generally, in this
`case the assumption is made that finding this substance (and its
`use) was not obvious to the skilled person, and hence, the
`statutory requirement of inventive step is met. However, by the
`same token, this assumption of non-predictability places an
`additional burden on an applicant in the case where a broader
`group of
`substances
`is claimed,
`for example, a generic
`compound class or a so-called “Markush-structure” (i.e., a
`structural formula with two or more residues that can vary
`independently). In this case, providing one synthetic route and
`the activity data of one compound may not be sufficient to
`support the assumption that all claimed permutations of this
`compound can be synthesized and are active. Recent case law
`from courts in the US and overseas in the area of chemistry and
`life sciences is used to illustrate the inventive step advantage
`and the increasing demand to provide a larger number of
`working compounds and activity data in the case where a
`broader class of substances is to be protected.
`
`■ WHAT IS OBVIOUS AND PREDICTABLE IN
`ENGINEERING MAY NOT BE IN CHEMISTRY
`The following case was decided by the German Federal
`Supreme Court1 but stands as a representative example of how
`patent offices and courts throughout the world decide whether
`or not a new compound is obvious in view of the existing prior
`art. In this case, the prior art did disclose “generic” 4′-(N-
`methylpiperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine (1)
`with the unspecified residues R1 and R2 (Figure 1).
`
`Published: March 27, 2015
`
`© 2015 American Chemical Society
`
`364
`
`DOI: 10.1021/acsmedchemlett.5b00116
`ACS Med. Chem. Lett. 2015, 6, 364−366
`
`See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
`
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`ACS Medicinal Chemistry Letters
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`Viewpoint
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`Figure 1. Generic formula 1, Olanzapin (2), and Flumezapin (3).
`
`The court had to decide whether (a) the claimed compound
`Olanzapin (2) falling under the generic formula 1 with R1 = H
`and R2 = methyl, is disclosed by said generic formula 1, and if
`(a) is answered in the negative, whether (b) 2 is rendered
`obvious (“suggested”) by the fluorine derivative Flumezapin
`(3), which was individualized in the same prior art document as
`1.
`
`While logically, the generic formula 1 does include the
`compound Olanzapin, an important general principle in patent
`law as applicable to chemistry states that a generic structural
`formula does not necessarily inherently disclose the specific
`compounds falling under this formula (otherwise no future
`chemistry inventions would be possible since all conceivable
`new compounds fall under one known generic formula or
`another). Therefore, the court held that the general formula 1
`does not disclose the specific compound Olanzapin.
`Next was the question whether knowledge of Flumezapin
`suggests to the skilled person that the modification of the same
`would arrive at Olanzapin, in an obvious manner. Based on the
`activity data disclosed in the prior art,
`the reasonable
`expectation of a medicinal chemist would have been that the
`presence of the fluorine substituent in position 7 enhances the
`antipsychotic potency of the compound. Also, the prior art did
`not disclose any individualized compound falling under the
`generic formula 1 that is not halogenated. Therefore, the skilled
`person had no reason or incentive to modify Flumezapin to
`arrive at a compound that is not halogenated at all. This
`example shows that the intrinsic feature of lack of predictability
`helps to get compounds patented even if they are structurally
`closely related to a sister compound.
`In 2007, the US Supreme Court had decided, in the famous
`KSR case2 (from the area of engineering), that the teaching-
`motivation-success standard, previously used to determine
`whether or not claimed subject-matter is obvious, is too strict.
`Simply put, there needs to be no explicit motivation in the prior
`art to modify a given teaching to arrive at the claimed subject-
`matter. More specifically, the Supreme Court stated that when
`there is a need to solve a problem and there is a finite number
`of identified, predictable solutions, a person of ordinary skill has
`good reason to pursue the known options within his or her
`technical grasp. If this leads to the claimed solution, the same is
`likely an obvious product of ordinary skill and not the product
`of innovation. The subject-matter underlying the KSR decision
`is from the predicable art and relates to a mechanism for
`combining an electronic sensor with an adjustable automobile
`pedal. All elements as such and their function were known from
`the art, and the result of the combination was predictable and
`hence obvious.
`For applicants in the unpredictable art, the question was
`whether the KSR decision would also make it easier to
`challenge chemistry patents as obvious. The consensus based
`on subsequent decisions by the next-highest court, i.e., the US
`Court of Appeal for the Federal Circuit (CAFC) is that this is
`not the case and that there still needs to be some reason
`
`(motivation) to modify a starting compound in order to arrive
`at the claimed compound. Among many similar decisions, the
`Rabeprazole case3 illustrates this principle. Lansoprazole (4),
`the starting compound known from the art,
`is structurally
`rather similar to the claimed compound Rabeprazole (5). The
`compounds only differ in regard to the substituent at the 4-
`position of the pyridine ring (Figure 2).
`
`Figure 2. Structures of Lansoprazole (4) and Rabeprazole (5).
`
`Although structurally similar, the CAFC could not find any
`motivation in the art
`to substitute the active groups.
`In
`particular, the court stated: “The record shows no discernible
`reason for a skilled artisan to begin with Lansoprazole only to
`drop the very feature, the fluorinated substituent, that gave this
`advantageous property [lipophilicity].”
`■ LACK OF PREDICTABILITY LIMITS THE BREADTH
`OF CHEMISTRY/BIOLOGICS CLAIMS
`On the flip-side of the acknowledgment that activity found in
`one compound does not predetermine activity in a structurally
`similar compound, applicants for chemistry and life sciences
`applications generally have the burden of proof to show that,
`for a larger class of compounds (e.g., defined by a generic
`structure and/or a Markush structure), supported only by a few
`explicit examples; indeed all of the members of this larger class
`have the claimed activity or effect. In patent terms this means
`that an invention must be enabled (over the whole range
`claimed) and that the applicant must have had full possession
`of
`the invention on the filing date (written description
`requirement). Also,
`the activity underlying the claimed
`compounds must be present over the whole range claimed.
`Over
`the last years,
`these requirements have become
`particularly relevant in the unpredictable arts.
`For example, in the 2014 decision AbbVie v. Janssen Biotech,4
`the CAFC held invalid a claim directed at a class of antibodies
`in which none of the antibodies was structurally defined, but
`only functionally in terms of a certain disassociation constant to
`a binding site. The claim was found invalid for lacking sufficient
`support in terms of written description since “the claimed scope
`reaches beyond what the inventors have contributed to the art,”
`in particular since the inventors have not provided structural
`examples of antibodies that fulfill the claimed function.
`Similarly, in the 2013 decision Wyeth v. Abbott Laboratories,5
`the CAFC declared invalid a broad genus claim directed at
`Rapamycin and its derivatives since the disclosure of the patent
`only supported one single compound falling within the scope of
`the claims (Sirolimus). As the description of the patent was
`silent on how to structurally modify Sirolimus to produce
`Rapamycin derivatives with the desired properties, the skilled
`person essentially has to synthesize and biologically evaluate
`thousands of compounds to determine which derivatives have
`the claimed properties and which do not. This was seen as an
`undue burden and the patent was declared to be invalid for lack
`of enablement.
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`365
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`DOI: 10.1021/acsmedchemlett.5b00116
`ACS Med. Chem. Lett. 2015, 6, 364−366
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`ACS Medicinal Chemistry Letters
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`Viewpoint
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`A similar case from a Board of Appeal of the European
`Patent Office is T 1151/04. The Board held invalid a reach-
`through-type of claim (“Use of activity-lowering effectors of
`dipeptidyl peptidase [for
`the] oral
`therapy of [diabetes
`mellitus]”). Such functional claims without a pointer to the
`identity/structure of the potential compounds are generally not
`allowable in proceedings before the EPO, not least because
`future, not-yet synthesized compounds are also encompassed.
`In response to this rejection, the patentee filed a generic
`structural claim (“Use of aminoacyl-thiazolidides or of alanine-
`pyrolidide as inhibitor of the enzyme activity of dipeptidyl
`peptidase [for the] oral therapy of [diabetes mellitus]”). Similar
`to the Wyeth decision above, the Board/Court held that an
`unmanageable pool of thousands of compounds is covered by
`the claim and that it would be an undue burden to test all
`claimed thiazolidides and pyrolidides for their effectiveness in
`inhibiting DPP-IV. In particular, the application provides no
`selection or guidance how to distinguish effective from
`noneffective compounds.
`These decisions highlight the increasing demand, both in
`Europe and the US, for applications to not just provide one
`example but
`to cover as much breadth as possible with
`examples/data and to provide guidance in the description how
`to extrapolate from these examples/data to the remaining
`scope.
`
`■ AUTHOR INFORMATION
`Corresponding Author
`*E-mail: tostmann@wallinger.de.
`Notes
`Views expressed in this editorial are those of the author and not
`necessarily the views of the ACS.
`The authors declare no competing financial interest.
`
`■ REFERENCES
`(1) German Federal Supreme Court. Olanzapin (X ZR 89/07) as
`decided on December 16, 2008.
`(2) United States Supreme Court. KSR Int’l Co. v. Telef lex, Inc., 550
`U.S. 398 (2007).
`(3) United States Court of Appeal for the Federal Circuit. EISAI v.
`DR. REDDY’S LABORATORY and TEVA PHARMACEUTICALS No.
`07−1397 (Fed. Cir. July 21, 2008).
`(4) US CAFC. AbbVie Deutschland GmbH & Co. KG v. Janssen
`Biotech Inc.; No. 13−1338 (Fed. Cir. July 1, 2014).
`(5) US CAFC. Wyeth v. Abbott Laboratories; No. 12−1223 (Fed. Cir.
`June 26, 2013).
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`366
`
`DOI: 10.1021/acsmedchemlett.5b00116
`ACS Med. Chem. Lett. 2015, 6, 364−366
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`Rigel Exhibit 1013
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