ISSUES IN SMALL ORGANIC MOLECULES

1. 1 ISSUES IN SMALL ORGANIC MOLECULES Michael G. Hartley Supervisory Patent Examiner US Patent & Trademark Office Art Unit 1618 571-272-0616 Thanks to SPEs Joe McKane in 1626 and Doug Schultz in 1639 for help in preparing this presentation.Thanks to SPEs Joe McKane in 1626 and Doug Schultz in 1639 for help in preparing this presentation.

2. 2 Overview Small Molecule Examples � �Markush� claims. Combinatorial Chemistry-small molecule libraries Search Strategy � difficulties in searching broad �Markush� claims. Examination Issues/35 U.S.C. 112 first and second paragraph Issues with Method of Use/Pharmaceutical Composition Examples Here is an overview of my talk today. It will cover issues in examining small organic molecule claims, mainly those examined in the 1610 and 1620 workgroups. Examples of various claim format, such as, chemical Markush claiims, will be discussed, including narrowly claimed compounds and those encompassing millions of compounds. Some of the examining and searching related issues that arise with small molecule claims will be discussed. Also, it will briefly cover combinatorial chemistry relating to small molecule libraries and how they are examined, usually in Art unit 1639. Some of the difficulties that arise in the search strategy for Markush claims will be discussed. Examination issues with regard to some potential 112 issues will be addressed, and what can be done to help avoid these issues. At the end there will be time for questions & answers.Here is an overview of my talk today. It will cover issues in examining small organic molecule claims, mainly those examined in the 1610 and 1620 workgroups. Examples of various claim format, such as, chemical Markush claiims, will be discussed, including narrowly claimed compounds and those encompassing millions of compounds. Some of the examining and searching related issues that arise with small molecule claims will be discussed. Also, it will briefly cover combinatorial chemistry relating to small molecule libraries and how they are examined, usually in Art unit 1639. Some of the difficulties that arise in the search strategy for Markush claims will be discussed. Examination issues with regard to some potential 112 issues will be addressed, and what can be done to help avoid these issues. At the end there will be time for questions & answers.

3. 3 Definition Small organic molecules Usually excludes: Biomolecules DNA, proteins Polymers In this context, small organic molecules, usually excludes biomolecules, such as, DNA, proteins and polymers.In this context, small organic molecules, usually excludes biomolecules, such as, DNA, proteins and polymers.

4. 4 Generic variation presents complexity in searching Markush compound claims �One of the major problems with Markush structures, besides their inherent variability and complexity, is the representation of generic groups [homology, position and frequency variation] and the matching of these against specific examples of them.� �A generic group can be considered as one which cannot be shown by a single atom-bond connection table, and examples include expressions like �alkyl�, �heterocyclic� and �cycloalkyl: In some cases the expression may have no direct association with structural features, like �electron-withdrawing group.� � Barnard et al. �Use of Markush structure analysis techniques for descriptor generation and clustering of large combinatorial libraries� J Mol Graphics Vol 18 452-463 August-October 2000 Chemical Markush structures are inherently complex, and can be further complicated by generic groups, which can be of various types, such as, homology, position and frequency variation. These types of generic groups will be further exemplified in the next slide. Such generic groups may make it difficult for searching for prior art, as well as, for matching prior art compounds to the claimed Markush structure. Examples of generic groups include �alkyl� heterocycle, cycloalkyl. Also, the generic groups may be defined by function, for example, �electron withdrawing group� (which when examined would have to be considered that if the substituent of the prior art is capable of acting as an electron withdrawing group, it may meet the claim. For example, if an examiner found a prior art reference which taught a compound falling within the scope of the Markush claim, having halogen at the position of the R group corresponding to the �electron withdrawing group� this may meet the claim, as halogen is inherently an electron withdrawing group. However, it may be burdensome to include all the groups having this functionality in a search and comparison with the prior art without having a structure. Defining a functional group in the specification can ease the burden.Chemical Markush structures are inherently complex, and can be further complicated by generic groups, which can be of various types, such as, homology, position and frequency variation. These types of generic groups will be further exemplified in the next slide. Such generic groups may make it difficult for searching for prior art, as well as, for matching prior art compounds to the claimed Markush structure. Examples of generic groups include �alkyl� heterocycle, cycloalkyl. Also, the generic groups may be defined by function, for example, �electron withdrawing group� (which when examined would have to be considered that if the substituent of the prior art is capable of acting as an electron withdrawing group, it may meet the claim. For example, if an examiner found a prior art reference which taught a compound falling within the scope of the Markush claim, having halogen at the position of the R group corresponding to the �electron withdrawing group� this may meet the claim, as halogen is inherently an electron withdrawing group. However, it may be burdensome to include all the groups having this functionality in a search and comparison with the prior art without having a structure. Defining a functional group in the specification can ease the burden.

5. 5 Four Types of Variation in a Markush Structure (Read the 4 types of variation). Thus, not all Markush Claims are the same��some forms of variation are more complex and difficult than others(Read the 4 types of variation). Thus, not all Markush Claims are the same��some forms of variation are more complex and difficult than others

6. 6 Small Molecule Examples - Species Here are species examples. 1st and 3rd are true species�that is, a single compound having no variables, the 2nd one includes frequency variation, the p subscript. We often see claims drawn to species and while not the norm, there have been situations wherein an entire application is drawn to a species�which usually yields an easier prosecution. This is example of what usually should be elected in response to an election of species requirement in an application drawn to small organic compounds having a Markush claim. Even these structures may represent Markush claims if they are further defined as stereoisomers.Here are species examples. 1st and 3rd are true species�that is, a single compound having no variables, the 2nd one includes frequency variation, the p subscript. We often see claims drawn to species and while not the norm, there have been situations wherein an entire application is drawn to a species�which usually yields an easier prosecution. This is example of what usually should be elected in response to an election of species requirement in an application drawn to small organic compounds having a Markush claim. Even these structures may represent Markush claims if they are further defined as stereoisomers.

7. 7 Small Molecule Examples (cont.) A compound of formula: Here is an example of a Markush claim having a defined heterocyclic core and limited and narrowly defined variables. A Markush claim such as this is usually somewhat easy to search using a chemical database and for comparing the prior art to the claimed compounds.Here is an example of a Markush claim having a defined heterocyclic core and limited and narrowly defined variables. A Markush claim such as this is usually somewhat easy to search using a chemical database and for comparing the prior art to the claimed compounds.

8. 8 Small Molecule Examples (cont.) A compound of Formula (II): Here we jump to an example of a much broader Markush claim, having numerous variables as well as, position variation. In this situation, it may be difficult to determine a starting place for classification, since the various ring structures would control the classification. Also due to the breadth, developing a search strategy for the compounds may be difficult. If R1 is C, the formula may have a somewhat defined core; however, due to the breadth of R2-R5 as various chemical moieties, including heterocylcles, it can expand out as R2-R5 vary. Thus, the claim encompasses various unrelated species, as the core may change due to the breadth of the homology variation included in the R2-R5 groups. For example, R4 being a 12-membered heterocyclic ring would effectively change the core of the R1 containing ring structure.Here we jump to an example of a much broader Markush claim, having numerous variables as well as, position variation. In this situation, it may be difficult to determine a starting place for classification, since the various ring structures would control the classification. Also due to the breadth, developing a search strategy for the compounds may be difficult. If R1 is C, the formula may have a somewhat defined core; however, due to the breadth of R2-R5 as various chemical moieties, including heterocylcles, it can expand out as R2-R5 vary. Thus, the claim encompasses various unrelated species, as the core may change due to the breadth of the homology variation included in the R2-R5 groups. For example, R4 being a 12-membered heterocyclic ring would effectively change the core of the R1 containing ring structure.

9. 9 Small Molecule Examples (cont.) Claim 1: A compound of formula: A-B-C-D-E-F A is: wherein, Z is CH2, O, S, or NH; Y is CH2, O, S or NH Q is a 5-6 membered carbocyle or heterocycle; B is alkylene; C is isoquinoline, pyrrolidine, piperidine or indole; D is CH2, O, CHOH or CCI2; E is wherein Y1 is NH or CH2; and F is naphthalene optionally substituted by 1-3 substituents. Sometimes compound are defined by letters defining various �Markush� groups. Note here the substitutions, include pyrrolidines class 548; piperidines = class 546; as well as, heterocycles having nitrogen + sulfur in the ring, including thiazines, class 544, and so forth. Since the variables can be various atoms and/or substitutions, independently, the number of possible combinations increases dramatically, thereby encompassing a very large number of compounds. As will will see later, a claim such as this may create a burdensome search.Sometimes compound are defined by letters defining various �Markush� groups. Note here the substitutions, include pyrrolidines class 548; piperidines = class 546; as well as, heterocycles having nitrogen + sulfur in the ring, including thiazines, class 544, and so forth. Since the variables can be various atoms and/or substitutions, independently, the number of possible combinations increases dramatically, thereby encompassing a very large number of compounds. As will will see later, a claim such as this may create a burdensome search.

10. 10 Small Molecule Examples (cont.) A compound of formula (I): X-Ar1-Ar2- L1-L2-Ar3-L3-Y wherein X is a leaving group; L1, L2, and L3 are a bond or a divalent linker having a main chain of 1 to 10 atoms, or represented by the formula Q-R-S, wherein Q is O, S, N, and C; R is independently a bond, hydrogen, alkyl, alkylene, alkynyl, aryl, and alkylaryl; S is is independently C, S, N, SO, and O(C R3R4)m, provided that L1 and L2 are not simultaneously a bond. Ar1, Ar2, and Ar3 are independently, C1-8 alkyl, C2-8 alkenyl, C3-8 cycloakane, C1-8 alkylaryl, -C(O)C1-8 alkyl, -C(O)OC1-8 alkyl, C1-8 alkylcyloalkane, (CH2)nC(O)OR5, (CH2)nNSO2 R1R5, and (CH2)nNSO2R5, wherein each of the alkyl, alkenyl, aryl are each optionally substituted with one to five groups independently selected from C1-8 alkyl, C2-8 alkenyl, phenyl, and alkylaryl, and wherein L1, L2, may be taken together and with the nitrogen atom to which they are attached or with 0, 1, 2, or 3 atoms adjacent to the nitrogen atom to form a nitrogen containing heterocycle with may have 1 or 2 substituents independently selected from R1, provided that when L1 is a bond and L2 is phenyl, Ar2 and Ar3 are not phenyl, and Y is a basic group, or a pharmaceutically acceptable salt thereof. This is an Example of a broad Markush claim that is further complicated by the inclusion of negative provisos. The negative provisos may carve out a specific prior art compound or may have various scenarios, which are underlined. These can complicate the search strategy since it may be difficult to incorporate such exclusionary provisions into a structure search. Also complicating the structure are variables that can be either aliphatic or heterocyclic, for example, wherein L1 and L2 is alkyl� or wherein L1 and L2 are taken together with a N to form a ring. Sometimes, these types of �Markush� claims can cover multiple pages for a single claim, which further complicates the searching and examination thereof. One thing to note, is that negative provisos should have support in the specification when added by amendment. Any negative limitation or exclusionary proviso must have basis in the original disclosure. If alternative elements are positively recited in the specification, they may be explicitly excluded in the claims. See In re Johnson, 558 F.2d 1008, 1019, 194 USPQ 187, 196 (CCPA 1977) (�[the] specification, having described the whole, necessarily described the part remaining.�). This is an Example of a broad Markush claim that is further complicated by the inclusion of negative provisos. The negative provisos may carve out a specific prior art compound or may have various scenarios, which are underlined. These can complicate the search strategy since it may be difficult to incorporate such exclusionary provisions into a structure search. Also complicating the structure are variables that can be either aliphatic or heterocyclic, for example, wherein L1 and L2 is alkyl� or wherein L1 and L2 are taken together with a N to form a ring. Sometimes, these types of �Markush� claims can cover multiple pages for a single claim, which further complicates the searching and examination thereof. One thing to note, is that negative provisos should have support in the specification when added by amendment. Any negative limitation or exclusionary proviso must have basis in the original disclosure. If alternative elements are positively recited in the specification, they may be explicitly excluded in the claims. See In re Johnson, 558 F.2d 1008, 1019, 194 USPQ 187, 196 (CCPA 1977) (�[the] specification, having described the whole, necessarily described the part remaining.�).

11. 11 �Combinatorial� Chemistry? In combinatorial technology there is no good set of terms that can cover every scenario. Commonly seen terminology: �combinatorial�, �library�, �collection�, �plurality�, �array�, �linker�, �resin�, �bead�, �diversity�, �tag�, �solid support/supported�, �high-throughput�, �iterative�, �deconvolution�.. Absent evidence to the contrary, �A combinatorial library can be defined as any ensemble of molecules� Janda, K. D. PNAS, 1994 Another situation we deal with in TC1600 relating to small molecules is Combinatory Chemistry, usually examined in art unit 1639,, which, as you can see, goes by many different names. Another situation we deal with in TC1600 relating to small molecules is Combinatory Chemistry, usually examined in art unit 1639,, which, as you can see, goes by many different names.

12. 12 Markush Structures in Combinatorial Chemistry Markush format is the main way to represent combinatorial libraries. Libraries can be split into two groups, 1st is the precursors and reactants used to synthesize a library and 2nd is the reaction products themselves. The reaction products of a combinatorial library are often claimed using �Markush� format, which may have a core in which substituents, or R groups, are attached.Markush format is the main way to represent combinatorial libraries. Libraries can be split into two groups, 1st is the precursors and reactants used to synthesize a library and 2nd is the reaction products themselves. The reaction products of a combinatorial library are often claimed using �Markush� format, which may have a core in which substituents, or R groups, are attached.

13. 13 Factors that Complicate Generic Representations (Read slide) �these complications,�..can make the examination difficult. However, a Markush claim having a common core, and wherein applicant has identified the common core, is a good place to start to ease the examination of these libraries.(Read slide) �these complications,�..can make the examination difficult. However, a Markush claim having a common core, and wherein applicant has identified the common core, is a good place to start to ease the examination of these libraries.

14. 14 Dependent variation may be inaccurate (Read title) � basically this means that some combinations are not feasible- and while inoperative embodiments are permitted under 112 1st for enablement, inclusion of these in a Markush claim, or individually, may present problems These inaccuracies may include valency problems, and the like. So when drafting Markush claims, chemical inaccuracies should be avoided, if possible. Inaccuracies, such as improper valencies, in a claim may also render the claim indefinite.(Read title) � basically this means that some combinations are not feasible- and while inoperative embodiments are permitted under 112 1st for enablement, inclusion of these in a Markush claim, or individually, may present problems These inaccuracies may include valency problems, and the like. So when drafting Markush claims, chemical inaccuracies should be avoided, if possible. Inaccuracies, such as improper valencies, in a claim may also render the claim indefinite.

15. 15 �Combinatorial� Chemistry Anticipation and Obviousness A case for prima facie obviousness If the parent molecule in a series is known; and substituents and the substitution pattern claimed are established in the prior art, Obviousness to make the library becomes the question. To have anticipation for a claimed combinatorial library usually requires that the library is known, since each and every element must be present. However, for a case of prima facie obviousness, one can consider if the parent molecule in a series is known and substitutions or patterns thereof are known in the art, then a case for obviousness may exist, because the library would provide the advantage of synthesizing active compounds and/or those with desired properties (e.g., solubilities, etc.)To have anticipation for a claimed combinatorial library usually requires that the library is known, since each and every element must be present. However, for a case of prima facie obviousness, one can consider if the parent molecule in a series is known and substitutions or patterns thereof are known in the art, then a case for obviousness may exist, because the library would provide the advantage of synthesizing active compounds and/or those with desired properties (e.g., solubilities, etc.)

16. 16 �Combinatorial� Chemistry Obviousness �The goals of combinatorial organic synthesis are to create populations of molecular structures� in order to search them for more potent derivatives of known pharmacophores. Gordon et al. J. Med. Chem., 1994 The fact that properties rely on a number of variables �precludes the truly rational design�and provides a clear invitation to use the power of combinatorial chemistry to accelerate discovery�. Francis et al. �Combinatorial libraries of transition-metal complexes, catalysts and materials�, Cur. Opin. Chem. Biol., 1998 Basically, it may be obvious to make the library to provide an automated means of finding active drugs that is provided by the use of combinatorial chemistry.Basically, it may be obvious to make the library to provide an automated means of finding active drugs that is provided by the use of combinatorial chemistry.

17. Search StrategyCHEMICAL SUBSTANCES, INCLUDING:MOLECULAR STRUCTURES, CHEMICAL REACTIONSBasically two means of searching: - CHEMICAL COMPOUND SEARCHING USING THE US CLASSIFICATION SYSTEM-BASED ON STRUCTURE - CLASSES 532-570 (various heterocycles, etc.)- REGISTRY, BEILSTEIN, MARPAT, CASREACT BIBLIOGRAPHIC, OR TEXT SEARCHES - CHEMICAL ABSTRACTS BIBLIOGRAPHIC FILES, NAPRALAERT - USPATFULL - WPI, DPCI, JICST - BIOSIS, MEDLINE, EMBASE, AGRICOLA, FSTA, FROSTI, JAPIO Now we jump to how to search Markush claims. To search small molecule claims, there are two means routinely employed by examiners. The first is searching the compounds using the US classification system, which classifies based on structure. For example, a compound having a tropanyl core would classify in class 546/ subclasss 124. The second is the use of various commercial databases. Both structures and reactions can be searched using either method. For database searching, after the results of a structure search are obtained, the answer set can be further searched using bibliographic data (e.g., inventor, date, etc.) or text searching to find methods of use, etc..Now we jump to how to search Markush claims. To search small molecule claims, there are two means routinely employed by examiners. The first is searching the compounds using the US classification system, which classifies based on structure. For example, a compound having a tropanyl core would classify in class 546/ subclasss 124. The second is the use of various commercial databases. Both structures and reactions can be searched using either method. For database searching, after the results of a structure search are obtained, the answer set can be further searched using bibliographic data (e.g., inventor, date, etc.) or text searching to find methods of use, etc..

18. 18 Search Strategy (cont.) Here is a example of how a search strategy may be drawn for this Markush claim. Note the structure is drawn with undefined bonds to allow for tautomerization. A structure like this, having limited substitutions and variables would most likely go to completion and yield a finite answer set.Here is a example of how a search strategy may be drawn for this Markush claim. Note the structure is drawn with undefined bonds to allow for tautomerization. A structure like this, having limited substitutions and variables would most likely go to completion and yield a finite answer set.

19. 19 Search Strategy (cont.) Here is an example of hits retrieved. These hits may be in a single reference or in multiple references. Then one must cross over to a bibliographic data base to find document info, (e.g. patent no. or publication), inventor/author, publ. dates,, etc.Here is an example of hits retrieved. These hits may be in a single reference or in multiple references. Then one must cross over to a bibliographic data base to find document info, (e.g. patent no. or publication), inventor/author, publ. dates,, etc.

20. 20 Search Stratecy (cont.) A compound of Formula (II): This is the claim we saw previously in slide 8.This is the claim we saw previously in slide 8.

21. 21 Search Strategy (cont.) A search of this compound left open for the variation defined by the Markush claims retrieves 353,917 hits. As you can see, the number of hits can be very large. Another situation which may arise with broad Markush structures is that if the search strategy is too broad it will not run to completion. This happens when there are too many hits for the search engine, that is STN or Diaglogue, to obtain results. Thus, the examiner has to narrow the search strategy and repeat the search. This can create a dilemma� Create the search strategy too broad� and it will not go to completion -- too narrow and critical hits that qualify as prior art may be missed. However, even if the search runs to completion, the number of hits can be very high, as shown here, which can still create a burden to consider hundreds or thousands of hits. Markush claims having a defined and identified core can ease the burden of searching by allowing the search to run to completion.A search of this compound left open for the variation defined by the Markush claims retrieves 353,917 hits. As you can see, the number of hits can be very large. Another situation which may arise with broad Markush structures is that if the search strategy is too broad it will not run to completion. This happens when there are too many hits for the search engine, that is STN or Diaglogue, to obtain results. Thus, the examiner has to narrow the search strategy and repeat the search. This can create a dilemma� Create the search strategy too broad� and it will not go to completion -- too narrow and critical hits that qualify as prior art may be missed. However, even if the search runs to completion, the number of hits can be very high, as shown here, which can still create a burden to consider hundreds or thousands of hits. Markush claims having a defined and identified core can ease the burden of searching by allowing the search to run to completion.

22. 22 Search Strategy (cont.) Repeating structure searches in order for the search to go to completion can be expensive and time consuming. Structure searching is usually the most costly type of searching in terms of both time and database cost (e.g., as compared to text searching which is usually cheaper). Costs can jump as high as $2500 and time can sometimes exceed 8 hours.Repeating structure searches in order for the search to go to completion can be expensive and time consuming. Structure searching is usually the most costly type of searching in terms of both time and database cost (e.g., as compared to text searching which is usually cheaper). Costs can jump as high as $2500 and time can sometimes exceed 8 hours.

23. 23 Search Strategy (cont.) Chemical search databases can be used to show recognized synonyms for compounds. Also, structure information can be crossed over to a bibliographic data base to allow for text searching for methods of use of the compounds.Chemical search databases can be used to show recognized synonyms for compounds. Also, structure information can be crossed over to a bibliographic data base to allow for text searching for methods of use of the compounds.

24. 24 Search Strategy (cont.) Information obtained includes patent family information which enables the examiner to find the best publication date for prior art purposes.Information obtained includes patent family information which enables the examiner to find the best publication date for prior art purposes.

25. 25 Search Strategy (cont.) Databases can also be used to search non-patent literature (or NPL). Databases can also be used to search non-patent literature (or NPL).

26. 26 Examination Issues - Indefiniteness Evaluation of the claim language depends on whether one of skill in the art would understand what is claimed, in light of the specification Questions of indefiniteness are determined on a case-by-case basis Things to consider are definitions in the specification and whether or not the words are recognized �terms of art� Things to consider are definitions in the specification and whether or not the words are recognized �terms of art�

27. 27 Examination Issues - Indefiniteness Relative Language-examples: large, high, etc. The fact that claim language-including terms of degree- may not be precise, does not automatically render the claim indefinite under 112(2). The specification must be considered. The next few slides will cover terms frequently seen in Markush claims, that may raise indefinite issues. The examiner must consider each situation on a case-by-case basis and rely on the specification and the knowledge of the art. The more information that is provided in the specification defining and/or describing such terms will help avoid potential 112 rejections. Exemplified here are relative terms, such as, large, high, etc., which may raise 112 2nd issues.The next few slides will cover terms frequently seen in Markush claims, that may raise indefinite issues. The examiner must consider each situation on a case-by-case basis and rely on the specification and the knowledge of the art. The more information that is provided in the specification defining and/or describing such terms will help avoid potential 112 rejections. Exemplified here are relative terms, such as, large, high, etc., which may raise 112 2nd issues.

28. 28 Examination Issues - Indefiniteness Metabolite(s) �A compound of formula I � and its metabolites or salts thereof.� Residue �B is a residue capable of binding to a compound.� �Y is a residue of an azole compound, solvates or salts thereof.� With terms such as, metabolite or residue, it may be impossible to determine the structure of what is claimed, thus, the metes and bounds of the claim may not be clear. It may also not be clear on how to make the compound, since the structure is not known. However if such term are defined in the specification, then 112 issues may be avoided. But again, this is on a case by case situation.With terms such as, metabolite or residue, it may be impossible to determine the structure of what is claimed, thus, the metes and bounds of the claim may not be clear. It may also not be clear on how to make the compound, since the structure is not known. However if such term are defined in the specification, then 112 issues may be avoided. But again, this is on a case by case situation.

29. 29 Examination Issues - Indefiniteness Analogues thereof Derivatives thereof Derived from �A compound of formula II�and its pharmaceutically acceptable salts or derivatives thereof.� �A is derived from a group��� It certain situations, it may not be clear what the structure of such chemical �derivatives� or �analogues� would include. Again, the more disclosure in the specification for these terms, the less likely the terms will raise 112 issues. It certain situations, it may not be clear what the structure of such chemical �derivatives� or �analogues� would include. Again, the more disclosure in the specification for these terms, the less likely the terms will raise 112 issues.

30. 30 Examination Issues - Indefiniteness Prodrugs Functional derivatives �A compound of formula III � and its prodrugs, functional derivatives or pharmaceutically acceptable salts thereof.� Prodrugs and functional derivatives- may be raise 112 issues. For example, it may be unclear what the structure of the prodrug would be that would yield an active drug after administration. There should be some evidence of the predictability for the prodrug is intended for, as prodrugs may have different structures based on what they treat or the route of administration, etc. However, the specification and the general knowledge in the art must be considered for these terms.Prodrugs and functional derivatives- may be raise 112 issues. For example, it may be unclear what the structure of the prodrug would be that would yield an active drug after administration. There should be some evidence of the predictability for the prodrug is intended for, as prodrugs may have different structures based on what they treat or the route of administration, etc. However, the specification and the general knowledge in the art must be considered for these terms.

31. 31 Examination Issues - Indefiniteness Precursor(s) Linking group(s) Organic moiety �A Ketorolac compound and its precursors� �X is a linking group or an organic moiety� A substituent that binds receptor X Some substituents are defined by function only, which may make it hard to determine the structure being claimed. Thus, the more information provided in the specification as far as defining and/or describing these terms is beneficial for avoiding potential rejections of such terms. Some substituents are defined by function only, which may make it hard to determine the structure being claimed. Thus, the more information provided in the specification as far as defining and/or describing these terms is beneficial for avoiding potential rejections of such terms.

32. 32 Examination Issues - Enablement A pharmaceutical composition for preventing cancer comprising compound A.� A prophylactic pharmaceutical composition to mediate a delta opioid receptor comprising compound A. Per MPEP 2164.01. any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention. Per In re Wands , even though the statute does not use the term �undue experimentation,� it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. Along with the small molecule claims are often composition claims (which may be with or without �intended use� and/or �mechanism of action� recitations). The intended use recitations may have to be considered for 112 1st enablement issues. Per MPEP 2164.01. any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention. Per In re Wands , even though the statute does not use the term �undue experimentation,� it has been interpreted to require that the claimed invention be enabled so that any person skilled in the art can make and use the invention without undue experimentation. Along with the small molecule claims are often composition claims (which may be with or without �intended use� and/or �mechanism of action� recitations). The intended use recitations may have to be considered for 112 1st enablement issues.

33. 33 Examination Issues - Enablement A method of treating cancer in a patient comprising administering to said patient a daily unit dose of compound A of 10 mg/kg of body weight for at least 7 consecutive days. A method of the treatment and prevention of liver necrosis, obesity, diabetes, depression, cardiovascular disorders, CNS disorders, and asthma comprising administering compound A in an effective amount. Here we have methods of use claims. The claims may be drawn to treating and/or preventing a large diverse Markush group of different diseases having diverse etiologies. The treatment and prevention of these diseases must considered for enablement, and scope of enablement issues. While the claims may be enabled for treatment of certain diseases, the claims may not be enabled for the entire Markush group of diseases. The more guidance in the specification for the use of the claimed compounds for the diverse group of diseases can help avoid enablement issues. For lack of enablement rejection, it is important for the examiner to address the Wands Factors. And possibly to rely on a reference to support the position of lack or enablement. In the absence of a reference, sound scientific reasoning may be employed. Again providing guidance in the specification, or in the state of the prior art, can help avoid these enablement issues, or for rebutting them later. Here we have methods of use claims. The claims may be drawn to treating and/or preventing a large diverse Markush group of different diseases having diverse etiologies. The treatment and prevention of these diseases must considered for enablement, and scope of enablement issues. While the claims may be enabled for treatment of certain diseases, the claims may not be enabled for the entire Markush group of diseases. The more guidance in the specification for the use of the claimed compounds for the diverse group of diseases can help avoid enablement issues. For lack of enablement rejection, it is important for the examiner to address the Wands Factors. And possibly to rely on a reference to support the position of lack or enablement. In the absence of a reference, sound scientific reasoning may be employed. Again providing guidance in the specification, or in the state of the prior art, can help avoid these enablement issues, or for rebutting them later.

34. 34 THANK YOU! Mike Hartley SPE, Art Unit 1618 571-272-0616 michael.hartley@uspto.gov