DETAILED ACTION
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Claims 1-12, and 14-21 are pending.
Priority
This application is filed 09/04/2024, and claims the benefit of domestic priority as below:
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Information Disclosure Statements
One IDS(s) received on 5/07/2025 have been considered unless marked with a strikethrough.
Claim Rejections - 35 USC § 112, Enablement
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-12, 14-17 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while providing examples of treatment and in vitro activity data for selected exemplified compounds of Formula (I) against selected protozoan organisms, does not reasonably enable the full scope of the claimed methods of treatment or prevention without undue experimentation. The specification does not enable any person skilled in the art to make and use the claimed invention commensurate in scope with the claims.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, and state and predictability of the art
The instant claims relates to method of treating and/or preventing of diseases caused by
protozoan parasites in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of general formula (I) or any of the pharmaceutically acceptable isomers, solvates or salts thereof. The claims also include compounds and pharmaceutical compositions connected to the same broad Formula (I) genus and therapeutic field. The treatment and/or prevention of protozoan parasite diseases with broad Formula (I) genus and/or combination Formula (I) genus with another antiparasitic agent are not reasonably predictable across the full scope of the claims because antiprotozoal activity may depend on parasite genus, species, strain, life cycle stage, host cell model, assay conditions, compound uptake, metabolism, toxicity, formulation context, and synergy effects. Thus, activity observed for selected compounds in selected in vitro does not allow a person of ordinary skill in the art to predict therapeutic effectiveness across all claimed parasite species and disease indications.
Cohen et al. ( Challenges and Tools for In Vitro Leishmania Exploratory Screening in the Drug Development Process: An Updated Review, Pathogens, 10(12), 1608, pub’d 12/10/2021) explains that in vitro Leishmania exploratory screening faces practical and biological challenges, including the need to select appropriate models, the presence of different parasite forms and host cell environments, long-term treatments, severe adverse side effects, the parasite’s development of increasing resistance, difficulties in harmonizing results across different research teams, and the need to identify screening methods that better predict relevant antiLeishmanial activity (introduction and challenges involved in implementing exploratory screening to identify in vitro hit compounds against Leishmania section). The same point is reinforced by Lamotte et al. (Discovery of novel hit compounds with broad activity against visceral and cutaneous Leishmania species by comparative phenotypic screening, Sci. Rep., 9(1), 438, pub’d 01/24/2019), which teaches that activity can be stage and/or species specific (abstract and introduction). Lamotte performs to retest ‘GSK Leish-Box’ hits in more physiologically relevant assays and found that only 23 of 188 hits validated as active at 10 uM against intramacrophage L. donovani (abstract, and results). Thus, Cohen and Lamotte support that exploratory in vitro data are highly model dependent, and identified as hits in one Leishmania screening context may fail to validate in a more physiologically relevant assay, even within the same general therapeutic field. Therefore, biological activity in a limited set of in vitro assays does not enable treatment and/or prevention across the full scope of protozoan parasite disease recited in the claims.
Although the specification provides certain in vitro data for selected compounds against limited organisms, including L. donovani, T.b. brucei, and T. cruzi. However, the claims are not limited to those organisms, strains, disease contexts, or assay contexts. Accordingly, in view of the prior arts by Cohen, and Lamotte, antiprotozoal activity is highly dependent on the parasite species, parasite stage, assay format, and biological model used. Limited activity data for selected compounds and selected organisms would not allow one of ordinary skill in the art to reasonably predict the full scope of the claimed compounds, including their pharmaceutically acceptable isomers, solvates or salts, would be enable for treating and/or preventing the full scope of protozoan parasite diseases recited in the claims.
The breadth of the claims
The claims are very broad insofar as they recite methods of treatment based on compounds from a broad Markush genus. Claims 1-12, and 14-17 recites that treatment and/or prevention of diseases caused by protozoan parasites, including numerous Leishmania and Trypanosoma species. For example, claim 1 recites that a method of treatment and/or prevention of diseases caused by protozoan parasites in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of general formula (I) or any of the pharmaceutically acceptable isomers, solvates or salts thereof, and claims 14-17 further extend the method to protozoan parasites of the genera Leishmania and Trypanosoma, numerous individual species, and trypanosomiasis, and American trypanosomiasis.
Moreover, the claims cover a broad Formula (I) Markush genus defined by multiple variable groups, including R1, R2, R3, R3’, Z, X, and Y with pharmaceutically acceptable isomers, solvates, and salts of that genus. Although, claim 12 recites selected compounds, the subjected claims as a group are not limited to a single exemplified compound, a single parasite species, a single strain, or a single disease model. Claim 20 further recites a pharmaceutical composition comprising a compound of Formula (I) together with a pharmaceutically acceptable excipient, adjuvant, and/or carrier, and claim 21 further broadens the composition by requiring another antiparasitic agent.
The specification provides selected examples and selected in vitro data, but it does not provide representative data or a predictive structure activity relationship sufficient to identify which Formula (I) compounds, including their isomers, solvates, or salts, would be effective across the claimed parasite species and diseases. The data are concentrated on selected compounds and selected organisms, while claim 15 lists many Leishmania and Trypanosoma species for which no corresponding activity data are provided. In view of Lamotte, and Cohen as discussed above, exploratory in vitro screening results are model dependent and require careful validation, even within the same general therapeutic field. Therefore, the disclosure does not establish that the entire claimed therapeutic scope is enabled.
Moreover, although Leishmania and Trypanosoma are kinetoplastid protozoan parasites, they present distinct biological contexts. Different parasite genera and species may differ in relevant targets, uptake mechanisms, metabolism, life cycle forms, host cell environments, and susceptibility to chemical compounds. Alkhaldi et al. (AntiLeishmanial and antitrypanosomal activity of symmetrical dibenzyl-substituted α,β-unsaturated carbonyl-based compounds, drug design, development and therapy, 13, 1179–1185, pub’d 04/24/2019) further supports that antiLeishmanial and antitrypanosomal activities are not necessarily interchangeable with the scope of the enabling disclosure (abstract).
The amount of direction or guidance provided and the presence or absence of working examples
The specification provides synthetic disclosure for many compounds and working examples for selected compounds. However, the specification does not provide sufficient guidance how to use substantially the full claimed genus to treat/prevent the full scope of the claimed protozoan parasite species and diseases without undue experimentation.
The working examples are primarily in vitro and are limited to selected compounds and selected organisms, including L. donovani, T.b. brucei, and T. cruzi. These examples may support narrower claims directed to particular compounds and organisms for which activity is actually shown. However, they do not provide sufficient direction for practicing the full scope of the present claims 1-12 and 14-17, including treatment or prevention across the broad list of Leishmania and Trypanosoma species recited in claim 15, and the disease recited in claim 17.
The specification also does not provide guidance commensurate with therapeutic use across the full claimed scope, including dosing regimen, route of administration, formulation, therapeutic window, pharmacokinetics, toxicity, selectivity, host cell effects, and in vivo efficacy. While such information is not always required in every case, it absence is significant because the claims cover a broad chemical genus, numerous parasite species, multiple diseases, and both treatment and prevention as taught by Cohen and Lamotte that show antiparasitic efficacy is compound and organism dependent and cannot be broadly extrapolated from limited in vitro activity against selected parasites.
In addition, with respect to claims 20 and 21, the specification does not provide sufficient guidance for pharmaceutical compositions across the full genus, particularly where claim 21 further requires another antiparasitic agent. The disclosure does not identify representative combinations across the claimed genus, dosage ratios, compatibility considerations, toxicity effects, or whether combinations would produce additive, synergistic, or antagonistic effects.
Accordingly, the instant specification lacks sufficient therapeutic direction and representative working examples commensurate with the full scope of the claimed methods of treatment/prevention, and the breadth of the compositions.
The quantity of experimentation necessary
Given the limited predictability of the art, the breadth of the claims, and absence of sufficient guidance or representative working examples, a person having ordinary skill in the art would be required to engage in extensive experimentations to determine which compounds retain activity against each of the recited parasite genera and species, and establishing therapeutic efficacy in the various claimed disease contexts. Such experimentation would include 1) determining which compounds within Formula (I), including pharmaceutically acceptable isomers, solvates, and salts, retain activity against each recited parasite species, strain, and relevant life cycle stage, 2) determining whether such activity translates to the claimed disease contexts, and 3) establishing suitable therapeutic conditions for treatment and/or prevention.
Cohen and Lamotte show that antiLeishmania exploratory screening requires careful assay selection and validation, and that activity may vary depending on parasite species, parasite stage, and biological model (Cohen’s Challenges Involved in Implementing Exploratory Screening to Identify In Vitro Hit Compounds against Leishmania section, and Lamotte’s discussion section). Therefore, practicing the full scope of the claims would require substantial screening, selection, and/or optimization across both compound structure and parasite genera/diseases context.
For claims 20 and 21, further experimentation would be required to identify suitable pharmaceutical compositions and, for claim 21, suitable additional antiparasitic agents. Such work would include determining formulation compatibility, dosage ratios, toxicity, and whether the combination produces additive, synergistic, or antagonistic effects.
Accordingly, the instant claims 1-12, 14-17, 20, and 21 do not comply with the enablement requirement of §112, because practicing the claimed invention would require undue experimentation by a person of ordinary skill in the art without reasonable assurance of success.
Claim Rejections - 35 USC § 112, Written description
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-12, and 14-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. (see MPEP 2163).
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by applicants. (see MPEP 2163.02)
An objective standard for determining compliance with the written description requirement is, "does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed." In re Gosteli, 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989). Under Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64, 19 USPQ2d 1111, 1117 (Fed. Cir. 1991), to satisfy the written description requirement, an applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention, and that the invention, in that context, is whatever is now claimed. (Emphasis added)
Further, the MPEP states that for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. (see MPEP 2161.01)
For instance, generic claim language in the original disclosure does not satisfy the written description requirement if it fails to support the scope of the genus claimed. Ariad, 598 F.3d at 1349-50, 94 USPQ2d at 1171 ("[A]n adequate written description of a claimed genus requires more than a generic statement of an invention’s boundaries.") (citing Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1405-06); Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002) (holding that generic claim language appearing in ipsis verbis in the original specification did not satisfy the written description requirement because it failed to support the scope of the genus claimed); Fiers v. Revel, 984 F.2d 1164, 1170, 25 USPQ2d 1601, 1606 (Fed. Cir. 1993) (rejecting the argument that "only similar language in the specification or original claims is necessary to satisfy the written description requirement").
As set forth in the en banc decision in Ariad Pharmaceuticals Inc. v. Eli Lilly and Company, 94 USPQ2d 1161 (Fed. Cir. 2010) at 1171, the court stated as follows:
We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus. Id. At 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. At 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 [25 USPQ2d 1601] (Fed. Cir. 1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F.3d at 964 (quoting 66 Fed. Reg. 1099 (Jan. 5, 2001)). But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.
The specification describes that “the term isomer mainly refers to structural isomers, such as tautomers. Specifically, the term tautomer refers to one of two or more structural isomers of a compound that exist in equilibrium and are easily converted from one isomeric form to another. Common tautomeric pairs are, for example, amine-imine.” (page 6, lines 4-7)
However, this general definition dose not reasonably convey possession of the full scope of the claimed “pharmaceutically acceptable isomers” of the Formula (I) genus. Although, the specification generally refers to structural isomers such as tautomer, and identifies amine-imine pairs as common tautomeric pairs, the disclosure does not provide a compound by compound identification of the particular pharmaceutically acceptable isomeric or tautomeric forms encompassed by Formula (I). The specification also does not depict or name representative alternative tautomeric or structural isomeric forms across the full Formula (I) genus, and does not provide sufficient structural guidance identifying the atoms, functional groups, bonding arrangements, or equilibrium forms involved for the claimed isomeric scope.
The specification also fails to provide sufficient structural or chemical information showing possession of the claimed isomeric scope. It does not provide representative structures of the claimed pharmaceutically acceptable isomers, does not disclose isolated or characterized isomeric species, does not provide tautomeric equilibrium data, analytical data, spectroscopic assignments, isolation data, or other evidence identifying particular isomeric forms, and does not provide a method of making, isolating, resolving, or characterizing the full scope of the claimed isomers.
Isomeric forms of drug compounds may differ materially in pharmacological properties, including pharmacokinetic and pharmacodynamic behavior. Chhabra et al. (A review of drug isomerism and its significance, Int. J. Appl. Basic Med. Res., 3(1), 16-18, pub’d 01/15/2013) teaches that isomers differ in their pharmacokinetic and pharmacodynamic properties (Abstract).This includes small changes like stereoisomerism, as well as constitutional isomerism, which are molecules with the same atomic composition but different bonding arrangements between atoms.
In view of Chhabra, one of ordinary skill would not expect these compounds to have similar properties and a person skilled in the art would not be able to determine whether the structure or function of the claimed invention would be maintained across the full scope of the claimed pharmaceutically acceptable isomers. Specifically, in view of the teachings of Chhabra, if small structural changes to compounds within the field of the invention cause a change in the order of magnitude, a person skilled in the art could not predict what would be expected of large structural changes. In the absence of disclosed representative structures or other identifying characteristics for the claimed isomeric forms, there is no adequate correlation between the disclosed compounds and the full scope of the claimed “pharmaceutically acceptable isomer”.
The specification provides multiple specific structural examples of compounds within Formula (I), but it does not provide a representatives number of examples of the claimed pharmaceutically acceptable isomers. Nor does it provide sufficient identifying characteristic that would allow one of ordinary skill in the art to recognize which isomeric forms are included and possessed. Therefore, the specification has failed to provide a representative number of examples to establish possession of the structural space that would entail the claimed pharmaceutically acceptable isomers or their compound structures.
In view of such unpredictability taught by Chhabra and the lack of any disclosed structure function or mechanism based correlation, a person of ordinary skill in the art would not recognize that the inventors had possession of the structural space that would entail the claimed pharmaceutically acceptable isomers or their compound structures would achieve the claimed sensitization effect at the time of filing.
In the instant case, the claims 1 and 18 are recite “a compound of general formula (I) or any of the pharmaceutically acceptable isomers, solvates or salts thereof”. Claims 2-12, and 14-17 depend, directly or indirectly, from claim 1 and therefore incorporate that same subject matter. Claim 19 depends from claim 18, and claims 20-21 are directed to pharmaceutical compositions comprising the compounds of claims 18 and/or 19.
As set forth in the en banc decision in Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010), to satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention at the time of filing. Specifically, the specification must describe the claimed invention in a manner understandable to a person of ordinary skill in the art in a way that shows that the inventor actually invented the claimed invention at the time of filing. Id.; Ariad, 598 F.3d at 1351, 94 USPQ2d at 1172. (see MPEP 2161.01).
Accordingly, in view of the breadth of the claimed combinations, the lack of representative examples, and the unpredictability of the art as discussed above, the specification does not reasonably convey to those skilled in the art that the inventors are in possession of the full scope of claims 1-12 and 14-21 at the time of filing.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
The present rejection under 35 U.S.C. 103 is made alternative and is independent of the rejection under 35 U.S.C. 112(a). The 103 rejection is not cooperated with other rejections, and applied the prior art to the claims under their broadest reasonable interpretation and specification.
Claim(s) 1-4, 6-8, 10, 14-18, 20, and 21 is/are rejected under 35 U.S.C. 103 as being unpatentable over Rios Martinez et al. (Lowering the pKa of a bisimidazoline lead with halogen atoms results in improved activity and selectivity against Trypanosoma brucei in vitro, Eur. J. Med. Chem., 101, 806-817, pub’d 07/07/2015), in view of Beltran-Hortelano et al. (The role of imidazole and benzimidazole heterocycles in Chagas disease: A review, Eur. J. Med. Chem., 206, 112692, pub’d 08/05/2020), and further in view of Ismail et al. (Dicationic biphenyl benzimidazole derivatives as antiprotozoal agents, Bioorg. Med. Chem., 12(20), 5405-13, pub’d 08/23/2004).
With respect to independent claim 1, the claim recites that a method of treatment and/or prevention of diseases caused by protozoan parasites in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of general formula (I) or any of the pharmaceutically acceptable isomers, solvates or salts thereof.
Rios teaches structurally related bisimidazoline antiprotozoal compounds useful against Trypanosoma brucei (abstract and discussion section). Rios further teaches 4-(imidazolidin-2-ylideneamino)-N-(4-(imidazolidin-2-ylideneamino)phenyl)benzamide, and lowing the pKa of the basic 2-iminoimidazolidine groups by introducing halogenated aryl and pyridyl groups results in improved activity and selectivity against Trypanosoma brucei (abstract, introduction, and discussion section).
Rios fails to teach the claimed R3/R3’ group as a benzimidazole or picolinimidamide type substituent.
Beltran-Hortelano teaches that imidazole and benzimidazole heterocycles are broadly studied and recognized scaffolds in Chagas Disease (i.e., American Trypanosomiasis) and other parasitic diseases (starting point: chagas disease section). Beltran-Hortelano further teaches that the scaffolds of imidazole and benzimidazole containing compounds have been studied in the antiprotozoal/trypanosomatid therapeutic field (introduction and concluding remarks sections). Thus, Beltran-Hortelano provides benzimidazole containing heterocycles as known antiprotozoal pharmacophores in place of, or as analogs of, imidazole type heterocycles.
The combined teachings of Rios and Beltran-Hortelano fail to teach a dicationic aromatic antiprotozoal compound in which benzimidazole containing terminal heterocyclic groups are incorporated into a structurally related scaffold, nor do they provide a specific example showing that such benzimidazole containing analogs retain antitrypanosomal activity.
Ismail teaches dicationic biphenyl benzimidazole derivatives as antiprotozoal agents (abstract). Ismail further teaches that benzimidazole containing dicationic aromatic compounds are synthesized and evaluation as antiprotozoal agents, including compounds activity against Trypanosoma brucei rhodesiense. Thus, Ismail's research demonstrates that benzimidazole-containing analogs can retain antitrypanosomal activity within the class of antiprotozoal dicationic aromatic compounds.
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It would have been prima facie obvious to one of ordinary skill in the art at the time of the invention to administer a benzimidazole containing analog of the benzamide based bisimidazoline scaffold of Rios for the treatment for Trypanosoma brucei that is a species of single-celled, flagellated protozoan parasites that cause Human African Trypanosomiasis (HAT), commonly known as African sleeping sickness. The motivation would have been to apply a known antiprotozoal benzimidazole heterocyclic pharmacophore to a structurally related dicationic aromatic antiprotozoal scaffold, with the expectation of obtaining compounds having antiprotozoal activity. The advantage of the modification would have been to obtain structurally related antiprotozoal analogs having modified pKa, lipophilicity, DNA binding properties, activity, and selectivity, as taught by Rio, while using benzimidazole containing dicationic antiprotozoal groups shown by Ismail to be active against Trypanosoma brucei rhodesiense. A person of ordinary skill would have had a reasonable expectation of success because Rios teaches that modification of terminal cationic heterocyclic groups affects pKa, activity, and selectivity against Trypanosoma brucei, Beltran-Hortelano identifies benzimidazole as a known antiprotozoal heterocyclic scaffold, and Ismail demonstrates that benzimidazole containing dicationic aromatic compounds possess antitrypanosomal activity.
The references is directed to the same field of endeavor and address related to the application. The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Alternatively, applying KSR example rationale (B) and (D) in the independent claim 1, it would have been prima facie obvious to replace the terminal imidazoline type antiprotozoal heterocyclic group of Rios with known benzimidazole containing antiprotozoal heterocyclic groups taught by Beltran-Hortelano and Ismail. The substitution would have been expected to provide structurally related dicationic aromatic antiprotozoal analogs retaining antitrypanosomal activity, yielding predictable improved results as pKa, activity, and selectivity. (see MPEP 2141)
With respect to claims 2 and 3, claims recite that the method, according to claim 1, wherein R1 and R2 are the same as H.
Rios teaches the compound 6 has R1 and R2 are the same as H.
With respect to claims 4, and 6, claims recite that the method, according to claim 1, wherein R1 and R2 are the same as Cl or F.
The combined teachings of Rios, Beltran-Hortelano, and Ismail fail to teach R1 and R2 are the same as Cl or F.
However, Rios teaches Cl and F substituted analogs and teaches that inducing halogen atoms lowers pKa and improves activity and selectivity against Trypanosoma brucei. Therefore, it would have been obvious to select Cl or F substituent for R1 and R2 of Formula (I) to obtain the pKa-lowering and activity advantages taught by Rios.
With respect to claims 7, and 8, claims recite that the method, according to claim 1, wherein X and Y are CH for claim 7, and , wherein X is CH, and Y is N for claim 8
Rios teaches the compound 2a has X and Y are CH, as required in claim 7, and the compound 6 has X is CH and Y is N, as required in claim 8.
With respect to claims 10, claim recites that the method, according to claim 1, wherein Z is -C(O)NH- or -CH2CH2-.
Rios teaches the compound 2a has -C(O)NH-.
With respect to claims 14-16, claim 14 recites that the protozoan parasites are of the genera Leishmania or Trypanosoma, claim 15 recites that specific Leishmania or Trypanosoma species, and claim 16 recites T. brucei, T. cruzi and/or L. donovani.
Rios teaches activity against Trypanosoma brucei. Ismail further teaches benzimidazole containing dicationic compounds having antiprotozoal activity, including activity against Trypanosoma brucei rhodesiense. Beltran-Hortelano teaches imidazole and benzimidazole scaffolds in the Chagas disease field, which is associated with Trypanosoma cruzi. Therefore, the combined teachings suggest the claimed treatment of diseases caused by Trypanosoma parasites, including T. brucei and T. cruzi.
With respect to claims 17, claim recites that the disease is selected from Leishmaniasis, human African trypanosomiasis, animal tripanosomiasis or American tripanosomiasis.
Rios teaches activity against Trypanosoma brucei, a protozoan parasite associated with human African trypanosomiasis and animal trypanosomiasis. Beltran-Hortelano teaches imidazole and benzimidazole scaffolds in the Chagas disease field, which is associated with American trypanosomiasis. Ismail further teaches benzimidazole containing dicationic compounds activity against Trypanosoma brucei rhodesiense. Therefore, the combined teachings suggest the claimed compounds for Trypanosoma related diseases recited in claim 17.
With respect to claim 18, the claim recites that a compound of general formula (I) or any of the pharmaceutically acceptable isomers, solvates or salts thereof, with the recited proviso.
As discussed above with respect to independent claim 1, Rios teaches the corresponding benzamide based bisimidazoline scaffold.
Rios fails to teach terminal benzimidazole containing R3/R3’ groups.
Beltran-Hortelano teaches benzimidazole containing heterocycles as recognized antiprotozoal scaffolds, and Ismail teaches benzimidazole containing dicationic aromatic antiprotozoal compounds activity against Trypanosoma brucei rhodesiense.
For the same reasons and rationale discussed above with respect to claim 1, it would have been prima facie obvious to one of ordinary skill in the art to modify the terminal imidazoline type groups of Rios with benzimidazole containing terminal heterocycles to obtain structurally related Formula (I) compounds having modified pKa, lipophilicity, DNA binding properties, activity, and selectivity.
With respect to claim 20, the claim recites that a pharmaceutical composition comprising a compound of general Formula (I) together with a pharmaceutically acceptable excipient, adjuvant and/or carrier.
The combined teachings of Rios, Beltran-Hortelano, and Ismail fail to teach a pharmaceutical composition comprising a compound with a pharmaceutically acceptable excipient, adjuvant and/or carrier.
However, as discussed above, the compound of claim 18 would have been obvious the combined teaching of Rios, Beltran-Hortelano, and Ismail. Rios, Beltran-Hortelano, and Ismail each related to compounds having antiprotozoal therapeutic activity. It have been obvious to one of ordinary skill in the art to formulate such as antiprotozoal compound with a pharmaceutically acceptable excipient, adjuvant, and/or carrier to prepare a pharmaceutical composition suitable for administration to a subject. The motivation would have been to provide the active antiprotozoal compound in a pharmaceutically administrable form. The use of pharmaceutically acceptable excipients, adjuvants and carriers for formulating therapeutically active compounds was conventional in pharmaceutical arts. (see MPEP 2144.03)
With respect to claim 21, the claim recites that the pharmaceutical composition further comprises another antiparasitic agent.
Beltran-Hortelano teaches that a novel administration regimen of existing drugs for Chagas disease may include lower doses, shorter treatment duration, and combination regimens, including a benznidazole and fos-ravuconazole combination therapy. Benznidazole is a nitroimidazole antiparasitic drug used against T. cruzi, and fos-ravuconazole is a prodrug of the azole compound ravuconazole that has been investigated as an antiparasitic/antitrypanosomal agent against T. cruzi.
Art of Record but not Applied
Rios et al. (Antiprotozoal activity and DNA binding of N-substituted N-phenylbenzamide and 1,3-diphenylurea bisguanidines, Eur. J. Med. Chem., 81, 481-491, pub’d 05/09/2014) teaches N-hydroxy and N-alkoxy derivatives of bisimidazoline lead compounds as antitrypanosomal agents and explains that reducing the basicity of the imidazoline type groups can improve properties relevant to Trypanosoma brucei therapy. Rios further teaches modification of X in instant Formula (I) of a structurally related dicationic antitrypanosomal scaffold, and lacks enough of the same embodiments to qualify as 103 prior art.
Conclusion
Claims 1-12, and 14-21 are rejected.
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/SEONG JONG KIM/ Examiner, Art Unit 1621
/CLINTON A BROOKS/ Supervisory Patent Examiner, Art Unit 1621
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