DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
Applicant’s election of Group (I) with the addition of compound 110
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as the elected compound species in the reply filed on 08/10/2026 is acknowledged.
This compound reads on the compound of the formula (I)
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wherein:
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Is
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;
Q is CH2;
R1 is Cl;
R2 is F;
R3 and R4 are each H;
R6 is hydrogen;
R7 is C2-alkyl; and
R8 is C1-akyl substituted heteroaryl where heteroaryl is benzimidazoly. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claims 5, 8-9, 12-15, and 19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species/invention, there being no allowable generic or linking claim.
Priority
This application is a national stage application of International Patent Application No.
PCT/US2023/011304 filed January 23, 2023, which claims the benefit of U.S. Provisional Patent Application No. 63/302,715, filed January 25, 2022.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 08/12/2024, 07/08/2025, and 09/30/2025 has been considered by the examiner.
Claim Status
Claims 1-15 and 18-19 are pending. Claims 5, 8-9, 12-15, and 19 are withdrawn. Claims 16-17 are canceled. Claims 1-4, 6-7, 10-11, and 18 are examined to the extent they read on the elected compound species, Compound 110. The instant disclosure identifies Examples 109 and 110 as stereoisomeric compounds and provides their preparation and separation. See pp. 91-92 (Examples 109 and 110).
Claim Objections
Claims 1 and 3 are objected to because of informalities in the Markush wording defining R8. The claims recite, in substance, that R8 is “selected from the group consisting of phenyl or heteroaryl.” A closed Markush expression conventionally identifies the listed alternatives with “and,” e.g., “selected from the group consisting of phenyl and heteroaryl.” Because the presently recited alternatives are nevertheless reasonably understood as phenyl or heteroaryl, the defect is treated as an informality rather than as rendering the claims indefinite. Applicant is required to correct the working without changing claim scope.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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 1-4, 6-7, 11, and 18 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.
The specification discloses Formula I and separately enumerates alternatives for A, Q, B, R1-R10, Rx, and Ry. The rejection is not premised on the absence of literal disclosure of the individual variable definitions. Rather, the issue is whether the original disclosure reasonably conveys possession of the full combinatorial genus produced by unrestructured cross-combination of the disclosed alternatives.
Claim 1 permits, inter alia, A to be O, or -CH2-; Q to be -CH2- or absent, B to be selected from materially different aromatic azoles and saturated nitrogen-containing heterocycles; independent variation of R1-R7; alternative ring formation by R6 and R7; and R8 to encompass phenyl or monocyclic or bicyclic heteroaryl, with further substitution through Rx and Ry. The disclosure therefore generates a genus having substantial structural variation at several independently variable regions of the molecule.
The specification provides specifically prepared Examples 1-138, but those examples represent selected combinations within the much broader combinatorial space of claim 1. Elected compound 110 is one particular combination; its preparation and stereoisomer separation are disclosed at pp. 91-92. The examples do not, on the present record, demonstrate species representative of the full structural variation permitted by simultaneous selection among all claimed alternatives, nor does the specification identify a structure-function correlation showing that the disparate alternatives collectively define the full scope claimed genus.
Accordingly, while the generic formula and individual variable lists provide literal terminology corresponding to the claim, the disclosure does not reasonably convey pssiton of the claimed gnus as a whole over its full combinatorial breadth. See MPEP §2163. Claims 2-4 and 6-7 retain substantial portions of the generic breadth and do not cure the deficiency. Claims 11 and 18 incorporate the compound genus through claim 1 and therefore retain the same written-description deficiency.
Claim 10 is not included in this written-description rejection because it is limited to the expressly identified compounds 1-138 (or pharmaceutically acceptable salt thereof), which are individually disclosed.
Claims 1-4, 6-7, 11, and 18 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for compound 1-138, does not reasonably provide enablement for full scope of the substantially broader claimed genus without undue experimentation. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The test for compliance with the enablement requirement is whether the disclosure, considered together with the knowledge of one of ordinary skill in the art at the time of filing, would have enabled such person to make and use the full scope of the claimed invention without undue experimentation. In determining whether experimentation is undue, the factors set forth in in re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988), are considered, including (1) the breadth of the claims; (2) the present or absence of working examples; (3) and (4) the nature of the invention and the predictability or unpredictability of the art; (5) the amount of guidance presented; (6) the quantity of experimentation necessary; (8) and (9) the state of the prior art and the relative skill of those in the art. See MPEP §§2164.01 and 2164.1(a).
The factors are considered together. No single factor is dispositive.
Breadth of the claims
Claim 1 encompasses compounds of Formula I, having multiple independently variable structural regions. Specifically, A may be O or -CH2-; Q may be -CH2- or absent; B encompasses several structurally distinct nitrogen-containing heterocycles, including aromatic heterocycles and saturated nitrogen-containing heterocycles; R1-R5 independently encompass multiple substituent alternatives; R6 and R7 independently encompass hydrogen, halo, hydroxy, cyclopropyl, C1-6 alkyl, substituted alkyl and related groups, or may be takin together with the carbon to which they are attached to form a cycloalkyl or heterocyclyl ring; and R8 encompasses phenyl or monocyclic or bicyclic heteroaryl groups that may themselves contain further substitution through Rx and Ry.
Accordingly, the scope of claim 1 extends substantially beyond the particular structural combinations represented by the specifically prepared compounds. The claim permits simultaneous cross-combination of numerous alternatives at several structurally significant portions of the molecule. Claims 2-4 and 6-7 narrow particular variables but continue to encompass substantial portion of this generic structural diversity. Claim 11 and 18 incorporate the Formula I compound genus and therefore retain the underlying breadth.
Working examples and experimental data
The specification provides a substantial number of working examples, and this factor weighs in Applicant’s favor with respect to the specifically exemplified compounds. Examples 1-133 are individually prepared and structurally identified, and the specification reports plasma Kallikrein (pKal) IC50 values for each examples 1-138. See pp. 61-103 and Plasma Kallikrein Assay and Accompanying Tables, pp. 103-107.
For example, elected compound 110 is specifically prep0ared and experimentally demonstrated to have a pKal IC50 of 1.0 µM. Thus, the rejection does not question whether the specifically disclosed compounds 1-138 can be made or whether the specification demonstrates plasma kallikrein inhibitory activity for those compounds.
Rather, the enablement issue concerns whether the disclosure enables the substantially broader structural territory encompassed by the generic claims beyond the 138 compounds actually synthesized and tested. Athought 138 working examples constitute significant experimental disclosure, the number and nature of the examples must be considered relative to the breadth and structural diversity of the claimed genus. Claim 1 is not limited to compounds 1-138 or to compounds differing from the exemplified species only by predictable peripheral substitutions. Instead, the claim permits independent and simultaneous variation of A, Q, B, R1-R8, including materially different heterocyclic systems at B, alternative ring formation through Rx/Ry, and broad monocyclic and bicyclic heteroaryl alternative at R8 with additional substitution.
Nature and predictability of the invention
The claimed subject matter concerns structurally diverse small-molecule plasma-Kallikrein inhibitors. The relevant enablement inquiry is therefore not limited to whether a person of ordinary skill could employ known synthetic chemistry to prepare an individual candidate falling within formula I. The disclosure must enable the skilled artisan to make and use substantially the full scope of the claimed invention without undue experimentation.
The specification itself demonstrates that plasma-kallikrein activity is an experimentally determined property. The disclosed compounds were subjected to pKa assay, and their IC50 values are reported in the Tables at pp. 104-107. Moreover, the experimental results demonstrate appreciable variation in pKal potency even among Applicant’s specifically selected, synthesized and tested compounds. Reported pKal IC50 values range from subnanomolar values-for example, 0.8 µM for Example 45-to-values exceeding 50 µM, including 56.6 µM for Example 77.
The Examiner does not rely upon this variation to establish that any of these examples are inoperative. Rather, the data demonstrate that pKal inhibitory potency is dependent upon molecular structure and is experimentally determined. The specification does not identify a generally applicable structure-activity relationship or other predictive principle by which a skilled artisan could reliably extrapolate from the 138 experimentally demonstrated compounds to the substantially broader combinations of structurally variables encompassed by claim 1.
Amount of direction and guidance
The specification provides extensive synthetic guidance, including general synthetic schemes, intermediates, reagents, reaction conditions and detailed preparations of the exemplified compounds. See pp. 26-103. Accordingly, the rejection does not take the position that Applicant failed to teach conventional synthetic methodology or that the specifically exemplified compounds cannot be prepared.
The deficiency concerns the amount of guidance commensurate with the full claimed scope. Although the disclosure tells the skilled artisan how selected compounds were prepared and provides an assay by which newly prepared compounds were tested, it does not provide a generally applicable teaching correlating the numerous permissible combinations of A. Q, B, and R1-R8 with pKal inhibitory potency.
Thus, the extensive structural territory beyond the 138 tested compounds, the skilled artisan is principally provided with a broad menu of permissible structural alternatives, synthetic techniques for making candidate compounds, and an assay for determining after synthesis whether a particular candidate has the desired biological property. The disclosure does not provide a predictive principle sufficient to identify, across the full scope, which combinations will provide the disclosed activity before those compounds are made and tested.
Post-filling evidence-Merchant et al. (ACS Med. Chem. Lett. 2026, 17, 744−749).
Further evidence relevant to the predictability of the claimed chemical space and the quantity of experimentation associated with it is provided by Merchant et al.
Merchant et al is not relied upon as prior art and is not relied upon to supply knowledge that became available only after Applicant’s effective filing date. Rather, the publication is cited as post-filling evidence illuminating the structure-activity behavior and experimentation associated with this spinocarbamate plasma-Kallikrein inhibitor chemical program. See MPEP §2124 regarding appropriate consideration of later evidence in evaluating what the original disclosure actually enabled. MPEP §2124-Exception to the Rule that the critical reference date must precede the filing date.
Merchant et al. describes an iterative structure-based medicinal chemistry program in which structural changes were made to address pKal potency, CYP3A4 time-dependent inhibition, metabolic stability, and other properties. The authors describe structure-based drug design to engineer hydrogen-bonding interactions followed by optimization through N-alkyl and N-aryl substation and other structural modifications. The reported SAR further demonstrates that localized structural modifications within this comparatively focused portion of the spinocarbamate chemical space resulted in differing pKal potency and pharmacological properties.
Merchant et al. additionally describes a parallel synthetic strategy permitting preparation of more than 100 analogs during the medicinal-chemistry program. The evidence is consistent with the conclusion drawn from the original disclosure that exploration of the claimed chemical space requires iterative structural selection, synthesis, biological testing and structure-activity analysis rather than straightforward prediction of biological activity merely from membership in Formula I.
Quantity of experimentation
A person of ordinary skill in the art could employ the synthetic techniques disclosed in the specification or otherwise known in the art to prepare additional Formula I compounds and could use Applicant’s disclosed pKal assay to determine the resulting activity. However, the existence of methods for synthesizing and screening candidate compounds does not itself establish enablement of the full genus.
For the substantial unexemplified structural territory encompassed by the claims, the artisan would be required to select among numerous independently variable alternatives, synthesize candidate compounds, determine their pKal inhibitory activity experimentally, analyze the resulting structure-activity relationships, and prepare and test additional candidates as necessary.
The individual synthesis and assay operations may constitute techniques within ordinary skill in the art. Nevertheless, the experimentation required is not merely the routine execution of a finite number of embodiments identified or predicted by the specification. Instead, the disclosure leaves the artisan to engage in iterative synthesis and screening across a substantially larger structural space without a disclosed structure-activity relationship or other predictive guidance commensurate with that scope.
Merchant et al.’ description of the preparation and evaluation of more than 100 analogs within comparatively focused medicinal-chemistry program further corroborates the quantity and iterative experimentation associated with structural exploration of the scaffold.
State of the art and the level of ordinary skill
The level of ordinary skill in medicinal and synthetic chemistry is recognized as high. A person of ordinary skill would have been familiar with conventional organic synthesis, purification and characterization techniques, medicinal-chemistry principles and biological assay methods. These factors favor Applicant insofar as the specification need not teach routine techniques already known in the art.
However, a high level of ordinary skill does not itself supply a predictive structure-activity relationship absent from the disclosure and the art. The issue is not whether the skilled artisan knows how to perform organic synthesis or conduct a pKal assay. Rather, the issue is whether the disclosure together with the knowledge available in the art, provides sufficient guidance to practice substantially the full claimed structural scope without requiring an undue program of iterative synthesis and screening.
Conclusion
Considering the Wands factors as a whole, the specification provides substantial enabling disclosure for the specifically exemplified compounds 1-138, including synthetic preparations and experimentally measured pKal activity. The presence of those working examples, the detailed synthetic disclosure, and the high level of skill in the art weigh in Applicant’s favor.
Those considerations, however, are outweighed with respect to substantial broader claimed genus by the breadth and structural diversity of the claims, the structure-dependent nature of pKal inhibitory activity demonstrated by Applicant’s own experimental data, the absence of a generally applicable structure-activity relationship permitting reliable extrapolation beyond the tested compounds, and the quantity of iterative synthesis and biological screening that would be required to explore the substantial unexemplified portions of the genus.
Accordingly, the specification does not enable a person of ordinary skill in the art to make and use the full scope of claims 1-4, 6-7, and 18 without undue experimentation.
The rejection does not extend to claim 10 on this basis, because claim 10 is limited to the specifically disclosed compounds 1-138, for which the specification provides individual structural disclosure, synthetic preparation, and experimental pKal activity. The separate issue concerning claim 10 is addressed under 35 U.S.C. § 103.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 10 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 10 recites “the compound of claim 1 is selected from any one of compounds 1-138.” However, compounds 1-138 are not structurally or chemically defined in the claim. Rather, the numerical designations “compounds 1-138” refer to compounds identified elsewhere in the specification. Accordingly, the metes and bounds of the claim cannot be determined from the claim itself without resort to the specification to ascertain which chemical structures are intended by the numerical compound designations.
Although the specification provides individual structures corresponding to Examples/Compounds 1-138, including Compound 110, such disclosure does not cure the failure of claim 10 itself to particularly identify the compounds being claimed. Applicant is required to amend claim 10 to particularly defined the claimed compounds, for examples by recited the appropriate chemical structure(s), structural formula, or other definite chemical identification in the claim.
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 1-4, 6-7, 11, and 18 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of the alternative compounds encompassed by Formula I, particularly the alternatives resulting from the independent selection of A, Q, B, R1-R8, Rx, and Ry is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Claims 1 permits simultaneous selection among structurally diverse alternatives at multiple portions of Formula I. A may be O or -CH2-, and Q may be -CH2- or absent. More significantly, B encompasses structurally different heterocyclic groups, including different aromatic nitrogen-containing heterocycles having different numbers and arrangements of ring nitrogen atoms, as well as saturated nitrogen-containing heterocycles. R8 independently encompasses phenyl or monocyclic or bicyclic heteroaryl groups, which may themselves bear further structurally diverse substituents selected from Rx and Ry. R1-R7 are likewise independently variable, and R6 and R7 may alternatively be taken together with the carbon atom to which they are attached to form a cycloalkyl or heterocyclic group.
Consequently, the alternatives encompassed by Formula I are not merely compounds having a single common chemical scaffold bearing different peripheral substituents. Complete compounds selected from different branches of the claim may differ simultaneously in the nature of the spirocyclic framework as determined by A and Q, the identity, aromaticity, saturation, ring size, and heteroatom arrangement of B, and the identity and substitution of the terminal R8 group. For example, one branch encompasses a compound having A = 0, Q = -CH2-, and aromatic azole B group, and a bicyclic nitrogen-containing heteroaryl R8 group whereas another branch permits A = -CH2-, Q absent, a saturated nitrogen-containing B heterocycle, and a different monocyclic heteroaryl or phenyl R8 group.
The specification discloses plasma-kallikrein inhibition as a common use and provides pKal inhibitory data for specifically prepared compounds. However, the disclosure does not establish that the common plasma-kallikrein inhibitory use of the entire Formula I genus flows from a substantial structural feature shared by all of the structurally disparate alternatives encompassed by the claim. Rather, the specifically prepared examples 1-138 occupy selected portions of the considerably broader Formula I genus. The presence of a common asserted utility therefore does not, by itself, establish the requisite single structural similarity among all members of the claimed Markush grouping.
Claims 2-4 and 6-7 do not overcome the improper grouping because their additional limitations narrow individual variables while leaving other structurally disparate alternatives of claim 1 intact. For example, although claim 4 limits A to O, claim 4 continues to encompass the materially different B and R8 alternatives inherited from claim 1. Similarly, the limitations added to claims 2, 3, 6, and 7 do not restrict the claimed compounds sufficiently to eliminate alternatives responsible for improper groupings.
Claim 11 and 18 likewise retain the improper Markush grouping. Claim 11 incorporates the compounds of claim 1 into a pharmaceutical composition comprising a pharmaceutically acceptable carrier and claim 18 further requires the additional therapeutic agent. Neither limitation restricts the Formula I compound alternatives so as to eliminate the structurally diversity giving rise to the improper grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
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.
Claims 1-4, 6-7, 10-11, and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Bao et al. (WO2022/109161 A1).
Bao concerns the same field of plasma-kallikrein inhibitors and teaches compounds of Formula I
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for inhibiting plasma kallikrein and treating conditions associated with plasma-kallikrein activity. See Summary/Detailed description, approximately pp. 2-4. Compound 59
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is relied upon as the closest specifically exemplified starting compound to elected compound 110. See p. 54 Bao does not merely
Bao further teaches a pharmaceutical composition comprising a Formula I compound and a pharmaceutically acceptable carrier and teaches brining the formula I compound into a suitable administration form using a pharmaceutically acceptable carrier. See claim 10. Bao additionally teaches its plasma kallikrein inhibitor compositions may optionally include these same classes of agents claimed in claim 18. See claims 17-18.
Bao does not merely provide an undifferentiated genus. Its Formula I disclosure expressly permits X to be N or CH and specifically identifies embodiment where X is N. It further provides R6 and R7 alternatives encompassing hydrogen and lower alkyl within Formula I definitions/embodiments, and permits R8 to be a heteroaryl bearing substituent Rx, wherein Rx encompasses hydrogen or C1-6 alkyl. See pp. 3-11. Most significantly for the elected compound species, the definition of heteroaryl expressly includes benzimidazolyl. See pp. 10-11 (heteroaryl definition).
Prior Art Compound 59 Elected compound 110
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Thus, beginning with specifically exemplified compound 59, Bao supplies the structural alternatives needed to arrive at the corresponding substitution pattern of the elected compound 110: the reference teaches closely related scaffold, permits the relevant H/C1-6 alkyl selections at the variable positions, permits the terminal heteroaryl/Rx substitution, expressly identifies benzimidazolyl as a heteroaryl, and permits X = N.
To the extent compound 110 differs from the closest compound species of Bao in the position of nitrogen atom in the triazole ring, the difference represents a closely related positional-isomer modification at the same heteroaromatic nucleus. A person of ordinary skill, seeking additional plasma kallikrein inhibitors within the expressly taught Formula I class, would have had reason to prepare the alternative triazole positional isomer because the reference teaches the invention encompasses all stereoisomeric forms of the compounds of Formula I. See ln. 8-9 of page 7. The skilled artisan would have reasonably expected the closely related positional isomer to retain kallikrein inhibitory activity absent evidence to the altered nitrogen position was critical to activity.
The reasoning is consistent with MPEP § 2144.09: close structurally similarity can support obviousness where structurally similar compounds have similar utility, and positional isomerism is a fact considered with all other relevant facts. See in re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). The rejection does not rest on isomerism alone, it rests on compound 59 together with Bao’s express Formula I teachings, contemplated heteroaryl/benzimidazolyl alternatives, X=N, substituent selection, and the same plasma-kallikrein utility.
Conclusion
Claims 1-4, 6-7, 10-11, and 18 are not allowed.
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/JEAN P CORNET/Primary Examiner, Art Unit 1628
