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 .
Status of the Claims
Claims 1, 4 – 8, 10 – 12 and 26 – 32 are pending.
Claims 1, 4 – 8, 10 – 12, 26 – 27 and 29 – 32 are rejected.
Claim 28 is withdrawn.
Response to Applicant’s Remarks
Applicant’s remarks/ amendments filed on December 30, 2025 have been fully considered.
The objection to claim 31 is withdrawn in view of amendment to recite proper units “μg/ml” in the limitation “… minimum inhibitory concentration (MIC of 0.1 μg/ml to 10 μg/ml to inhibit…”.
The rejection under 35 U.S.C. 112(d) of claim 9 as being of improper dependent form is withdrawn in view of cancellation of the claim.
Regarding the rejection under 35 U.S.C. 102(a)(1) of claims 1, 5 – 7, 10 – 12, 26 – 27 and 31 as being anticipated by Ahn et al., Bioorg. Med. Chem. Lett. (1999), 9: pp. 2073-2078 (publ. 1999), Applicant’s remarks are addressed below:
On page 7, 4th – 5th paragraph, Applicant cited board decisions and restated the basis of anticipation with respect to the claims. On page 8, 1st paragraph, Applicant refer to Table 2 of Ahn and discusses compound 4e and 4f were found most promising, with TR IC50 values of 56 nM and 52 nM, respectively. Applicant notes that the reliance on Ha-TRAP Induced Aggregation IC50 and Thrombin Induced Aggregation IC50 value to provide alleged teachings of claimed MIC is in error. The aggregation studies with ha-TRAP uses a 30 fold higher ligand concentration and differ from the binding studies that are performed at a ha-TRAP concentration close to its Kd. Thus, the relevant IC50 value is 56 nM, which is equivalent to 0.02 μg/ml. The concentration falls below the range as recited in the instant claims.
However, as cited in point 18 (page 8) of Non-Final action dated July 2, 2025, the instant claims specifically recites the limitation “… pharmaceutical composition at a minimum inhibitory concentration (MIC of 0.1 μg/ml to 10 μg/ml to inhibit growth of cells of a disease…”. The instant disclosure does not provide or suggest a specific definition for the limitation “minimum inhibitory concentration (MIC)”. According to Official Notice, the broadest reasonable interpretation of the concentration is the least amount of' concentration (μg/mL) that completely inhibits the test organism. Thus, the limitation “wherein the compound of Formula (I) is present in the pharmaceutical composition at a minimum inhibitory concentration (MIC) of 0.1 μg/ml to 10 μg/ml” can be interpreted as any concentration that is greater than the claimed concentration. Emphasis added. Ahn teaches the in-vitro biological activity of compound 4e is expressed as IC50 (half-maximal inhibitory concentration) of 300 nM and 3000 nM, which is defined as the amount of drug or inhibitor needed to reduce a biological process by half. 300 nM and 3000 nM is converted to 0.11 μg/ml and 1.1 μg/ml respectively. Further, the limitation “to inhibit growth of cells of a disease” is an intended use limitation as governed by MPEP 2111.02(II). Intended use limitations are interpreted based on the structural limitations they impart to the invention. In this case, the intended use only requires the pharmaceutical composition is capable of being used to inhibit growth of cells of a disease, but does not impart any specific limitations to the structure. According to Ahn, the pharmaceutical composition comprising compound 4e is within the concentration range of 0.1 μg/mL to 10 μg/mL. Thus, said pharmaceutical composition is capable of being used to inhibit growth of cells of a disease. Applicant remarks are not persuasive and the rejection is maintained.
Regarding the rejection under 35 U.S.C. 103 of claims 1, 4 – 8, 10 – 12 and 29 – 32 (claim 9 is cancelled) as being unpatentable over Ledig CA 1093555 A1 (pub. 1981) in view of Ahn et al., Bioorg. Med. Chem. Lett. (1999), 9: pp. 2073-2078 (publ. 1999), Applicant’s remarks are addressed below:
On page 9, 4th paragraph, Applicant cited board decisions and restated the prima facie case of obviousness basis with respect to the claims. Applicant assert Ledig and Ahn, alone or in combination, fail to disclose the limitations of claims 1 and 31: 1) a pharmaceutical composition with a compound of Formula (1) wherein at least one of R1 and R4 are alkyl or cycloalkyl, 2) wherein the composition’s minimum inhibitory concentration (MIC) is between 0.1 μg/mL to 10 μg/mL to inhibit the growth of cells of a disease. On page 10, 3rd paragraph, Applicant states that the Office Action compares two different IC50 values (Aggregation IC50 for Compound 2a and TR IC50 value for Compound 4a). It is noted that the different IC50 values was an inadvertent error. The correct values are presented below:
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According to MPEP §2141(III)(G), Ahn teaches that compound 4a (wherein, at least one of R1 and R4 is C1 alkyl) is significantly potent to inhibit the activity of high affinity thrombin receptor agonist peptide (ha-TRAP) by half compared to compound 2a (R1 and R4 are each hydrogen). Thus, a PHOSITA would have been motivated to substitute the hydrogen of one of R1 and R4 with a methyl group because Ahn identifies that compound 4a is a lead compound and possesses improved pharmaceutical properties. The PHOSITA would have a reasonable expectation that compound 4a, wherein at least one of R1 and R4 is C1 alkyl, would also possess enhanced antifolic acid and antibacterial activity as taught by Ledig because similar pharmaceutical properties would have been expected from structurally similar compounds. Applicant’s remarks are not persuasive and the rejection is maintained. The rejection has only been amended to correct the inadvertent error for the IC50 value of compound 4a and the claims pending in the instant application.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 5 – 7, 10 – 12, 26 – 27 and 31 are rejected under 35 U.S.C. 103 as being anticipated by Ahn et al., Bioorg. Med. Chem. Lett. (1999), 9: pp. 2073-2078 (publ. 1999).
Ahn et al. teach compound 4e. See, e.g., pp. 2075, Scheme 2 and Table 2. Compound 4e is shown below:
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Ahn also teaches that the compound is a “novel small molecule inhibitor of the intramolecular ligand of the thrombin receptor” and has beneficial cardiovascular effects. See, e.g., Abstract and pp. 2073, 1st paragraph. Ahn further teaches that the cyclopropylamino substitution as a mono- or dialkylamino substituent is well tolerated and optimal for the potency of the compound. See, e.g., pp. 2075, 2nd paragraph. The in-vitro biological activity of the compound is expressed as IC50 (half-maximal inhibitory concentration), which is defined as the amount of drug or inhibitor needed to reduce a biological process by half. The in-vitro biological activity of compound 4e is presented below:
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The prior art anticipates the instant claims as presented below:
Claims 1 and 31, directed to a pharmaceutical composition comprising a compound of Formula (I)
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, wherein:
At least one of R1 and R4 is cycloalkyl, and the other is hydrogen;
the variable “n” attached to R1 is 0;
R2 is aryl (phenyl), and the variable “n” attached to R2 is 1;
R3 is hydrogen;
X and Z are each C; and
Y is NR9R10, wherein R9 and R10 are each hydrogen.
With respect to the concentration “minimum inhibitory concentration (MIC)”, the instant disclosure does not provide or suggest a specific definition for the limitation. According to Official Notice, the broadest reasonable interpretation of the concentration is the least amount of' concentration (μg/mL) that completely inhibits the test organism. Thus, the limitation “wherein the compound of Formula (I) is present in the pharmaceutical composition at a minimum inhibitory concentration (MIC) of 0.1 μg/ml to 10 μg/ml” can be interpreted as any concentration that is greater than the claimed concentration. Emphasis added. Ahn teaches that the compound is present in the pharmaceutical composition at a half-maximal inhibitory concentration (IC50) of 300 nM and 3000 nM. 300 nM is converted to be 0.11 μg/ mL and 3000 nM is converted to be 1.1 μg/ mL. The calculations are shown below:
((300 nmol/ 1 L) x (1 L/1000 mL) x (1 mol/ 1x109 nmol) x (371.49 g/ 1 mol) x (1x106 μg/ 1 g)) = 0.111447 μg/ mL = 0.11 μg/ mL.
((3000 nmol/ 1 L) x (1 L/1000 mL) x (1 mol/ 1x109 nmol) x (371.49 g/ 1 mol) x (1x106 μg/ 1 g)) = 1.11447 μg/ mL = 1.1 μg/ mL.
The concentrations of 0.11 μg/ mL and 1.1 μg/ mL lies within the concentration of 0.1 μg/mL to 10 μg/mL as recited in the instant claims. Further, the phrase “to inhibit growth of cells of a disease” is an intended use limitation as governed by MPEP 2111.02(II). Intended use limitations are interpreted based on the structural limitations they impart to the invention. In this case, the intended use only requires the pharmaceutical composition is capable of being used to inhibit growth of cells of a disease, but does not impart any specific limitations to the structure. Based on Ahn, the pharmaceutical composition comprising compound 4e is within the concentration range of 0.1 μg/mL to 10 μg/mL. Thus, said pharmaceutical composition is capable of being used to inhibit growth of cells of a disease.
Claim 5, wherein X and Z are each C.
Claim 6, wherein R9 and R10 are each hydrogen.
Claim 7, wherein R3, R9 and R10 are each hydrogen, and X and Z are each C.
Claims 10 – 12, drawn to limitations that further limit the intended use limitation of claim 1. Based on Ahn, the pharmaceutical composition comprising compound 4e is within the concentration range of 0.1 μg/mL to 10 μg/mL. Thus, said pharmaceutical composition is capable of being used to inhibit growth of cells of a disease, wherein the cells are bacteria cells (claim 10), specifically gram negative bacteria cells (claim 11), or cancer cells (claim 12).
Claim 26, wherein the compound of Formula (I) is:
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, wherein:
At least one of R1 and R4 is cycloalkyl, and the other is hydrogen;
R3 is hydrogen;
X is C; and
Y is NR9R10, wherein R9 and R10 are each hydrogen.
Claim 27, wherein the compound of Formula (I) is:
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, wherein:
R3 and R4 are each hydrogen;
X is C; and
Y is NR9R10, wherein R9 and R10 are each hydrogen.
Claim Rejections - 35 USC § 103
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.
Claims 1, 4 – 8, 10 – 12 and 29 – 32 are rejected under 35 U.S.C. 103 as being unpatentable over Ledig CA 1093555 A1 (pub. 1981) in view of Ahn et al., Bioorg. Med. Chem. Lett. (1999), 9: pp. 2073-2078 (publ. 1999).
Determining the scope and contents of the prior art
Ledig teaches compound of Example 47. See, e.g., page 31, Table I, and page 75, Table IV. Ledig also teaches that the compound exhibits an antifolic acid activity. See, e.g., page 8, lines 6-21. Compound of Example 47 is shown below:
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Ledig teaches preparing a stock solution or suspension of the compound at a concentration of 2500 μg/mL in a suitable solvent or medium such as aqueous sodium hydroxide, aqueous lactic acid, methyl cellosolve, dimethylsulfoxide, dimethylacetamide, ethylene glycol, dimethylformamide, formamide, propylene glycol, acetone or methanol. Appropriate amounts of sterile water is added to make two-fold dilutions of solution or suspension. “One ml. quantities of each dilution are incorporated into seed agar or Wellcotest Sensitivity Test Agar fortified with 5% hemolyzed horse blood (9 ml. vol.) in sterile Petri dishes to give plates containing varying concentrations of the test compound. The hardened surfaces of each plate are incubated with the test organism, and the plates are incubated for 18 hours at 35° C. The in vitro antibacterial activity of the compounds tested is expressed as the minimal inhibitory concentration" (MIC) which is defined as the “least amount of' material (μg/mL) that completely inhibits the test organism”. See, e.g., page 69, 2nd paragraph. The in vitro antibacterial activity of the compound of Example 47 is presented below:
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The structure of naphthalenyl ring is presented below (using ChemDraw software, version 20.1.0.110):
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Compared to claims 1 and 31, the compound of Example 47 reads on instant Formula (I)
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, wherein:
R4 is hydrogen;
R1 is hydrogen, and the variable “n” attached to R1 is 0;
R2 is aryl (naphthalenyl), and the variable “n” attached to R2 is 1;
R3 is hydrogen;
X and Z are each C; and
Y is NR9R10, wherein R9 and R10 are each hydrogen.
Ascertaining the differences between the prior art and the claims at issue
The difference between compound of Example 47 and the claims is that R1 and R4 are each hydrogen (compound 47) instead of at least one of R1 and R4 is C1 alkyl as instantly claimed.
Rationale for a prima facie case of obviousness
Ahn et al. teach compound 4a. See, e.g., pp. 2075, Scheme 2 and Table 2. Compound 4a is shown below:
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.
Ahn also teaches that the compound is a “novel small molecule inhibitor of the intramolecular ligand of the thrombin receptor” and has beneficial cardiovascular effects. See, e.g., Abstract and pp. 2073, 1st paragraph. The in-vitro biological activity of the compound is expressed as IC50 (half-maximal inhibitory concentration), which is defined as the amount of drug or inhibitor needed to reduce a biological process by half. Ahn compares the in-vitro biological activities of compounds 2a and 4a as presented below:
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According to MPEP §2141(III)(G), one of the rationales in the KSR decision states “(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”. KSR, 550 U.S. at 418, 82 USPQ2d at 1396. Ahn teaches that compound 4a (wherein, at least one of R1 and R4 is C1 alkyl) is significantly potent to inhibit the activity of high affinity thrombin receptor agonist peptide (ha-TRAP) by half compared to compound 2a (wherein, R1 and R4 are each hydrogen). Thus, a person having ordinary skill in the art would have been motivated to substitute the hydrogen of one of R1 and R4 with a methyl group because Ahn identifies that compound 4a is a lead compound and possesses improved pharmaceutical properties. The PHOSITA would have a reasonable expectation that compound 4a, wherein at least one of R1 and R4 is C1 alkyl, would also possess enhanced antifolic acid and antibacterial activity as taught by Ledig because similar pharmaceutical properties would have been expected from structurally similar compounds.
The prior art would have rendered the instant claims prima facie obvious as presented below:
Claims 1 and 31, directed to a pharmaceutical composition comprising a compound of Formula (I)
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, wherein:
At least one of R1 and R4 is C1 alkyl, and the other is hydrogen;
the variable “n” attached to R1 is 0;
R2 is aryl (naphthalenyl), and the variable “n” attached to R2 is 1;
R3 is hydrogen;
X and Z are each C; and
Y is NR9R10, wherein R9 and R10 are each hydrogen.
Ledig teaches that the compound is present in the pharmaceutical composition at a minimum inhibitory concentration between 0.976 and 3.90 μg/mL, which lies within the claimed concentration range of 0.1 μg/mL to 10 μg/mL. Further, the phrase “to inhibit growth of cells of a disease” is an intended use limitation as governed by MPEP 2111.02(II). Intended use limitations are interpreted based on the structural limitations they impart to the invention. In this case, the intended use only requires the pharmaceutical composition is capable of being used to inhibit growth of cells of a disease, but does not impart any specific limitations to the structure. Based on Ledig, the pharmaceutical composition comprising compound of Example 47 is within the minimum inhibitory concentration (MIC) range of 0.1 μg/mL to 10 μg/mL. Ledig also teaches that the compound exhibits an antifolic acid activity. See, e.g., page 8, lines 6-21. Thus, said pharmaceutical composition is capable of being used to inhibit growth of cells of a disease.
Claim 4, wherein the aryl is a multicyclic ring system (naphthalenyl).
Claim 5, wherein X and Z are each C.
Claim 6, wherein R9 and R10 are each hydrogen.
Claim 7, wherein R3, R9 and R10 are each hydrogen, and X and Z are each C.
Claim 8, wherein the aryl of R2 is a multicyclic ring system (naphthalenyl).
Claims 10 – 12, drawn to limitations that further limit the intended use limitation of claim 1. Based on Ledig, the pharmaceutical composition comprising compound of Example 47 is within the concentration range of 0.1 μg/mL to 10 μg/mL. Thus, said pharmaceutical composition is capable of being used to inhibit growth of cells of a disease, wherein the cells are bacteria cells (claim 10), specifically gram negative bacteria cells (claim 11), or cancer cells (claim 12).
Claims 29 and 32, wherein at least one of R1 and R4 is C1 alkyl, and the other is hydrogen.
Claim 30, wherein the aryl of R2 is a multicyclic ring system (naphthalenyl).
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sagar Patel whose telephone number is (571)272-1317. The examiner can normally be reached Monday - Friday: 9am to 5pm EST.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Amy L. Clark can be reached at (571) 272-1310. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Sagar Patel/Examiner, Art Unit 1626
/KAMAL A SAEED/Primary Examiner, Art Unit 1626
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