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 .
This is a Final Office Action.
Claims 23, 24 and 28-45 are pending and claims 23, 24, 28, 29, 34, 35, 37 and 45 are under examination. Claims 28-44 are new claims. Claims 30-33, 36 and 38-44 are currently withdrawn based on the species election and restriction requirement.
Newly submitted claims 30-33, 36 and 38-44 directed to an invention that is independent or distinct from the invention originally claimed for the following reasons: said claims are not embraced by the species election.
Since applicant has received an action on the merits for the originally presented invention, this invention has been constructively elected by original presentation for prosecution on the merits. Accordingly, claims 30-33, 36 and 38-44 are withdrawn from consideration as being directed to a non-elected invention. See 37 CFR 1.142(b) and MPEP § 821.03.
To preserve a right to petition, the reply to this action must distinctly and specifically point out supposed errors in the restriction requirement. Otherwise, the election shall be treated as a final election without traverse. Traversal must be timely. Failure to timely traverse the requirement will result in the loss of right to petition under 37 CFR 1.144. If claims are subsequently added, applicant must indicate which of the subsequently added claims are readable upon the elected invention.
Should applicant traverse on the ground that the inventions are not patentably distinct, applicant should submit evidence or identify such evidence now of record showing the inventions to be obvious variants or clearly admit on the record that this is the case. In either instance, if the examiner finds one of the inventions unpatentable over the prior art, the evidence or admission may be used in a rejection under 35 U.S.C. 103 or pre-AIA 35 U.S.C. 103(a) of the other invention.
The first five species in claim 45 are free of the art. The MPEP- 803.02 states, “If the examiner determines that the elected species is allowable over the prior art, the examination of the Markush claim will be extended. If prior art is then found that anticipates or renders obvious the Markush claim with respect to a nonelected species, the Markush claim shall be rejected; claims to the nonelected species would still be held withdrawn from further consideration. The prior art search will not be extended unnecessarily to cover all nonelected species, and need not be extended beyond a proper Markush grouping.” Therefore, the two last species in claim 45 are withdrawn from further consideration.
Election/Restrictions
Applicant’s election, without traverse, of Group (III), drawn to a method of treating malaria comprising administering a compound of formulas (I), (II) or (III), embraced by claims 23 and 24 on December 11, 2024, is acknowledged.
Applicant elected the following species, the first structure of claim 20 (CB-27) also shown in figure 3A and below:
PNG
media_image1.png
147
182
media_image1.png
Greyscale
. Claims 23 and 24 read on said species.
The elected species was not found during the search, and thus, the search was expanded. Based on the search of formula (I), when Ar is pyrimidine, formula (I) is free of the art.
Claim Objections
Claims 35 and 45 (see the explanation above for claim 45) are objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
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 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.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 23 and 24 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over dos Santos Filho et al. (Bioorganic & Medicinal Chemistry, 2016, 24(22), 5693-5701).
The present application claims compounds of formula (I), wherein R1= H, R2= H, R3= H, R4= H, R5= OCH3, R6= H, R7= 3-phenyl-1,2,4-oxadiazole, with a OH at the 6-position of the phenyl ring, as treatments for malaria.
PNG
media_image2.png
167
161
media_image2.png
Greyscale
The reference teaches compounds of formula (I), wherein R1= H, R2= H, R3= H, R4= OH, R5= OCH3, R6= H, R7= substituted 3-phenyl-1,2,4-oxadiazole, with a H at the 6-position of the phenyl ring, as treatments for malaria,
PNG
media_image3.png
250
860
media_image3.png
Greyscale
, see page 5696, Table 1, SintMed 1-8.
The only difference between the claimed compound and the cited compounds is the substitution of the OH on the phenyl ring, 4-position versus Applicant’s 6-position. These compounds are positional isomers and are considered equivalent. The MPEP 2144.09 states “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
In re Grabiak 226 USPQ 870, "[w]hen chemical compounds have "very close" structural similarities and similar utilities, without more a primafacie case may be made", In re Deuel 34 USPQ2d 1210, "a known compound may suggest its analogs or isomers, either geometric isomers (cis v. trans) or position isomers (emphasis added) (e.g. ortho v. para)". Analogs differing only in the position of a single moiety are well known to be prima facie obvious in the law, as cited above, and require no secondary teaching.
Thus, said claims are considered obvious.
Applicant traverses by stating, “The cited references do not teach or suggest each and every feature of the claims.”
This is not persuasive.
Namely, Applicant notes, “Namely, the reference does not provide any motivation to make specific molecular modifications to arrive at the claimed compounds. The Office asserts that the claimed formula (I) is obvious in view of the reference, and the difference is merely a substitution of position of the hydroxyl on the phenyl ring, from the 4-position (para) position of the reference to the 6-position (ortho) of the claimed formula. However, Applicant argues that substituting the position on the phenyl ring, also known as "ring-walking", is not obvious.”
As noted in the rejection, MPEP 2144.09 states “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus)… are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). No secondary reference is required. Also note In re JONES 74 USPQ 152 (4-methyl naphthyl-l-acetic acid and 2- methyl naphthyl-l-acetic acid obvious over a reference teaching 1-methyl naphthyl-2-acetic acid), quoted with approval by Ex parte MOWRY AND SEYMOUR 91 USPQ 219, Ex parte Ullyot 103 USPQ 185 (4-hydroxy-l-oxo-l,2,3,4-tetrahydroisoquinoline obvious over a reference teaching 4-hydroxy-2-oxo-l,2,3,4-tetmhydroquinoline), "[p]osition isomers are recognized by chemists as similar materials", Ex parte BIEL 124 USPQ 109 (N-ethyl-3-piperidyl diphenylacetate obvious over a reference teaching N-alkyl-4-piperidyl diphenylacetate), "[appellant's arguments] do not, in any way, obviate the plain fact that appellant's DACTIL is an isomer of McElvain et al.'s compound. This close relationship places a burden on appellant to show some unobvious or unexpected beneficial properties in his compound in order to establish patentability", Ex parte Henkel 130 USPQ 474, (1-phenyl-3-methyl-4-hydroxypyrazole obvious over reference teaching 3-phenyl-5-methyl-4-hydroxypyrazole), "appellants have made no comparative showing here establishing the distinguishing characteristics they allege which we might consider as evidence that the claimed compounds are unobvious. It is clear from In re Henze, supra, and the authorities it cites, that at least this much is necessary to establish patentability in adjacent homologs and position isomers (emphasis added)".
Also, In re Surrey 138 USPQ 67, (2,6-dimethylphenyl-N-(3-dimethylaminopropyl) carbamate obvious over a reference teaching 2,4-dimethylphenyl N-(3-dimethylaminopropyl) carbamate), In re MEHTA 146 USPQ 284, (2-(1-methyl)-pyrrolidylmethyl benzilate obvious over a reference teaching 3-(1-methyl)-pyrrolidylmethyl benzilate), "[t]he fact that a position isomer (emphasis added) of a compound is known is some evidence of the obviousness of that compound. Position isomerism (emphasis added) is a fact of close structural (emphasis in original) similarity ...".Deutsche Gold-Und Silber-Scheideanstalt Formals Roessler v. Commissioner of Patents, 148 USPQ 412, (1-azaphenothiazines obvious over references teaching 2- azaphenothiazines, 3-azaphenothiazines, and 4-azaphenothiazines), In re Crounse, 150 USPQ 554 (dye with para (CONH2) and ortho (OCH3) obvious over a dye with the same nucleus and meta (CONH2) and para (OCH3) group), Ex parte Allais, 152 USPQ 66, (3-β-aminopropyl-6- methoxyindole obvious over a reference teaching 3- β-aminopropyl-5-methoxyindole), In re Wiechert 152 USPQ 247, (1-methyl dihydrotestosterones obvious over a reference teaching 2- methyl dihydrotestosterones), Monsanto Company v. Rohm and Haas Company, 164 USPQ 556, at 559, (3',4'-dichloropropionanilide obvious over references teaching 2',4'- dichloropropionanilide and 2',5'-dichloropropionanilide), Ex parte Naito and Nakagawa, 168 USPQ 437, (3-phenyl-5-alkyl-isothiazole-4-carboxylic acid obvious over a reference teaching 5- phenyl-3-alkyl-isothiazole-4-carboxylic acid), "[t]his merely involves position isomers (emphasis added) and under the decisions cited, the examiner's holding of prima facie obviousness is warranted." In re Fouche, 169 USPQ 429, (10-aliphatic substituted derivatives of dibenzo[a,d]cycloheptadiene obvious over reference teaching 5-aliphatic substituted derivatives of dibenzo[a,d]cycloheptadiene). In re Hass 60 USPQ 552, which found a prima facia case of obviousness of 1-chloro-1-nitrobutane over 1-chloro-1-nitroisobutane taught in the prior art, and In re FINLEY, 81 USPQ 383, 2-ethyl hexyl salicylate over octyl salicylate.
Applicant further states, “First, the reference provides no motivation to modify or substitute the position of the hydroxyl in the compounds described in the reference. The reference states that oxadiazoles have antimalarial activity (paragraph 2) and shows numerous substitutions on the phenyl group attached to the oxadiazole (Table 1). Inhibition, in vitro potency, cytotoxicity, and selectivity are highly sensitive to these substitutions (Table 1-2). In addition, the reference did not make modifications or substitutions to the phenyl (with methoxy and hydroxyl constituents; right-side of the molecule) of SintMed1-8. The reference provides no suggestions to indicate that altering that portion of the structure can improve the antimalarial properties. Furthermore, potent antimalarials arose from both the structure of SintMed1-8 and the structure of SintMed9-16, suggesting there is flexibility in the right side of the molecule. Thus, the reference only provided motivation to modify the "active", oxadiazole (left side) of the molecule.”
The motivation is that the compounds are positional isomers and similar compounds are expected to have similar properties. In re Grabiak 226 USPQ 870, "[w]hen chemical compounds have "very close" structural similarities and similar utilities, without more a prima facie case may be made", In re Deuel 34 USPQ2d 1210, "a known compound may suggest its analogs or isomers, either geometric isomers (cis v. trans) or position isomers (emphasis added) (e.g. ortho v. para)". Analogs differing only in the position of a single moiety are well known to be prima facie obvious in the law, as cited above, and require no secondary teaching.
Applicant goes on to state, “Second, Applicant disagrees that substituting the position of the hydroxyl would be expected to result in structural similarity in the context of sterics, which is important in protein binding. Functional groups in an ortho and para position are not sterically equivalent and would be expected to result in a differently "shaped" molecule. The data of this disclosure demonstrates that shape is highly important to antimalarial properties. The PbGST H-site targeted by the claimed antimalarial compounds includes a structured binding pocket (FIG. 4A). Using a shape similarity screening, Applicant was able to generate additional structures with antimalarial activity (Example 4; CB-41 to CB-64; and Table 2) based on shape and docking to the binding site. Example 4 suggests that the PbGST H-site may favor sterically bulky groups ranging from hydroxyl groups in the ortho position to fused benzene rings with hydroxyl constituents. The most potent antimalarial compounds from that screening (those which appear in Table 3) are shown below:
PNG
media_image4.png
379
685
media_image4.png
Greyscale
PNG
media_image5.png
168
642
media_image5.png
Greyscale
In conclusion, changing the position of the hydroxyl is not sterically equivalent and is not suggested by the cited reference. Therefore, Applicant respectfully requests the withdrawal of this rejection.”
This is not sufficient to overcome the rejection. The obviousness is based on the substitution of the OH on the phenyl ring, 4-position versus Applicant’s 6-position. There is nothing in the explanation provided that supports unexpected results for this comparison.
Therefore, the rejection is maintained.
Claims 23, 24, 28 and 29 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Camacho et al. (Bioorganic & Medicinal Chemistry, 2011, 19(6), 2023-2029).
The present application claims compounds of formula (I), wherein R1= H, R2 and R3= form a phenyl ring, R4= H, R5= H, Ar= benzimidazole, R6= H, R7= 5-nitro-2-furanyl or 5-nitro-2-thienyl, with an OH at the 2-position of the naphthyl ring substituted at the 1-position to the hydrazide, as treatments for malaria.
PNG
media_image2.png
167
161
media_image2.png
Greyscale
The reference teaches compounds of formula (I), wherein R1= H, R2= H, R3 and R4= form a phenyl ring, R5= H, Ar= benzimidazole, R6= H, R7= 5-nitro-2-furanyl or 5-nitro-2-thienyl, with an OH at the 2-position of the naphthyl ring substituted at the 3-position to the hydrazide, as treatments for malaria.
PNG
media_image6.png
204
536
media_image6.png
Greyscale
PNG
media_image7.png
198
502
media_image7.png
Greyscale
, see page 2024, Scheme 1, and page 2025, 5i and 6i.
The only difference between the claimed compound and the cited compounds is the substitution of the naphthyl ring to the hydrazide, 3-position versus Applicant’s 1-position. These compounds are positional isomers and are considered equivalent. The MPEP 2144.09 states “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
In re Grabiak 226 USPQ 870, "[w]hen chemical compounds have "very close" structural similarities and similar utilities, without more a primafacie case may be made", In re Deuel 34 USPQ2d 1210, "a known compound may suggest its analogs or isomers, either geometric isomers (cis v. trans) or position isomers (emphasis added) (e.g. ortho v. para)". Analogs differing only in the position of a single moiety are well known to be prima facie obvious in the law, as cited above, and require no secondary teaching.
Thus, said claims are considered obvious.
Claims 23, 24, 34 and 37 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Bekhit et al. (European Journal of Medicinal Chemistry, 2019, 163, 353-366).
The present application claims compounds of formula (I), wherein R1= H, R2= H, R3= H, R4= H, R5= H, 6-position= OH, Ar= pyrazole, R6= phenyl, R7= 4-methoxy-phenyl, as treatments for malaria.
PNG
media_image2.png
167
161
media_image2.png
Greyscale
The reference teaches compounds of formula (I), wherein R1= H, R2= H, R3= H, R4= H, R5= OH, 6-position= H, Ar= pyrazole, R6= phenyl, R7= 4-methoxy-phenyl, as treatments for malaria.
PNG
media_image8.png
462
725
media_image8.png
Greyscale
, see page 355, Scheme 1, compound 4c.
The only difference between the claimed compound and the cited compounds is the substitution of the OH on the phenyl ring, 5-position versus Applicant’s 6-position. These compounds are positional isomers and are considered equivalent. The MPEP 2144.09 states “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).
In re Grabiak 226 USPQ 870, "[w]hen chemical compounds have "very close" structural similarities and similar utilities, without more a primafacie case may be made", In re Deuel 34 USPQ2d 1210, "a known compound may suggest its analogs or isomers, either geometric isomers (cis v. trans) or position isomers (emphasis added) (e.g. ortho v. para)". Analogs differing only in the position of a single moiety are well known to be prima facie obvious in the law, as cited above, and require no secondary teaching.
Thus, said claims are considered obvious.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 SUSANNA MOORE whose telephone number is (571)272-9046. The examiner can normally be reached Monday - Friday, 10:00 am to 7:00 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Jeffrey Murray can be reached on 571-272-9023. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SUSANNA MOORE/Primary Examiner, Art Unit 1624