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 .
DETAILED ACTION
1. This application is a 371 of PCT/CN2022/130953 11/09/2022; FOREIGN APPLICATIONS: CHINA 202111441550.3 11/30/2021 CHINA 202210044528.3 01/14/2022.
Claims 1-16 are pending.
Response to Restriction Election
2. Applicant’s election of group I and the species, the first compound in claim 11
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, in the reply filed on May 6, 2026 is acknowledged. The election was made without traverse. According to applicants’ representative claims 1-7, 11-12 read on the elected species. As detailed in the following rejections, the elected species was not found patentable. The search and examination was conducted until prior art was found that anticipated or rendered obvious the elected species. As per MPEP 803.02 II. C. “[T]he examiner must continue to search the species of the claim unless the claim has been found to be unpatentable over prior art.” The examiner “need not continue to search the claim if the claim is rejected over prior art”. [ibid. D.] Therefore, the search and examination is restricted to the claims reading on the elected species, and claims not reading on the elected species are held withdrawn. Accordingly, claim 8-10, which do not read on the elected species are withdrawn.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
3. Claim(s) 1-7, 12 is/are rejected under 35 U.S.C. 102(a) (1) and 102 (a) (2) as being anticipated by Bobinski WO 2021050915 A1 (Cited on the IDS). Bobinski teaches a number of anticipatory compounds on page 29 ff.. including but not limited to:
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These are compounds of claim 1 where L is a bond, R1 is alkyl, R2 is H, R3/R7 are CN, F, Cl, H, F, CH2F, CF2H, R4/R6 are H, Cl, alkyl (methyl, ethyl, propyl), C0-O-R20, where R20 is cycloalkyl, 3 to 12 membered heterocyclyl (THF), 5-10 membered heteroaryl pyrazole, thiazole), C0-O-R20, where R20 is alkyl or alkyl substituted with F, cycloalkyl, R5 is H, chloro, alkyl (methyl, ethyl, propyl, isopropyl, pyrazole, thiazole, C0-O-R20, where R20 is alkyl, cycloalkyl, or where two adjacent substituents R3, R4, R5, R6 and R7 form various rings including pyridine, phenyl (to form naphthalene), tetrahydropyran, thiazole, pyrazole, X1, X2 and X3 are CR15, where R15 is H, O-alkyl, alkyl, CF3, F, Cl, R8 is H, one of R9, R10, R11 is C0-alkyl-NR22R23, where R22 and R23 are H, the others are H, D, alkyl, CHF2.
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.
4. Claims 1-7, 11-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Bobinski WO 2021050915 A1 as applied to claims 1-7, 12 above and further in view of Fleming “Nitrile-Containing Pharmaceuticals: Efficacious Roles of the Nitrile Pharmacophore.” J. Med. Chem. 2010, 53, 7902–7917. 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 are summarized as follows:
Determination of the scope and content of the prior art (MPEP 2141.01)
Bobinski teaches the compounds as discussed above, including the naphthalene congeners that have the same base structure as the elected species:
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The compounds in Example 16 have all the features of the elected species except the -CN group.
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According to Table 11 on page 316, Example 4-203 was one of the most potent compounds, giving nanomolar potentcy:
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The atropisomer, 16-1, was the most potent of the 4-203 mixture:
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The compound on page 36 (Example 4-203), and the last compound on page 39 (Peak 1 Example 16-1) and the first compound on page 39 (Example 16-2), have all of the structural features of the elected species and the 2nd and 4th compounds in claim 11, except the R15 as -CN:
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In the context of the genus description on page 12, the instant R15 is the R1 variable:
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The R1 group is listed as CN, just as in the elected species.
Ascertainment of the difference between the prior art and the claims
The elected species has a –CN group in the 5-position of the phthalazine, as compared to the prior art Example 4-203 (Example 16-1/16-2) compounds with an H atom.
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vs
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An additional compound differs only by the location of the -CN group
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Finding of prima facie obviousness
(MPEP 2142-2143)
It would have been obvious to one of ordinary skill in the art at the time the claimed invention was made to prepare the –CN analogs of claim 11 to produce the instantly elected species other compounds of the instant claims. As discussed above the –CN group was described as a preferred substituent in a very discrete generic description in exactly the same position. Bobinski shows that the substitution of the –CN in these compounds was part of his disclosure and the –CN analog would behave in the same or similar manner towards the same targets in cancer cells. Success is practically guaranteed. There is evidence that an electron withdrawing group can lead to increased potency. Upon chlorination improved potency over the hydrogen compound was achieved, compare compound 4-147 to 10-1.
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Since the nitrile is also electron withdrawing and similar in size a similar improvement would be expected. An additional compound differs only by the location of the -CN group
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Positional isomers, having the same radical on different positions of the molecule, have been deemed prima facie obvious, requiring no secondary teaching. There is an expectation that position isomers, as close analogues, would have similar properties and upon the routine nature of such position isomer experimentation in the art of medicinal chemistry. In re JONES 74 USPQ 152 (4-methyl naphthyl-1-acetic acid and 2-methyl naphthyl-1-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-1-oxo-1,2,3,4-tetrahydroisoquinoline obvious over a reference teaching 4-hydroxy-2-oxo-1,2,3,4-tetrahydroquinoline), "[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)". Ex parte Engelhardt, 208 USPQ 343 at 349, "[i]f functional groups capable of withdrawing or repelling electrons are located in the chain or ring (emphasis added) of a biologically active compound, transfer of such groups to other positions in which their electronic effects are lessened or enhanced may alter the biological activity of the modified compound. Hence, position isomerism (emphasis added) has been used as a tool to obtain new and useful drugs", 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)".
Beyond the Bobinski disclosure itself, there are additional reasons to make a –CN analog including those discussed in Fleming. According to Fleming page 7902 col. 1, “Over 30 nitrile-containing pharmaceuticals are prescribed for a diverse variety of medicinal indications with more than 20 additional nitrile-containing leads in clinical development. Trends identifying the roles of the nitrile in medical agents have emerged as the number of nitrile-containing pharmaceuticals has increased.” Page 7909, describes the nitrile as improving various drug properties:
The nitrile group improves ADME178-toxicology profiles. Computational properties and empirical rules such as Lipinski’s rules179 are routinely employed to guide structure-based drug design. While a potent molecule is essential for drug discovery, ultimately ADME-Tox properties decide which molecule is advanced into clinical trials. During optimization, leads tend to increase in size and lipophilicity180 which can be offset by introducing the sterically insignificant nitrile group. Replacing a hydrogen with a nitrile can roughly lower cLogP181 by half an order of magnitude and nearly an order of magnitude reduction for logD.182 A more dramatic decrease in lipophilicity by over a full order of magnitude for cLogP/logD often occurs when replacing a halogen or methyl group by a nitrile.
For these additional reasons: less susceptibility to oxidative metabolism, improvements in toxicology, and lowering cLogP and logD, one would be motivated to make–CN analogs to produce the elected species and other claimed compounds.
Conclusion
5. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/DAVID K O'DELL/Primary Examiner, Art Unit 1621
Prosecution Insights