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 .
Response to Arguments
Applicant’s arguments and allegations of unexpected results have been thoroughly considered by the examiner. Applicant argues that the instant claims provide unexpected results as compared to other compounds. Compounds set forth in Table 2-1 are alleged to be superior because they have a 1 or 2 substituted halogen as compared to a compound without a halogen (i.e., compound 1 of the Table 2-1). The examiner expounds on the prima facie showing and addresses the allegations of unexpected results, which require further clarity.
The examiner notes that the instant claims include the following compounds as specific compounds claimed within a more generic formula of independent claim 34:
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. The examiner notes that a mono-substituted compound with one halogen is also claimed wherein halogen is bromine or chlorine.
The prior art teaches:
The following two compounds constitute the closest prior art embodiments.
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, wherein the sole difference is a single fluorine atom. Further, the prior art teaches the following core formula:
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and provides for the substituents to include the following limited listing:
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Even further, examples are provided in which R3a-R3d include 2 chlorine atoms in the claimed positions, as shown below.
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As an additional note, the Specification includes many compounds that are not halogenated, including the compound above shown on pages 343-355 of the Specification. It would be inconsistent to provide a Specification directed to compounds that include no halogen atoms and provide unexpected results compared to the closest prior art wherein halogen atoms are required.
Patani teaches the substitution of a fluorine for a hydrogen is one of the most commonly employed bioisosteric substitutions. See p3149, 4th full par. Numerous examples are provided in which a fluorine was substituted for a hydrogen in antineoplastic drugs and it worked, including for the drug 5-fluorouracil (5-FU). Overall, “the ability of fluorine to replace hydrogen is
an effective method of exploring the affinity of an agent to the target site (receptor or enzyme) by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are maintained.” See p3150, 2nd par.
The examiner provides 2 separate and specific examples for establishing a prima facie showing. The first reasons is a single fluorine atom for a hydrogen. The second reason is the established core with 2 chlorine atoms shown to be in the claimed positions and substituted for variable substituents among a limited list. No showing of unexpected results has been established because any data must show a comparison to the closest prior art. This includes the compounds shown above.
With respect to Applicant’s allegations of unexpected results the examiner responds.
The results show percentages in different assays. It is not clear there is a statistically significant difference between the compound 1, which is taught by the art and the other halogenated forms. Here is why.
No statistical significance is shown. It is also not clear what the confidence intervals of the comparisons are. More importantly, the IDO and TDO cell-based assays (which are the most important assays for simulating in vivo conditions) do not show superiority for the breadth of compounds claimed. Claim 1 is a compound taught by the prior art with no halogen. For compound 1 IDO and TDO percentages in the cell-based assays are 11% and -3%, respectively. For compound 2 that is halogenated with a fluorine atom, the percentages are 7% and 7%, respectively. It is not clear that this 4% and 10% distinction constitutes a statistically significant advantage.
Moreover, compound 7 has a single chlorine atom (i.e., is halogenated) and has values of 0% and -1% for IDO and TDO assays, respectively. Compound 6 has 4 fluorine atoms with an IDO value well above 11%; and compounds 2, 7, and 10 (which are each halogenated) have values for IDO that are well below 11%. For TDO, compound 1 has a value of -3% while compounds 7 and 10 have values of -1% and 2%. Compound 36 (which has 2 chlorine atoms) has a TDO value of -15%.
Overall, the values of compounds that are halogenated are not clearly better than compound 1 nor are they shown to be statistically different. In each column of the IDO and TDO cell-based assays, compounds that are halogenated as compared to a non-halogenated compound taught by the prior art are inclusive of higher and lower percentages. It is not clear how this is a showing of a statistically significant advantage as compared to the closest prior art.
As such, no claim is allowed.
Status of the Claims
Claims 34 and 37-43 are pending and examined.
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.
Claims 34 and 37-43 are rejected under 35 U.S.C. 103 as being obvious over Cadieux et al., (US2010/0240713), in view of Patani et al., “Bioisosterism: A Rational Approach in Drug Design,” Chem. Rev. 1996, 96, 3147-3176.
Cadieux teaches a generic formula wherein each substituent on a benzene, e.g., can be at any location. The formula below is the most generic formula that provides for substituents to be acceptable at any position on a benzene ring.
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Cadieux also teaches Examples in which the substituents are on adjacent positions of a claimed cyclic structure. See both structures below wherein the ring is benzene or naphthalene in Examples 3.15 and 3.20. Thus, the claimed molecule as shown below is preferred, with the exception of a halogen substituent.
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Cadieux also provides examples in which isomers of these include compounds with a claimed ring structure (i.e., a thiophene), include halogens at claimed positions. See Example 9, below.
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.
Even further, Cadieux teaches isomers and mixtures thereof. Cadieux also teaches specific core formula structures wherein the undefined variables include R3a, R3b, and R3e.
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See par. 442.
Compounds of formula Ib-1 can be prepared by those methods known in the art. See par. 443.
The above generic formula is a claimed formula wherein R3a, R3b, R3c, and R3d are halo. They are defined to not only include halogen, but halogen is preferred as it is shown among a limited list of potential substituents. See paragraph 196, below wherein R3a-R3e include halogen among only 6 options.
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Thus, in view of Formula (Ib-1), a POSA would understand and immediately envisage a halo at the position of 3a-3e on a benzene ring. This is the sole distinction between the instant claims and Cadieux. Moreover, the halogens above include chlorine in two positions.
Applicant also claims the below compound.
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the sole difference between these compounds is the substitution of a hydrogen for a fluorine at a single position.
Patani teaches the substitution of a fluorine for a hydrogen is one of the most commonly employed bioisosteric substitutions. See p3149, 4th full par. Numerous examples are provided in which a fluorine was substituted for a hydrogen in antineoplastic drugs and it worked, including for the drug 5-fluorouracil (5-FU). Overall, “the ability of fluorine to replace hydrogen is
an effective method of exploring the affinity of an agent to the target site (receptor or enzyme) by virtue of its greater electronegativity while other parameters such as steric size and lipophilicity are maintained.” See p3150, 2nd par.
Applicant has claimed compounds that fall within the scope of Cadieux. Applicant has not provided an allegation of unexpected results and as such the examiner is determining if a prima facie showing is established in view of the cited prior art. Cadieux is a POSA that would almost certainly recognize the claimed compounds as those that would have efficacy of the compounds taught by Cadieux.
Carriers and excipients can be included with the claimed compound. See par. 388. It is taught to treat cancer. See par.’s 357 and 365. The compound can be used in combination with one or more additional therapeutic agents. See Example 3.2, among others. Compounds can be used as a prodrug, with an excipients, and/or a salt form can be used. See p4, lines 6-16. A carrier can be used. See p15, line 13.
It would have been prima facie obvious prior to the filing of the instant application to arrive at the claimed compounds and methods in view of the cited prior art. One would be motivated to do so because Cadieux teaches similar compounds, including a generic core formula that is identical to compounds claimed with the exception of specifying halogen substituents on the benzene ring. Additionally, halogens are among a limited list of substituents taught to be included at the claimed positions. A POSA would be able to arrive at the claimed compounds for treating cancer, e.g., in view of the teachings of Cadieux because they are similarly structured comprise the same and a limited list of constituents. Including one or two halogens, including a chlorine or bromine are taught and shown in examples. Even further, Patani provides a reasonable and predictable expectation of success in using fluorine for hydrogen substitution including in anticancer agents. As such, there is a reasonable and predictable expectation of success in arriving at the claimed compounds and methods taught by Cadieux.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 34 and 37-43 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 7-9, 11, 13-17, 20, 29, and 31 of copending Application No. 18/942,152, in view of Cadieux et al., (US2010/0240713), in view of Patani et al., “Bioisosterism: A Rational Approach in Drug Design,” Chem. Rev. 1996, 96, 3147-3176. The claims of the ‘152 application include compounds and methods of treating cancer with compounds presently claimed and those rendered obvious in view of the cited prior art. Claim 7 of the ‘152 application is directed to the same core formula presently claimed. In view of the overlapping compounds and methods of use, including for those reasons set forth above, the claims are provisionally rejected.
This is a provisional nonstatutory double patenting rejection.
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 extension fee 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 JARED D. BARSKY whose telephone number is (571)-272-2795. The examiner can normally be reached on Monday through Friday from 8:30 to 5:30. If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Amy L. Clark can be reached on 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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/JARED BARSKY/Primary Examiner, Art Unit 1628