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.
Election/Restrictions
Applicant's election without traverse of Group IV in the reply filed on October 7, 2025 is acknowledged. Group IV, drawn to compounds of formula (I), LSD derivatives, embraced by claims 9-15 was elected by Applicant.
Applicant elects the following species:
PNG
media_image1.png
166
187
media_image1.png
Greyscale
and indicates claims 9 and 11-15 read on said species. The dependency of claim 16 has been changed from claim 8 to claim 9.
Claims 1-6, 8-16, 26, 27, 31 and 32 are pending and claims 9, 11-16 and 31 are under examination. Claims 10 and 32 are withdrawn based on the species election and claims 1-6, 8, 26 and 27 are withdrawn based on the restriction requirement.
Specification
The objection to the title of the invention is withdrawn based on the amendments.
Claim Objections
The objection to claim 13 because of the point of attachment to the tetracyclic core, is withdrawn based on the amendments.
The objection to claim 14 because of a period is required at the end of the claim, is withdrawn based on the amendments.
Claim 9 is objected to because of the following informalities: the term “fluoro” should be replaced with “fluorines” in the definition of R1. Appropriate correction is required.
Claim Rejections - 35 USC § 112
Claim 11 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for the broad recitation C1-5 haloalkyl, and the claim also recites CH2CH2F which is the narrower statement of the range/limitation, is withdrawn based on the amendments.
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 9, 11-16 and 31 are rejected under AIA 35 U.S.C. 103(a) as being unpatentable over Hoffman et al. (J. Med. Chem., 1985, 28, 12-52-1255) in view of Armer et al. (WO 2016118541) and Patani et al. (Chem. Rev., 1996, 96, 3147-3176).
The present application claims the following species, bottom right compound, of formula (I), bottom left formula, wherein R1= N(CH2CH3)2, R2= CH2CH2F and R3= H:
PNG
media_image2.png
429
352
media_image2.png
Greyscale
PNG
media_image1.png
166
187
media_image1.png
Greyscale
.
Hoffman et al. teach compounds of formula (I), R1= N(CH2CH3)2, R2= CH2CH3 and R3= H:
PNG
media_image3.png
204
363
media_image3.png
Greyscale
, see page 1252, right column, compound 2.
The only difference between the claimed species and the Hoffman compound is the substitution at R2, H versus Applicant’s F.
Armer et al. teaches the equivalency of H and F at this position, see page 2, formula (I), and the definition of R3.
Moreover, Patani et al. teaches that “[b]ioisosterism represents one approach used by the medicinal chemist for the rational medication of lead compounds into safer and more effective agents,” see page 3147. Patani also teaches that “[t]he substitution of hydrogen by fluorine is one of the more commonly employed monovalent isosteric replacements,” see page 3149. Patani further teaches that “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 page 3150.
Therefore, the instant invention is prima facie obvious from the teachings of the prior arts. One of ordinary skill in the art would have known to replace H with F and claim bioisosteres equivalents of prior arts’ compound at the time the invention was made. The motivation is from knowing that bioisosteres equivalents would have similar biological properties, and that H and F are art recognized equivalents.
Alternatively, given the teachings of the prior arts, it would have been obvious for one ordinary skill in the art to try bioisosteres equivalents and/or replacement of H with F at the time the invention was made because such limited and obvious options are well-known in the art. The choice of which to replace H with F is an obvious selection available for the preference of an artisan. The substitution is routinely done by organic chemists. The instant compounds and those by the prior arts have the same utilities. Such is a predictable result.
This is not a new concept, but a well-known substitution in the art of medicinal chemistry. Fluorination has been used to develop important drugs for many years. Uracil became 5-Fluorouracil, 5-FU, for treating cancer, which was developed in the 1950s, as was 9-Fluorohydrocortisone as an anti-inflammatory and for a range of other uses. Familiar names like Lipitor®, Risperdal®, Advair®, Cipro® and Prevacid® have been enormous successes. Prozac® (Fluoxetine), Citalopram® (Celexa) and indeed, most SSRI antidepressants, have F present. The F helps these drugs get into the brain and help improve pharmacokinetic properties.
However, such substitution is obvious from well-known knowledge of organic chemistry of replacing H with F. “When a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result.” United States v. Adams, 383 U.S. 49, 50-51 (1966). Cited in KSR Int. Co. v. Teleflex Inc, 127 S.Ct 1727, 550 U.S. 398, 82 USPQ2d 1385 (2007). The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR, supra.
When chemical compounds have "very close" structural similarities and similar utilities, a prima facie case of obviousness may be made. In re Grabiak (CAFC 1985) 769 F2d 729, 226 USPQ 870. Similarly, obviousness can be based on the concept of "isosterism", viz., the substitution in a parent compound of one atom or a group of atoms for another atom or group of atoms having a similar electronic and steric configuration. Ex parte Engelheardt (POBA 1980) 208 USPQ 243; In re Merck &Co. Inc. (CAFC 1986) 800 F2d 1091, 231 USPQ 375.
The compositions are taught in Armer et al., see pages 39-40.
Thus, said claims are rendered obvious.
Applicant traverses by stating, “The Examiner's rationale is flawed. Contrary to the Examiner's allegations, a person of ordinary skill in the art would not have understood Patani as indicating that compounds replacing hydrogen with fluorine would have similar and predictable properties. Patani illustrates that pharmacological differences are often attributed to fluorine substitution due to the introduction of the electron withdrawing group. See 3149, left column. Moreover, Patani specifically indicates that differences in electronic effects are of then the basis for interaction with biological receptors or enzymes as well as on metabolic fates of the drug. See 3149, left column. Thus, contrary to the Examiner's allegations, the substitution of hydrogen with fluorine is not a routine and predictable modification in organic and medicinal chemistry.”
This is not persuasive. Of course there will be differences in properties of the molecule when making a substitution for an atom or group with another, which is the reason for making said substitutions.
Applicant further states, “[A]s shown only in the present application, the presently claimed compounds exhibit properties that would not have been expected based on Hoffman's or Armer's disclosures (or any alleged bioisosteric replacement thereof). For example, only the present application shows that substitution of hydrogen with fluorine, particularly at the claimed R2 position, leads to compounds with highly advantageous and unexpected properties. For example, the presently claimed compounds are selective ligands of the 5-HT2A receptor. See Table 1 and 39:11-16. Furthermore, some compounds exhibit an advantageous subtype selectivity for 5-HT1A, 5-HT2A, and 5-HT2B over 5-HT2c. Put another way, these compounds show appreciable binding to 5-HT1A, 5-HT2A, and 5-HT2Bwhile showing no significant interaction with the 5-HT2c receptor. Moreover, the present application further demonstrates the presently claimed compounds fail to show any significant interaction with several other receptors such as the A2A receptor or the tested dopamine receptors. See, e.g., Table 1 and 39:11-16. The selectivity profiles of the presently claimed compounds would not have been expected at all-particularly based on general allegations of the equivalency of hydrogen and fluorine atoms in compounds.”
This also is not persuasive. Table 1 on page 39 from the specification is provided below:
PNG
media_image4.png
417
666
media_image4.png
Greyscale
Compounds 1-4 are also provided for comparison from pages 35-36 of the specification:
PNG
media_image5.png
258
370
media_image5.png
Greyscale
PNG
media_image6.png
259
405
media_image6.png
Greyscale
PNG
media_image7.png
243
338
media_image7.png
Greyscale
PNG
media_image8.png
235
281
media_image8.png
Greyscale
.
Compound 2, the elected species, is selective for 5-HT1A, 5-HT2A, and 5-HT2B over 5-HT2c, and compounds 1 and 3 show some selectivity, but a lot less than compound 2. However, the control, which should be LSD, is not provided and which is the comparison in the 103 rejection.
Applicant notes, “Hoffman, for example, does not teach or suggest fluorine replacement (as acknowledged by the Examiner), nor does it provide any motivation to explore substitution-and in particular, fluoro substitution at any position. If anything, Hoffman indicates that "[o]f the various structural modifications that have been carried out, few have yielded compounds that retain to any significant degree the remarkable potency of the diethylamide LSD" and a person would have reasonably expected that further modifications would be detrimental to activity. See 1252, left column. Moreover, Hoffman fails to teach or suggest that any particular selectivity profile-let alone the selectivity profiles of the presently claimed compounds.”
This is unpersuasive. For a 103 rejection, the primary reference does not have to teach the reason for the obviousness. The combination of references is sufficient to provide motivation.
Unexpected results should be commensurate in scope with the claims or provide sufficient data to show a trend. MPEP 716.02(D) states, “Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of non-obviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980). The non-obviousness of a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range if one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof. In re Kollman, 595 F.2d 48, 201 USPQ 193 (CCPA 1979).
Applicant contends, “Armer does not rectify these deficiencies. Armer discloses broad Markush formula, but provides no guidance that would have led a person of ordinary skill in the art to the presently claimed compounds. There is not a single exemplified compound (nor data associated therewith) in Armer with fluoroalkyl substitution at the heterocycle nitrogen. Moreover, Armer discusses different variants of agonizing/antagonizing profiles of LSD derivatives without providing any guidance whatsoever as to how and what compounds within its broad genus would result in these profiles. See, e.g., claims 15 to 22. Armer provides no focus or preference for these profiles and, in the absence of any experimental work, these recitations are nothing but laundry lists of multiple potential possibilities of agonism/antagonism on the receptors. These profiles are in no way substantiated by any experimental data, and consequently, cannot be considered to be reasonably enabled or provide any reasonable expectation of success. Based on Armer, the person of ordinary skill in the art would not have been motivated to any specific compounds nor would they have been provided any reasonable expectation that any compound would have had these profiles. Notably, Armer does not teach or suggest any selective binding of 5-HT2A, 5-HT1a, and 5-HT2B receptors, with no significant interaction with the 5-HT2c receptor (a result only disclosed in the present application). Not only does the cited art provide no reasonable expectation of compounds having any specific selectivity profile, none of the cited references teach or suggest such profiles being possible.”
This is also unpersuasive. As noted in the rejection, Armer et al. teaches the equivalency of H and F at this position, see page 2, formula (I), and the definition of R3.
Therefore, the rejection is maintained.
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
Prosecution Insights