DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 10/22/2025 has been entered.
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 .
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 01/07/2022 and 10/22/2025 is acknowledged. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 16 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 16 does not further limit the scope of claim 1 from which it depends because claim 16 is a compound claim not a method claim and thus is not further limited by the use of the compound. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103- Updated
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1-9, 13-16 and 18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Czarnik (Czarnik et al., US 2009/0076137 A1, 3/19/2009).
The closest prior art is Czarnik (US 2009/0076137 Al, IDS 01/07/2022), which teaches deuterium-enriched dronedarone (abstract, formula (I), fig. 1 depicted here) for treating cardiac arrhythmias. Wherein “R1 -R43 are independently selected from H and D” ([0022]); thus, this generic formula does cover the species of poyendarone as claimed in the formula of instant claim 1. Czarnik also teaches “The hydrogens present on dronedarone have different capacities for exchange with deuterium. Hydrogen atom R1 is easily exchangeable under physiological conditions and, if replaced by a deuterium atom, it is expected that it will readily exchange for a proton after administration to a patient. Hydrogen atoms R2-R4 may be exchanged for deuterium atoms under basic conditions such as those afforded by t-BuOK/t-BuOD. Hydrogen atoms R5 -R6 and R44 may be exchanged for deuterium atoms by the action of a deuteric acid system such as D2SO4 /D2O Should the sulfonamide be hydrolyzed under these conditions, it may easily be reinstalled. Under more forcing deuteric acid conditions, exchange may also occur at R17 and R19. The remaining hydrogen atoms are not easily exchangeable for deuterium atoms. However, deuterium atoms at the remaining positions may be incorporated by the use of deuterated starting materials or intermediates during the construction of dronedarone” [0014]. Since the R5 -R6 and R44 sites are specific mentioned as easily exchanged under specific conditions that would not significantly exchange additional sites then Czarnik likely produced the compound of instant formula I. This helps to
PNG
media_image1.png
437
962
media_image1.png
Greyscale
teach claims 1, 4, 5, 6 and 7.
Figure 1: Generic deuterium-enriched dronedarone, Czarnik (US 2009/0076137 Al, IDS 01/07/2022)
Czarnik teaches “wherein R1 -R43 are independently selected from H and D; and the abundance of deuterium in R1 -R43 is at least 2%. The abundance can also be (a) at least 5%, (b) at least 9%, (c) at least 14%, (d) at least 19%, (e) at least 23%, (f) at least 28%, (g) at least 33%, (h) at least 3 7%, (i) at least 42%, G) at least 47%, (k) at least 51 %, (I) at least 56%, (m) at least 60%, (n) at least 65%, (o) at least 70%, (p) at least 74%, (q) at least 79%, (r) at least 84%, (s) at least 88%, (t) at least 93%, (u) at least 98%, and (v) 100%”[0022]. This helps to teach claims 1-3 and 18.
Czarnik teaches “In another embodiment, the present invention provides novel pharmaceutical compositions, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a deuterium-enriched compound of the present invention” [0048]. This helps to teach claims 8 and 9.
Czarnik teaches “A method for treating cardiac arrhythmias comprising: administering, to a patient in need thereof, a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt form thereof” [reference claim 20]. This teaches claims 13-16.
Czarnik does not explicitly draw out the locations of all the hydrogens of instant formula (I) and (II).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to have modified Czarnik formula to get the formula of instant formula (I) and (II) because Czarnik specifically points out the method to make instant formula (I) and (II) and one would have been motivated to do so because they are among the easiest protons to exchange under acidic conditions that do not require a change in starting materials which would require additional costly synthetic steps. Additionally to know what method would exchange those specific protons Czarnik likely produced a compound of instant formulas I and II.
Response to Arguments
Applicant's arguments filed 10/22/2025 have been fully considered but they are not persuasive.
The applicant argues that the office fails to establish a prima facie case of obviousness because it lacks a motivation to modify with a reasonable expectation of success to arrive at the claim compounds. This argument is not persuasive because one of ordinary skill in the art given the reactants D2SO4 /D2O would have a reasonable expectation of success to achieve a simple exchange reaction as this is elementary acid-base chemistry. One would be motivated to do so because they are among the easiest protons to exchange under acidic conditions that do not require a change in starting materials which would require additional costly synthetic steps; for the purpose of a simple and obvious deuterated version of the desired compound for treating cardiac arrhythmias . "The scope of enablement ... is that which is disclosed in the specification plus the scope of what would be known to one of ordinary skill in the art without undue experimentation." National Recovery Technols. Inc. v. Magnetic Separation Sys., Inc., 166 F.3d 1190, 1196 (Fed. Cir. 1999). “It is true, as Genentech argues, that a specification need not disclose what is well known in the art. See, e.g., Hybritech Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1385, 231 USPQ 81, 94 (Fed. Cir. 1986). However, that general, oft-repeated statement is merely a rule of supplementation, not a substitute for a basic enabling disclosure. It means that the omission of minor details does not cause a specification to fail to meet the enablement requirement. However, when there is no disclosure of any specific starting material or of any of the conditions under which a process can be carried out, undue experimentation is required; there is a failure to meet the enablement requirement that cannot be rectified by asserting that all the disclosure related to the process is within the skill of the art. It is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement.” Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1366 (Fed. Cir. 1997). The applicants provide no evidence that obtaining these compounds by deuteration is not known in the art or is not achievable. Since the applicants have not provided any rebuttal evidence that Czarnik plus the knowledge of one skilled in the art is not enabling this argument is not considered persuasive.
The applicant argues that a person of ordinary skill would not be motivated to selectively incorporate deuterium at each R1, R2, R3 and solely/exclusively at R1, R2, R3, with reasonable expectation of success. This argument is not persuasive because it would be obvious to exchange at all three positions because the positions are all suggested to exchange under the same conditions. It would be obvious to one of ordinary skill in the art that one would solely exchange positions R1, R2, R3, under the suggested conditions because the other positions are said to require either basic conditions, even more acidic conditions, or are not easily exchanged at all and require deuterated starting material. One would be motivated to do so because they are among the easiest protons to exchange under acidic conditions that do not require a change in starting materials which would require additional costly synthetic steps; for the purpose of a simple and obvious deuterated version of the desired compound for treating cardiac arrhythmias. While it is true the tables do not provide an example of a compound with these positions exclusively deuterated, this is not a persuasive argument because paragraph [0014] gives enough details to make such a compound obvious to one of ordinary skill in the art.
The applicant also argues that a person of ordinary skill would not be able to make the compound or that the compound was never achieved by Czarnik because of lack of enabling details. This argument is not persuasive because one of ordinary skill in the art given the reactants D2SO4 /D2O would have a reasonable expectation of success to achieve a simple exchange reaction as this is elementary acid-base chemistry. "The scope of enablement ... is that which is disclosed in the specification plus the scope of what would be known to one of ordinary skill in the art without undue experimentation." National Recovery Technols. Inc. v. Magnetic Separation Sys., Inc., 166 F.3d 1190, 1196 (Fed. Cir. 1999). “It is true, as Genentech argues, that a specification need not disclose what is well known in the art. See, e.g., Hybritech Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1385, 231 USPQ 81, 94 (Fed. Cir. 1986). However, that general, oft-repeated statement is merely a rule of supplementation, not a substitute for a basic enabling disclosure. It means that the omission of minor details does not cause a specification to fail to meet the enablement requirement. However, when there is no disclosure of any specific starting material or of any of the conditions under which a process can be carried out, undue experimentation is required; there is a failure to meet the enablement requirement that cannot be rectified by asserting that all the disclosure related to the process is within the skill of the art. It is the specification, not the knowledge of one skilled in the art, that must supply the novel aspects of an invention in order to constitute adequate enablement.” Genentech, Inc. v. Novo Nordisk, A/S, 108 F.3d 1361, 1366 (Fed. Cir. 1997). The applicants provide no evidence that obtaining these compounds by deuteration is not known in the art or is not achievable. Since the applicants have not provided any rebuttal evidence that Czarnik plus the knowledge of one skilled in the art is not enabling this argument is not considered persuasive. Additionally, The comparison between “may cause stem cell mobilization” and “may be exchanged” is not a good comparison because while “may cause stem cell mobilization” could mean that it may not happen the other phrase can simply be read as “may be exchanged” if one so desires to exchange those positions.
The applicant also argues that no specific details are given on what would be considered “more forcing deuteric acid conditions” and so one would not know how to stop at R1-R3 and not R6. However this argument is not persuasive because it would be obvious to one of ordinary skill in the art that more forcing would simply mean stronger acid or higher concentration of acid which are obvious to any chemist of ordinary skill in the art. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955.)
The applicants also argue that no experimental data has been provided for any deuterated compounds in the reference. This is not a persuasive argument because just because no experimental evidence is provided does not mean it would not have been obvious based on the prior art to produce the instant compounds based on the prior art disclosure.
The applicant also argues that the prior art lacks enablement because it lacks any specific starting material and any of the conditions under with the process will be carried out. This argument is not persuasive because it would be obvious to one of ordinary skill in the art that the starting material in the prior art would be dronedarone and the conditions would be a deuteric acid system such as D2SO4 /D2O.
The applicant also argues unexpected effects over non-deuterated dronedarone as the closest art.
This is not a persuasive argument since unexpected results must be compared to the closet art which would be the deuterated compounds of Czarnik not non-deuterated dronedarone.
The applicant’s argument of unexpected results is not persuasive because the data provided by the published application [0293]-[0353] are not commensurate in scope with the claimed invention. For example, the compounds compared are dronedarone, poyendarone and the two compounds of table 3. These are not commensurate with the full scope of the claims, for example they do not cover or test a representative number for each possible R4, R5, and R6. Since differences in structure can impact activity; a simple statement of the applicant being unaware of any reason the same technical effects would not be observed upon making substitutions at specific positions is not persuasive. Additionally, different amount of deuterium incorporation above 45% were not tested. Since differences in isotope abundance can impact activity; a simple statement of the applicant being unaware of any reason the same technical effects would not be observed upon using different percentages of isotope abundance is not persuasive. Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness 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) (Claims were directed to a process for removing corrosion at "elevated temperatures" using a certain ion exchange resin (with the exception of claim 8 which recited a temperature in excess of 100C). See also In re Peterson, 315 F.3d 1325, 1329-31, 65 USPQ2d 1379, 1382-85 (Fed. Cir. 2003) (data showing improved alloy strength with the addition of 2% rhenium did not evidence unexpected results for the entire claimed range of about 1-3% rhenium); In re Grasselli, 713 F .2d 731,741,218 USPQ 769, 777 (Fed. Cir. 1983) (Claims were directed to certain catalysts containing an alkali metal. Evidence presented to rebut an obviousness rejection compared catalysts containing sodium with the prior art. The court held this evidence insufficient to rebut the prima facie case because experiments limited to sodium were not commensurate in scope with the claims.). To establish unexpected results over a claimed range, applicants should compare a sufficient number of tests both inside and outside the claimed range to show the criticality of the claimed range. In re Hill, 284 F.2d 955, 128 USPQ 197 (CCPA 1960).
Furthermore, applicants are required to identify and provide a side-by-side comparison of the closet art. The applicants have not identified what is the closet art and instead simply discuss the results in their own specification and mention Czarnik but do not discuss a comparison to the compounds of Czarnik.
Furthermore, the applicants are required to show statistical significance in their unexpected results, however, none were provided. For example, table 3 lacks any error in the data. “The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c).”MPEP 716.02(b).
The argument of unexpected effects is also not considered persuasive because Czarnik teaches the compounds of the instant invention for treating the same disease, thus one would have a reasonable expectation that the “unexpected results” would necessarily follow via administering of the same compound for the same disease as taught by Czarnik.
Applicant's arguments have been fully considered but they are not persuasive for the reasons stated above.
Allowable Subject Matter
Claim 17 is allowed.
Conclusion
Claims 1-9, 13-16 and 18 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALISON AZAR SALAMATIAN whose telephone number is (703)756-4584. The examiner can normally be reached Mon-Thurs 7:30am-5pm EST Friday 7:30-4pm EST (every other Friday off).
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, Kortney Klinkel can be reached at (571) 270-5239. 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.
/A.A.S./ Examiner, Art Unit 1627
/Kortney L. Klinkel/ Supervisory Patent Examiner, Art Unit 1627