DETAILED ACTION
Status of Application
The response filed 10/27/2025 has been received, entered and carefully considered. The response affects the instant application accordingly:
Claim 2 has been amended.
Claim 18 has been added.
Applicant had previously elected Group I in response to restriction requirement and the species
PNG
media_image1.png
216
264
media_image1.png
Greyscale
(decitabine) for the examination which was expanded to include where R1= H, R2=H or a the phosphoramidate of Wang, R3=H or OH, R4=H, R5=H.
Claims 1-18 are pending in the case.
Claims 1-14 and 18 are present for examination.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
All grounds not addressed in the action are withdrawn or moot as a result of amendment.
New grounds of rejection are set forth in the current office action as a result of amendment.
Claim Objections
Claim 8 is 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.
New Grounds of Rejection
Due to the amendment of the claims the new grounds of rejection are applied:
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 1-7, 9-14 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (WO 2012/094248).
Rejection:
Wang et al. teaches prodrugs of nucleosides in Formula IV where A includes O and CH2, and the modified pyrimidine/purine like 5-azapyrimidine
PNG
media_image2.png
286
228
media_image2.png
Greyscale
(A=O) and decitabine
PNG
media_image3.png
280
204
media_image3.png
Greyscale
(A=O) that fall within the scope of the prior art invention for formula IV (Page 15 line 29-Page 17 line 9, Table 1). Wang et al. also teaches phosphate prodrugs of nucleosides including
PNG
media_image4.png
266
404
media_image4.png
Greyscale
(has protected modified monophosphate, Page 19, Example 9, Page 27-28, claims 11 and 16).
Wherein while Wang et al. does not exemplify A=CH2, Wang et al. does expressly teach for the prodrug compounds to contain A=CH2 it wherein it would be prima facie obvious to one of ordinary skill in the art to exemplify the drug/prodrug where A is CH2 instead of O as taught by Wang et al. forming the compound claimed (i.e.
PNG
media_image5.png
200
400
media_image5.png
Greyscale
,
PNG
media_image6.png
200
400
media_image6.png
Greyscale
,
PNG
media_image7.png
188
216
media_image7.png
Greyscale
) with a reasonable expectation of success. The instant claims are compound claims wherein as the prior art rejection above teaches the compound it would be capable of the future intended use
Response to Arguments:
Applicant's arguments are centered on the assertion that the prior art does not disclose all the claimed limitation as Wang discloses broad formulas which is a near infinite number of compounds with only has a handful of exemplified compounds, and hindsight.
This is fully considered but not persuasive. The teaching of Wang is not held solely to its examples when Wang does expressly teach for the prodrug compounds to contain A=CH2 it wherein it would be prima facie obvious to one of ordinary skill in the art to exemplify the drug/prodrug where A is CH2 instead of O as taught by Wang et al. forming the compound claimed (i.e.
PNG
media_image5.png
200
400
media_image5.png
Greyscale
,
PNG
media_image6.png
200
400
media_image6.png
Greyscale
,
PNG
media_image7.png
188
216
media_image7.png
Greyscale
) with a reasonable expectation of success. The assertion that the teachings of Wang are broad and embrace infinite compounds is not persuasive as Wang is directed to specific teachings and formulas where exemplification of the teachings is prima facie obvious with a reasonable expectation of success.
As for the assertion for surprising hydrolytic stability with good biological activity citing the declaration by Dr. Carell, this is fully considered not persuasive for the breath claimed. Applicant asserts that the stability for base hydrolysis at the C6 of 5-azacytosine (triazine ring) is unexpected for the claimed breath, but one cannot demonstrate evidence of unexpected results without first establishing what was the expected activity/property of the modification of the oxygen to carbon for the compound formula by Applicant for the base hydrolysis the C6 of 5-azacytosine for the breath claimed - which have not been presented or established and also have not established that the results are of both statistical and practical significance.
The specification and the declaration addresses that the base hydrolysis of AzadC (decitabine) is at the triazine ring at the site of C6 of 5-azacytosine, and modifications for carbocyclic nucleosides are for typically for stability for the glycosidic bond, and in Example 3 of cAzadC 1
PNG
media_image8.png
280
208
media_image8.png
Greyscale
in comparison to AzadC there is no degradation in a pH of 5.5-8.5 after 14d (14 days), which is surprising and unexpected as it demonstrates the lack of hydrolysis of the triazine ring of the compound from the modification of the oxygen to carbon for the carbocyclic nucleoside rather than a glycosidic bond stabilization- and also had complete inhibition of DNMT enzymes despite reduced incorporation as it was incorporated 100 less than the known compound decitabine which provided less untargeted damage than decitabine (Example 4, item 17 of declaration) - however it is a showing for a single compound but not commensurate in scope with the breath of compounds claimed.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, this is not persuasive as Wang et al. teaches the formulation of these compounds with the formula wherein exemplification is prima facie obvious with a reasonable expectation of success; it must also be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Accordingly, the rejection stands.
Claims 1-7, 9-14 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Wang et al. (WO 2012/094248) in view of Mahmoud (Antiviral Nucleoside and Nucleotide Analogs: A Review).
Rejection:
Wang et al. teaches prodrugs of nucleosides in Formula IV where A includes O and CH2, and the modified pyrimidine/purine like 5-azapyrimidine
PNG
media_image2.png
286
228
media_image2.png
Greyscale
(A=O) and decitabine
PNG
media_image3.png
280
204
media_image3.png
Greyscale
fall within the scope of the prior art invention (Page 15 line 29-Page 17 line 9, Table 1). Wang et al. also teaches phosphate prodrugs of nucleosides including
PNG
media_image4.png
266
404
media_image4.png
Greyscale
(has protected modified monophosphate, Page 19, Example 9, Page 27-28, claims 11 and 16).
While Wang et al. does not exemplify when A=CH2, Wang et al. does expressly teach for the prodrug compounds to contain A=CH2.
Mahmoud et al. teaches that replacement of oxygen in the sugar moiety of nucleosides with carbon is known and commonly called carbocyclic nucleosides, and often display enhanced biostability because of their stability toward hydrolysis by phosphorylases. The replacement improved enzymatic resistance and reduced toxicity of the carbocyclic nucleosides compared with the conventional ones (Replacement of the oxygen with another atom, Carbocyclic nucleosides, Page 73 second column-Page 74 1st column).
Wherein it would be obvious to one of ordinary skill in the art to exemplify the drug/prodrug where A is CH2 instead of O as taught by Wang et al. and suggested by Mahmoud et al. and produce the claimed invention; as Wang teaches substituting the oxygen for CH2 in A and Mahmoud et al. expressly addresses that the replacement is known to be desirable for its enhanced stability and reduced toxicity resulting in the compound claimed (i.e.
PNG
media_image5.png
200
400
media_image5.png
Greyscale
,
PNG
media_image6.png
200
400
media_image6.png
Greyscale
,
PNG
media_image7.png
188
216
media_image7.png
Greyscale
) with a reasonable expectation of success. The instant claims are compound claims wherein as the prior art rejection above teaches the compound it would be capable of the future intended use.
Response to Arguments:
Applicant's arguments are centered on the assertion that the prior art does not disclose all the claimed limitation as Wang discloses broad formulas which is a near infinite number of compounds with only has a handful of exemplified compounds, the assertion for surprising hydrolytic stability with good biological activity with the modification as Mahmoud is to the enzymatic cleavage at the sugar and the present compounds are to addressing the instability of the base hydrolysis at the C6 of 5-azacytosine citing the declaration by Dr. Carell, and hindsight.
This is fully considered but not persuasive. The teaching of Wang is not held solely to its examples when Wang does expressly teach for the prodrug compounds to contain A=CH2 it wherein it would be prima facie obvious to one of ordinary skill in the art to exemplify the drug/prodrug where A is CH2 instead of O as taught by Wang et al. forming the compound claimed (i.e.
PNG
media_image5.png
200
400
media_image5.png
Greyscale
,
PNG
media_image6.png
200
400
media_image6.png
Greyscale
,
PNG
media_image7.png
188
216
media_image7.png
Greyscale
) with a reasonable expectation of success. The assertion that the teachings of Wang are broad and embrace infinite compounds is not persuasive as Wang is directed to specific teachings and formulas where exemplification of the teachings is prima facie obvious with a reasonable expectation of success, particularly as Mahmoud et al. expressly addresses that the replacement of the oxygen for carbon is known to be desirable for its enhanced stability and reduced toxicity resulting in the compound claimed (i.e.
PNG
media_image5.png
200
400
media_image5.png
Greyscale
,
PNG
media_image6.png
200
400
media_image6.png
Greyscale
,
PNG
media_image7.png
188
216
media_image7.png
Greyscale
) with a reasonable expectation of success.
As for the assertion for surprising hydrolytic stability with good biological activity with the modification of carbon for oxygen - as Mahmoud is to the enzymatic cleavage at the sugar and the present compounds are to addressing the instability of the base hydrolysis at the C6 of 5-azacytosine citing the declaration by Dr. Carell, this is fully considered but not persuasive for the breath claimed. With regards to the Applicant’s argument and the declaration by Dr. Carell, Applicant is asserting that the stability for base hydrolysis at the C6 of 5-azacytosine (triazine ring) is unexpected for the claimed breath, but one cannot demonstrate evidence of unexpected results without first establishing what was the expected activity/property of the modification of the oxygen to carbon for the compound formula by Applicant for the base hydrolysis the C6 of 5-azacytosine - outside the enhanced stability and reduced toxicity resulting in the compound as presented by the prior art of Wang and Mahmoud (i.e. stability for the glycosidic bond with phosphorylases), which have not been presented or established and also have not established that the results are of both statistical and practical significance.
The specification and the declaration addresses that the base hydrolysis of AzadC (decitabine) is at the triazine ring at the site of C6 of 5-azacytosine, and modifications for carbocyclic nucleosides are for stability for the glycosidic bond, and in Example 3 of cAzadC 1
PNG
media_image8.png
280
208
media_image8.png
Greyscale
in comparison to AzadC there is no degradation in a pH of 5.5-8.5 after 14d (14 days), which is surprising and unexpected as it demonstrates the lack of hydrolysis of the triazine ring from the modification of the oxygen to carbon for the carbocyclic nucleoside rather than a glycosidic bond stabilization- and also had complete inhibition of DNMT enzymes despite reduced incorporation as it was incorporated 100 less than the known compound decitabine which provided less untargeted damage than decitabine (Example 4, item 17 of declaration) - however it is a showing for a single compound but not commensurate in scope with the breath of compounds claimed.
In response to applicant's argument that the examiner's conclusion of obviousness is based upon improper hindsight reasoning, it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper. See In re McLaughlin, 443 F.2d 1392, 170 USPQ 209 (CCPA 1971).
Accordingly, the rejection stands.
Status of Claims with Regards to Prior Art
Claim 8 is directed to the compound of
PNG
media_image8.png
280
208
media_image8.png
Greyscale
where the specification and the declaration addresses that the base hydrolysis of AzadC (decitabine)
PNG
media_image9.png
370
328
media_image9.png
Greyscale
is at the triazine ring at the site of C6 of 5-azacytosine, and modifications for carbocyclic nucleosides are for stability for the glycosidic bond (i.e. typically the area of modification for stability to phosphorylases), and in Example 3 of cAzadC 1
PNG
media_image8.png
280
208
media_image8.png
Greyscale
in comparison to AzadC there is no degradation in a pH of 5.5-8.5 after 14d (14 days), which is surprising and unexpected as it demonstrates the lack of hydrolysis of the triazine ring from the modification of the oxygen to carbon for the carbocyclic nucleoside rather than a glycosidic bond stabilization and also had complete inhibition of DNMT enzymes despite reduced incorporation as it was incorporated 100 less than the known compound decitabine which provided less untargeted damage than decitabine (Example 4, item 17 of declaration)– which is unexpected and demonstrated by the a single compound as represented by claim 8 but not commensurate in scope with the breath of compounds claimed in claim 1. Wherein claim 8 is free of the prior art but subject to the claim objection above.
Conclusion
Claims 1-7, 9-14 and 18 are rejected.
Claim 8 is objected to.
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 GIGI GEORGIANA HUANG whose telephone number is (571)272-9073. The examiner can normally be reached Monday-Thursday 9:00-5:00pm.
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, Brian Kwon can be reached at 571-272-0581. 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.
/GIGI G HUANG/Primary Examiner, Art Unit 1613