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 .
Status of the Application
Claims 8-15, 23, 26-28 and 31-36 are pending.
Maintained Claim Rejections - 35 USC § 103
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.
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 of this title, 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.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
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:
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 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.
Claims 8-11, 13-14, 23, 26-28, and 31-36 are rejected under 35 U.S.C. 103 as being unpatentable over Garcia-Manero (Blood; 2016, 128 (22):114).
Determining the scope and contents of the prior art
Garcia-Manero discloses treating intermediate or HR MDS and reducing DNA methylation (LINE-1 methylation) with an oral fixed-dose combination ASTX727 (i.e. one composition) of cedazuridine (E7727) and hypomethylating agent decitabine wherein in oral combination ASTX727, human patient received E7727 from 20mg to 100mg and decitabine from 20-40mg daily on days 2-5 of 28 days cycle 1 and on days 1-5 in subsequent cycles (Cumulative decitabine per 28-day cycle 100mg (considering example of 20mg); and Cumulative E7727 per 28-day cycle 200mg-500mg (considering example of 40mg-100mg), wherein both compounds were administered concomitantly or an oral fixed-dose combination (whole article, especially methods, results, conclusion and Table 1).
The cited prior art further discloses administering decitabine on day 1 of 28 days cycle prior to giving combination ASTX727, wherein the combination contains cedazuridine E7727 in cycle 1(whole article, especially methods, results, conclusion and Table 1). Since the instant claim recites “comprising”, claim is open ended and (ii) is open to any additional ingredient besides E7727. Thus, cited prior art teaching of administering DAC on day 1 of 28 days cycle prior to giving combination ASTX727 meets limitation of claim 11.
Ascertaining the differences between the prior art and the claims at issue
Garcia-Manero discloses treating intermediate or HR MDS and reducing DNA methylation (LINE-1 methylation) with an oral fixed-dose combination ASTX727 (i.e. one composition) of cedazuridine (E7727) and hypomethylating agent decitabine wherein in oral combination ASTX727, human patient received E7727 from 20mg to 100mg and decitabine from 20-40mg daily on days 2-5 of 28 days cycle 1 and on days 1-5 in subsequent cycles. However, the cited prior art dose of decitabine 20-40 mg daily is different from the dose about 5mg to about 15mg daily of the instant claims; and the cited prior art is silent about % of reduction in DNA methylation or LINE-1 methylation
Resolving the level of ordinary skill in the pertinent art
With regard to limitations of % of reduction in DNA methylation or LINE-1 methylation - Since the cited prior art teaches same combination interacting through same mechanism or pathway of reducing DNA methylation and similar dose as in the instant claims, % of reduction in DNA methylation or LINE-1 methylation by same combination and similar dose is also expected to be similar, whether recognized by the cited prior art or not.
With regard to limitations of dose difference of decitabine 20-40 mg daily of the cited prior art Vs. about 5mg to about 15mg daily of the instant claims- As defined in the instant specification “about”
PNG
media_image1.png
78
427
media_image1.png
Greyscale
dose of the instant claims of about 5mg to about 15mg of decitabine includes dose 16.5mg close to of 20 mg dose of the cited prior art. Thus, based on the guidance of the cited prior art, it would have been prima facie obvious to a person of ordinary skill in the art with a reasonable expectation of success that dose of decitabine may be adjusted close to 20mg and dose may be effective in reducing DNA methylation, absent any evidence to the contrary. Further, it would have been prima facie obvious to a person of ordinary skill in the art with a reasonable expectation of success that dose of decitabine may be adjusted depending on patient’s health and tolerability to decitabine.
A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934)(the prior art, which taught about 0.7:1 of alkali to water, renders unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges); In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.).
Based on the above established facts, it appears that the teachings of above cited prior art read applicants’ process.
Therefore, all the claimed elements were known in the prior art and one skilled person in the art could have modified the elements as claimed by known methods with no change in their respective functions, and the modification would have yielded predictable results to one of ordinary skill in the art at the time of the invention.
Considering objective evidence present in the application indicating obviousness or nonobviousness
To establish a prima facie case of obviousness, three basic criteria must be met: (1) the prior art reference must teach or suggest all the claim limitations; (2) there must be some suggestion or motivation, either in the references themselves or in the knowledge generally available to one of ordinary skill in the art, to modify the reference or to combine reference teachings; and (3) there must be a reasonable expectation of success; and (MPEP § 2143).
In this case, Garcia-Manero discloses treating intermediate or HR MDS and reducing DNA methylation (LINE-1 methylation) with an oral fixed-dose combination ASTX727 (i.e., one composition) of cedazuridine (E7727) and hypomethylating agent decitabine wherein in oral combination ASTX727, human patient received E7727 from 20mg to 100mg and decitabine from 20-40mg daily.
In KSR International Vo. V. Teleflex Inc., 82 USPQ2d (U.S. 2007), the Supreme Court particularly emphasized “the need for caution in granting a patent based on a combination of elements found in the prior art,” (Id. At 1395) and discussed circumstances in which a patent might be determined to be obvious. Importantly, the Supreme Court reaffirmed principles based on its precedent that “[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” (Id. At 1395). See MPEP 2143 - Examples of Basic Requirements of a Prima Facie Case of Obviousness [R-9].
In this case at least prong (E) “Obvious to try” – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success would apply.
The rationale to support a conclusion that the claim would have been obvious is that “a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely that product [was] not of innovation but of ordinary skill and common sense. In that instance the fact that a combination was obvious to try might show that it was obvious under § 103.”KSR, 550 U.S. at ___, 82 USPQ2d at 1397. If any of these findings cannot be made, then this rationale cannot be used to support a conclusion that the claim would have been obvious to one of ordinary skill in the art. Further, there is a reasonable expectation of success that same combination of compounds interacting through same mechanism or pathway of reducing DNA methylation and similar dose as in the instant claims, may result similar % of reduction in DNA methylation or LINE-1 methylation and can be made by teachings of the above cited prior art.
Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention by taking the advantage of the teaching of the above cited reference and to make the instantly claimed process with a reasonable expectation of success.
Response to Arguments
Applicants’ IDS and remarks, filed on 08/26/2025, have been fully considered but not found persuasive.
Applicant presented two affidavits responding to application 18304396 and 18309440.
Applicant’s affidavit directed to application 18309440 has not been considered as it is irrelevant to the instant application. The affidavit must be directed to the application where it needs to be considered.
Applicant argued in affidavit and in argument section about 20 mg dose of decitabine and goals of the cited prior art, AUC for intravenous and oral doses and concludes that dose of 20mg of decitabine is ineffective to treat MDS according to the cited prior art. Applicant argued in affidavit and in argument section that dose of 20mg of decitabine even when combined with 100mg dose of cedazuridine, only produced a half day of AUC 53% of the intravenous AUC. Applicant argued in affidavit and in argument section that cited prior art dose of 20mg of decitabine provided only half the AUC of the therapeutic dose and not sufficient to reduce DNA methylation. Applicant argued and concluded that the cited prior art does not motivate to lower dose from 20mg to 16.5mg. Applicant argued that dose of 15mg is 25% lower and not obvious.
This is not found persuasive and the instant claims stand rejected under 103. This is because (1) applicant is arguing over AUC after oral, intravenous administration, which are not limitations of the instant claims; (2) the instant claims are not limited to 100mg of cedazuridine; (3) applicant only commented on prior art data, sometimes only with decitabine 20mg, other times 20mg of decitabine with 100mg of cedazuridine (none of which is a limitation of the instant claims) with no evidence or comparison of results of what is achieved with 16.5 mg of decitabine with 100mg of cedazuridine; (4) if 20mg dose of decitabine with 100mg cedazuridine is not expected to reduce DNA methylation in patient, according to the applicant, so is the composition of the instant claims; (5) Applicant only argued and commented but provided no comparative data to show any evidence of unexpected result, when dose is close to dose of the cited prior art (16.5mg vs 20mg).
An argument by the applicant is not evidence unless it is an admission, in which case, an examiner may use the admission in making a rejection. See MPEP § 2129 and § 2144.03 for a discussion of admissions as prior art.
Arguments presented by applicant cannot take the place of evidence in the record. See In re De Blauwe, 736 F.2d 699, 705, 222 USPQ 191, 196 (Fed. Cir. 1984); In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965); In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997) ("An assertion of what seems to follow from common experience is just attorney argument and not the kind of factual evidence that is required to rebut a prima facie case of obviousness."). See MPEP § 716.01(c) for examples of applicant statements which are not evidence and which must be supported by an appropriate affidavit or declaration.
Based on the guidance of the cited prior art, it would have been prima facie obvious to a person of ordinary skill in the art with a reasonable expectation of success that dose of decitabine may be adjusted close to 20mg and dose may be effective in reducing DNA methylation, absent any evidence to the contrary. Further, it would have been prima facie obvious to a person of ordinary skill in the art with a reasonable expectation of success that dose of decitabine may be adjusted depending on patient’s health and tolerability to decitabine.
A prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close. Titanium Metals Corp. of America v. Banner, 778 F.2d 775, 783, 227 USPQ 773, 779 (Fed. Cir. 1985) (Court held as proper a rejection of a claim directed to an alloy of "having 0.8% nickel, 0.3% molybdenum, up to 0.1% iron, balance titanium" as obvious over a reference disclosing alloys of 0.75% nickel, 0.25% molybdenum, balance titanium and 0.94% nickel, 0.31% molybdenum, balance titanium. "The proportions are so close that prima facie one skilled in the art would have expected them to have the same properties."). See also Warner-Jenkinson Co., Inc. v. Hilton Davis Chemical Co., 520 U.S. 17, 41 USPQ2d 1865 (1997) (under the doctrine of equivalents, a purification process using a pH of 5.0 could infringe a patented purification process requiring a pH of 6.0-9.0); In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955) (Claimed process which was performed at a temperature between 40°C and 80°C and an acid concentration between 25% and 70% was held to be prima facie obvious over a reference process which differed from the claims only in that the reference process was performed at a temperature of 100°C and an acid concentration of 10%); In re Scherl, 156 F.2d 72, 74-75, 70 USPQ 204, 205-206 (CCPA 1946) (prior art showed an angle in a groove of up to 90° and an applicant claimed an angle of no less than 120°); In re Becket, 88 F.2d 684 (CCPA 1937) ("Where the component elements of alloys are the same, and where they approach so closely the same range of quantities as is here the case, it seems that there ought to be some noticeable difference in the qualities of the respective alloys."); In re Dreyfus, 73 F.2d 931, 934, 24 USPQ 52, 55 (CCPA 1934)(the prior art, which taught about 0.7:1 of alkali to water, renders unpatentable a claim that increased the proportion to at least 1:1 because there was no showing that the claimed proportions were critical); In re Lilienfeld, 67 F.2d 920, 924, 20 USPQ 53, 57 (CCPA 1933)(the prior art teaching an alkali cellulose containing minimal amounts of water, found by the Examiner to be in the 5-8% range, the claims sought to be patented were to an alkali cellulose with varying higher ranges of water (e.g., "not substantially less than 13%," "not substantially below 17%," and "between about 13[%] and 20%"); K-Swiss Inc. v. Glide N Lock GmbH, 567 Fed. App'x 906 (Fed. Cir. 2014)(reversing the Board's decision, in an appeal of an inter partes reexamination proceeding, that certain claims were not prima facie obvious due to non-overlapping ranges); In re Brandt, 886 F.3d 1171, 1177, 126 USPQ2d 1079, 1082 (Fed. Cir. 2018)(the court found a prima facie case of obviousness had been made in a predictable art wherein the claimed range of "less than 6 pounds per cubic feet" and the prior art range of "between 6 lbs./ft3 and 25 lbs./ft3" were so mathematically close that the difference between the claimed ranges was virtually negligible absent any showing of unexpected results or criticality.); (6) contrary to applicant’s argument, applicant dose is not restricted to 15mg.
Objection
Claim 12 and 15 are 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.
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 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.
Conclusion
No Claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PANCHAM BAKSHI whose telephone number is (571)270-3463. The examiner can normally be reached M-Thu 7-4.30 EST.
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, Milligan Adam can be reached on 571-2707674. 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.
/PANCHAM BAKSHI/Primary Examiner, Art Unit 1623