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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 05/14/2026 has been entered.
Status of Application
The response filed 05/14/2026 has been received, entered and carefully considered. The response affects the instant application accordingly:
Claim 1 has been amended.
Claim 5-7, 9 are cancelled.
Claims 19-21 have been added.
Applicant had previously elected Group I in response to restriction requirement and the species
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(decitabine) for the examination and has now been expanded to the species embraced by the instant amended compounds of Formula I.
Claims 1-4, 8, 10-21 are pending in the case.
Claims 1-4, 8, 10-14,18-21 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All grounds not addressed in the action are withdrawn or moot as a result of amendment.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 1 is objected to because of the following informalities:
The chemical structure does not accurate depict the bond of R2O to the compound.
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verses
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.
Appropriate correction is required.
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.
Current Grounds of Rejection
Due to the amendment of the claims the new grounds of rejection are applied:
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-4, 10-14,18-21 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The claims are directed to modified phosphate groups but the disclosure does not provide adequate written description as to what compounds would constitute a modified phosphate group or the area or degree of modification to constitute what would be a modified phosphate group.
The claims as written and the specification has no structural formula or structure/function relationship described to address what would constitute a modified phosphate group that would be attached to the carbocyclic decitabine that would not impair its activity. The application provides support for only some compounds within the scope of what is claimed which could be viewed as anything containing a phosphate but if a large enough group would impair the ability of the carbocyclic decitabine enter a cell or potentially any activity (i.e. a large chain of phospholipids, multiple large bulky alkyl amines (e.g. C8 or more) off the phosphate). The specification does provide for phosphonate, phosphoramidate, and phosphorothioate groups. However, there is no written description as to the area or formula or degree of modification/derivation to arrive a phosphate group that would be attached to the carbocyclic decitabine that would allow the compound to have its activity other than phosphonate, phosphoramidate, and phosphorothioate groups.
To provide adequate written description and evidence of possession of a claimed grouping, the specification must provide sufficient distinguishing identifying characteristics of the genus/group. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation or any combination thereof. In the instant, the only factor present in the claims is a recitation of a phosphate atom, which encompass compounds with varying structure, activities andpharmacological profiles. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genera, aside from the specific compounds recited in the specification.
Therefore, the claimed invention is not supported by adequate written description.
Claims 11-14 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the compound to be useful for myelodysplastic syndrome and acute myeloid leukemia that is not following myeloproliferative neoplasms like myelofibrosis, it does not reasonably provide enablement for the compound to be useful for all cancers/hyperproliferative disorders, acute myeloid leukemia myeloproliferative neoplasms like myelofibrosis, atherosclerosis, or renal insufficiency. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the compound that is the invention commensurate in scope with these claims.
It is noted that while the claim is a compound claim, the compound must be capable of the recited intended use; wherein the claims as written are directed to an intended use that is embraces an non-enabled breath that is not commensurate in scope with the general state of the art as addressed in the rejection as follows.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
The claims are drawn to a compound of formula I that recites a future intended use of treating cancer/hyperproliferative disorder, acute myeloid leukemia, myeloid dysplastic syndrome (MDS), atherosclerosis, and renal insufficiency. Wherein the breath of the claims are to a compound that is intended to be useful for all these conditions such as useful for all cancers/hyperproliferative diseases.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The state of the art addresses that cancer is a complex disease and the fact is that we won’t ever fine one single cancer cure (Mayer-Why haven’t we cured cancer yet?, Page 2 1st paragraph), as it is not just one disease by many and a myriad mutations exist and every cancer is caused by a different set of mutation and as the tumour grows there are more mutations that accumulate so a drug that works for one might have absolutely no effect on another (high unpredictability, Page 2).
Qin et al. teaches that decitabine treatment had induced kidney thrombotic microangiopathy with glomerular crescents formation and tubular necrosis in a patient receiving low dose decitabine infusion treatment (caused renal insufficiency rather than useful for it).
Nicorescu et al. addresses that while decitabine restored MCT3 expression, it is still unclear whether restored function of MCT3 can prevent atherosclerosis development in vivo, and there is no data available on decitabine and its prodrugs for their use in atherosclerosis or cardiovascular disease as the drug has low specificity and stability (2.1.1 DNA methyltransferase inhibitor in clinic). .
Kckinnell et al. teaches that acute myeloid leukemia arising from myeloproliferative neoplasms like myelofibrosis, represent a small subtype of secondary AMD well known to be associated with poor responses to available treatment and dismal outcomes. There is no standardized treatment options and very little therapeutic advancement compared to other subsets of AML. The only treatment effective treatment is allogeneic stem cell transplantation (donor stem cell transplant, Abstract, Introduction, Conclusion).
(5) The relative skill of those in the art:
The relative skill of those in the art is high.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
The specification has not provided guidance or support or examples for the recited intended use conditions of the compound of formula I claimed.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by the references, specifically with regards to the unpredictability of the conditions recited for intended use for the compound as seen by the presented references, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation with regards to the compound claimed with the future intended use.
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-4, 10-14,18-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Independent claim 1 and these dependent claims are directed to “wherein R¹ is H, a free or protected, modified or unmodified phosphate group or a hydroxyl-protecting group, R² is H, a free or protected, modified or unmodified phosphate group, or a hydroxyl- protecting group” and the listed dependent claims are directed to a “free or protected, modified or unmodified phosphate group” wherein it is unclear how the phosphate group is free (unattached) as it must be bonded to the oxygen which is bonded to the carbon of the alkyl (methyl) attachment to the cyclopentyl ring or directly to the cyclopentyl ring itself, wherein it is unclear how the phosphate group can be free? It does not allow one to ascertain the metes and bounds of the claims as written.
For purposes of examination, the R1 and R2 is treated wherein the substituent is attached to the oxygen which is attached directly to the cyclopentyl ring (R1) or to the oxygen that is bonded to the methyl attached to the cyclopentyl ring.
The claims are also unclear as they are directed to a “free or protected, modified or unmodified phosphate group” and it is unclear as a protected phosphate is a modified phosphate but as written it is unclear what is considered a protected phosphate verses a modified phosphate, and also it is unclear what is a modified phosphate group and also how it is distinct from a protecting group. The specification describes protected phosphate groups of phosphate esters like monoesters and diesters; amidates including monoamidates, diamidates and amidate esters; but it is unclear if how that’s different from a modified phosphate or how a modified phosphate if different from the protecting phosphate group. It does not allow one to ascertain the metes and bounds of the claims as written.
For purposes of examination, it is treated as a protected phosphate group that are described in the specification, and a modified phosphate group (the written description issue of modified phosphate group is addressed above).
Claims 2 and 18 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 and its dependent claim 18 are directed to the compound of claim 1 wherein each phosphate group is independently selected from:
(i) a free or protected unmodified phosphate, wherein the phosphate group is a monophosphate, diphosphate or triphosphate group, and
(ii) a free or protected modified phosphate, wherein the modified phosphate group is selected from a phosphonate, phosphoramidate or phosphorothioate group;
but it is unclear which substituent the recitation in claim 2 is directed to. Is it to R1? Is it to R2? Is it to both? It is also unclear as it recites “a free or protected unmodified phosphate, wherein the phosphate group is a monophosphate, diphosphate or triphosphate group” but if the monophosphate, diphosphate, or triphosphate group is unmodified how can it be protected as a protected phosphate is a modification (i.e. ester group)? Does it also mean that R1 and R2 are not hydrogen or a hydroxyl protecting group, but a phosphate? Or is it further defining the phosphates for R1 and R2 but it may also be hydrogen or a hydroxyl protecting group? It is also unclear how the recited modified phosphate groups - a phosphonate, phosphoramidate or phosphorothioate group is a free or protected modified phosphate. How is the recitation of “protected” applied to the recited modified phosphate impacting the structure of the explicitly recited phosphonate, phosphoramidate or phosphorothioate group? The issue of a free phosphate group is addressed above.
It does not allow one to ascertain the metes and bounds of the claims as written.
Claim 18 is confusing as it recites “wherein the free or protected modified phosphate is a free or protected modified monophosphate, diphosphate, or triphosphate group” but it depends from claim 2 wherein the “monophosphate, diphosphate, or triphosphate group” is from the listing of unmodified phosphates – not modified phosphates. The modified phosphates are phosphonate, phosphoramidate or phosphorothioate; wherein it lacks antecedent basis. It is also unclear which substituent the recitation for claim 18 is directed to. Is it to R1? Is it to R2? Is it to both? It does not allow one to ascertain the metes and bounds of the claims as written.
For purposes of examination, claim 2 is treated to be wherein R1 is (i) a unmodified phosphate that is a monophosphate, diphosphate or triphosphate group; or (ii) a modified phosphate that is selected from a phosphonate, phosphoramidate or phosphorothioate group.
For purposes of examination, claim 18 is treated to be wherein R1 and R2 are a unmodified phosphate that is a monophosphate, diphosphate or triphosphate group.
Claims 19-21 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 19 and its dependent claim 20 are directed to wherein
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which is confusing as how can the modified or unmodified phosphate group be monophosphate, diphosphate, or triphosphate group and also be where the modified phosphate group be a phosphate (a repeat and a phosphate group is defined to also include unmodified forms which is further confusing), phosphoramidate or phosphorothioate. How can there be two definitions for a modified phosphate which conflicts each other and for it also to be generically a phosphate? It is also unclear if directed to R2 or R2 or both? It does not allow one to ascertain the metes and bounds of the claims as written. Claim 21 is confusing as it recites for R1 to be hydrogen and R2 to be hydrogen or an unmodified monophosphate, diphosphate, or triphosphate group – but as written it is unclear if the diphosphate or triphosphate are unmodified. It does not allow one to ascertain the metes and bound of the claims as written.
For purposes of examination, claim 19 is treated wherein the unmodified phosphate group for R1 and R2 is a monophosphate, diphosphate, or triphosphate group; and the modified phosphate for R1 and R2 is phosphonate, phosphoramidate or phosphorothioate as addressed in the specification. Claim 20 is treated where R1 is a hydrogen with R2 is treated as addressed above. Claim 21 is treated wherein R1 is hydrogen and R1 is hydrogen, an unmodified monophosphate, an unmodified diphosphate, or an unmodified triphosphate group.
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 18 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 18 recites “wherein the free or protected modified phosphate is a free or protected modified monophosphate, diphosphate, or triphosphate group” but it depends from claim 2 wherein the “monophosphate, diphosphate, or triphosphate group” is from the listing of unmodified phosphates – not modified phosphates. The modified phosphates are phosphonate, phosphoramidate or phosphorothioate; wherein it lacks antecedent basis and therein is broader than the claim is depends from.
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.
Status of Claims with Regards to Prior Art
Claim 8 is directed to the compound of
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where the specification and the declaration addresses that the base hydrolysis of AzadC (decitabine)
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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). The fact that that the area of concern in nucleosides with hydrolysis is typically the glycosidic bond is also supported by Seley-Radtke et al. which addresses that carboxylic nucleosides were attractive to researchers as it had several advantages including that the glycosidic bond was no longer an unstable hemiaminal ether effected by glycoside hydrolases which led to increased stability; wherein the specification and declaration’s showing that the base hydrolysis of AzadC (decitabine) was not at the glycosidic bond but at the triazine ring which is a different location is persuasive. The fact that in Example 3 of cAzadC 1
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showed there is no degradation in a pH of 5.5-8.5 after 14day (14 days) in comparison to AzadC which was strongly degraded in the same 14 days at the same pH’s, 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 (items 11-14 of declaration and example 3 of the specification) 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
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which is represented by claim 8 and as it is converted to a triphosphate within the cell there is a reasonable expectation that the compounds where R1 and R2 are monophosphate, diphosphate, triphosphate, a phosphonate, phosphoramidate, or phosphorothioate would also have a lack of hydrolysis of the triazine ring from the modification of the oxygen to carbon like the carbocyclic decitabine (carbocyclic decitabine triphosphate form supports for the smaller diphosphate and monophosphate, and a phosphoramidate prodrug of carbocyclic decitabine and related phosphonate and phosphorothioates are expected to perform similarly being prodrugs). Therein the prior art rejections are withdrawn. The 112 issues with the claims are addressed above.
Conclusion
Claims 1-4, 10-14,18-21 are rejected.
Claims 1 and 8 are objected to.
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.
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/GIGI G HUANG/Primary Examiner, Art Unit 1613
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