DETAILED ACTION
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 Claims
Claims 1, 46, and 51-54 are pending. Claims 2-45, 47-50, and 55 are cancelled.
Status of Priority
The present application is a 35 U.S.C. § 371 national stage patent application of International patent application PCT/CN2021/125237, filed on October 21, 2021. This application also claims the benefits of foreign priority to PCTCN2021117394, filed on September 9, 2021 and PCTCN2020123167, filed on October 23, 2020.
Election/Restriction
The restriction requirement filed on September 16, 2025 was withdrawn in the previous non-final office action. Accordingly, prosecution has proceeded without restriction and this office action is made final.
Specification - Disclosure
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claim 1 is objected to because of the following informalities:
“Ra is hydrogen, alkyl, …” should read
“wherein
Ra is hydrogen, alkyl, …”
Appropriate correction is required.
Withdrawn Rejections
Applicant is notified that any outstanding rejection or objection that is not expressly maintained in this office action has been withdrawn or rendered moot in view of applicant’s amendments and/or remarks.
Rejections necessitated by the amended claims
Claim Rejections - 35 USC § 112(a) – Scope of enablement
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, 46, 51, 53, and 54 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:
For formulas II and V:
L = a direct bond or C1-C6 alkyl
U = direct bond, phenyl, a heterocyclyl group comprising one heteroatom wherein the heteroatom is nitrogen
V = a direct bond or C1-C6 alkyl
W = a direct bond, phenyl, or a heterocyclyl group comprising one heteroatom wherein the heteroatom is nitrogen
Z = C1-C7 alkyl, NR1R2, OR3, or phenyl
R1, R2, and R3 are independently hydrogen or C1-C6 alkyl
Phenyl is optionally substituted with one or two C1-C6 alkyl
C1-C7 alkyl is optionally substituted with one or two substituents selected from the group consisting of cycloalkyl or Ph
For formula (V): Ra = hydrogen or C1-6 alkyl
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make/use the invention commensurate in scope with these claims.
As stated in the MPEP 2164.01(a), “There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue.”
In evaluating the enablement question, several factors are to be considered. According to In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988), these factors include:
1) The nature of the invention,
2) the state of the prior art,
3) the predictability or lack thereof in the art,
4) the amount of direction or guidance present,
5) the presence or absence of working examples,
6) the breadth of the claims, and
7) the quantity of experimentation needed, and
8) the level of the skill in the art.
In the instant case, the Wands factors are relevant for the following reasons:
The nature of the invention
The nature of the invention claims prodrugs for sustained releasing therapeutic agents, and methods for using such prodrugs for the treatment of diseases. The present disclosure provides a prodrug compound comprising a parent drug moiety and a tail moiety, wherein the parent drug moiety is derived from a parent drug comprising a reactive group selected from the group consisting of amine, amino, hydroxyl, carboxylate, ketone, and amide, the tail moiety is covalently linked to the parent drug moiety and has a Formula (I):
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,
a pharmaceutical composition comprising the prodrug compound provided herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, and a method of treating diseases in a subject in need thereof.
State of the prior art
See “Claim Rejections - 35 USC § 102” section below.
The level of the skill in the art
The level of ordinary skill in the art is relatively high. A person of ordinary skill would typically have formal training in medicinal chemistry and organic synthesis and would be familiar with standard methods for evaluating the therapeutic effectiveness of prodrugs.
The presence or absence of working examples
Instant claim 1 encompasses a myriad of prodrugs that can be represented by formulas II and V.
While the instant application does provide some working examples of 5-fluorouracil prodrugs having a structure represented by instant formulas II and V (structures provided on pg. 28-29; data from the instant compounds’ hydrolysis rate test, drug release rate test, and rat pharmacokinetics assay are provided on pg. 102-103), there are no working examples of 5-fluorouracil prodrugs with structural elements that are outside the scope of the enabling elements listed above.
According to MPEP § 2163:
“Satisfactory disclosure of a ‘representative number’ depends on whether one of skill in the art would recognize that the inventor was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’ Such correlations may be established ‘by the inventor as described in the specification,’ or they may be ‘known in the art at the time of the filing date.’ See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014).
In the instant case, even though the specification provides data on the drug release rate, hydrolysis rate, and pharmacokinetics of prodrugs of diverse structures, it does not include any data on the prodrugs of Formulas II or V with structural elements that are outside the scope of the enabling elements listed above. For example, there are no working examples of a compound of Formula II or V wherein U and W is a cycloalkyl and/or heteroaryl. Thus, the specification is not adequately reflecting the structural diversity of the claimed genus
The amount of direction or guidance present and quantity of experimentation necessary
As stated previously, the instant specification does not provide any working examples of a compound of Formula II or V wherein U and W is a cycloalkyl and/or heteroaryl. In the absence of clear guidance, a person of ordinary skill in the art would require undue experimentation to:
make all prodrugs comprising structural elements that are outside the scope of the enabling elements listed above and
test these compounds’ drug release rate, hydrolysis rate, and ability to release the drug in vivo.
The breadth of the claims
The claims are broad insofar as the instant claims recite prodrugs represented by formulas II and V wherein the prodrug can possess a structurally diverse range of chemical groups
Claims 46 and 51, 53, and 54, which are dependent on claim 1, are also rejected for further requiring and/or reciting elements that are outside the scope of the enabling elements listed above.
Note on 35 USC § 102 and § 103 Rejections
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 (i.e., changing from AIA to pre-AIA ) 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 § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
102 Rejection – Part 1:
Claims 1, 51, 53, and 54 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
Ashton et al. (Ashton) (WO 95/20567; published August 3, 1995)
Ashton teaches the following prodrug:
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(see pg. 33, scheme 1, product compound from the reaction of compounds (1) and (2); herein, referred to as 5FU/TRI-prodrug)
which is a prodrug represented by formula (II) wherein:
L = alkyl substituted with an oxo
U and V = a direct bond
W = heterocyclyl comprising two ring heteroatoms wherein the ring heteroatoms are O
and wherein the heterocyclyl is substituted with 4 methyl groups, 1 F, and 1 oxo
Z = OR3 wherein R3 = H
Note: According to the instant specification:
“‘alkyl’… refers to a saturated linear or branched-chain hydrocarbon radical, which may be optionally substituted independently with one or more substituents…” (pg. 9, para. 0021)
“‘heterocyclyl’ refers to a saturated or partially unsaturated carbocyclyl group in which one or more ring atoms are heteroatoms independently selected from oxygen, sulfur, nitrogen, phosphorus, and the like, the remaining ring atoms being carbon, wherein one or more ring atoms may be optionally substituted independently with one or more substituents” (pg. 13, para. 0038)
Neither the instant specification nor the claims define specific substituents. The instant specification merely states that the substituents are “suitable substituents” and that “substituents can themselves be substituted” (pg. 16, para. 0048).
Hence, the prodrug disclosed in Ashton anticipates instant claim 1.
Ashton further discloses that 5FU/TRI-prodrug is “moreover relatively insoluble so that a pellet can be compressed that does not dissolve in buffer at pH 7.4” (pg. 24, lines 20-22). 5-fluorouracil (i.e., the parent drug), on the other hand, is highly water-soluble and often used in cancer therapy (See Boisdron-Celle, M. et al. J. Pharm. Pharmacol. 1995, 47:108-114.; pg. 108, left col., 2nd paragraph, 1st sentence). Thus, the 5FU/TRI-prodrug, as disclosed in Ashton, has a lower solubility than its parent drug, 5-flurouracil, and instant claim 51 is anticipated by Ashton.
The 5FU/TRI-prodrug pellet placed in a buffer (which comprises water, a common pharmaceutically acceptable excipient; See Baldrick, P. Regulatory Toxicology and Pharmacology 2000, 32, 210-218.; pg. 210, right col., middle of 1st paragraph, sentence starts with “Indeed, the 12 most common excipients…”), is also considered a pharmaceutical composition comprising a prodrug encompassed by instant claim 1 and a pharmaceutically acceptable excipient. Hence, instant claim 53 is also anticipated by Ashton.
Ashton further discloses an in vivo study that “measures the release rate and vitreous concentrations of 5FU and TRI from pellets of 5FU/TRI in the rabbit vitreous” (pg. 18, Example 4). Results of this study show that the 5FU/TRI-prodrug can successfully release 5-fluorouracil in a rabbit. Given that 5-FU is widely used in the treatment of a range of cancers (including colorectal and breast cancers; see Longley, D. B. et al. Nat Rev Cancer 2003, 3, 330-338.; pg. 330, left col., 2nd paragraph), the disclosure that the 5FU/TRI-prodrug of Ashton can successfully release 5-FU in vivo (e.g., rabbits; pg. 18, Example 4) would therefore be suitable for use in methods of treating cancer (such as those listed in instant claim 54) in subjects by administering an effective amount of a prodrug of 5-FU such as 5FU/TRI-prodrug as disclosed in Ashton.
102 Rejection – Part 2:
Claim 1 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by:
Buur et al. (Buur) (Buur, A. et al. Acta Pharm. Suec. 1986, 205-216.)
Buur teaches how to synthesize the following 5-fluorouracil prodrug (compound V):
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wherein R2 = H and R1 = -CH2-O-(C=O)O-CH2CH3 which corresponds to a compound represented by instant formula II wherein:
L, U, and W = a direct bond
V = C1 alkyl
Z = C1 alkyl
Hence, Buur further anticipates instant claim 1.
Allowable Subject Matter
Claim 52 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form.
Conclusion
Claim 52 is objected to. Claims 1, 46, 51, 53, and 54 are rejected.
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.
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/KRISTEN W ROMERO/Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624