DETAILED ACTION
Applicants’ arguments, filed July 10, 2025 have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Status
Claims 23 and 24 are canceled.
Claims 1-22, 25, and 26 are pending and under examination.
Claim Interpretation
In claims 1 and 19, it is recited that if -X2- is -N(R5)-, -X3- is an amide and that the distance between the nitrogen of the -X3- amide and the carbon attached to both -X2- and -X1- (both marked with asterisks) must be 5, 6, or 7 atoms. The examiner notes the Applicant’s statement on page 29, lines 28-31 of the specification that “’distance between the nitrogen atom marked with an asterisk and the carbon atom marked with an asterisk’ refers to the total number of atoms in the shortest distance between the nitrogen and carbon atoms marked with the asterisk and also includes the nitrogen and carbon atoms marked with the asterisk.” The examiner interprets this statement to be a clearly set forth definition of this phrase. Per MPEP 2111.01(IV), the Applicant may be their own lexicographer. Thus, the examiner interprets the scope of the claimed distance to refer to the above definition that includes both atoms marked with an asterisk in the count of atoms.
In claim 1, it is required that -X3- be an amide. The examiner notes that on pg. 10, lines 6-15 of the specification, the Applicant defines that a moiety -C(O)N(RX)- may be attached to the two moieties on either side in either possible orientation (i.e., either as -C(O)N(RX)- or -N(RX)C(O)-). Therefore, the examiner interprets that -X3- may be present in either of the above orientations in -L1- in the scope of claim 1 and the claims dependent on claim 1 that do not further specify this structure. The examiner notes that claim 19 depicts -X3- in a single specific orientation, excluding the reverse orientation from the scope of claim 19 and the claims dependent on claim 19.
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.
Claims 1-4, 11-18, 22, 25 and 26 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhao (WO 2011/082368 A2 – provided by applicant in IDS submitted September 19, 2022).
Zhao teaches polymeric conjugates of biologically active agents containing reversibly releasable linkers (Abstract). The conjugates of Zhao are described by the following formula:
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wherein D is an amine-linked biologically active moiety or a hydroxyl-linked biologically active moiety; Y1 is O, S, or NR5; R5 may be hydrogen or C1-6 alkyl; R1 is hydrogen, C1-6 alkyl, or aryl; T1 is selected from structures including hydrogen, alkyl, alkenyl, alkynyl, and amide groups; T2 is selected from structures including hydrogen, alkyl, alkenyl, and alkynyl groups; (a), (b), (c), and (d) are independently zero or one and the sum of which is one, two, three, or four; and D is attached to its connecting carbon by an amine (pg. 2, line 1 through pg. 3, line 12). Zhao teaches that an advantage of the invention is a means for improving the pharmacokinetic properties of tyrosine kinase inhibitors, including through the means of conjugation to water soluble polymers (pg. 5, second paragraph). Zhao discloses several polymers which may be used in the conjugates (pg. 17-18). Zhao teaches that the biologically active agents that can be conjugated to the polymer include aromatic amine-containing structures such as those containing indolinone, indole, purine, or pyrimidine groups and indicates several nitrogens which can be linked to the linker of the invention (pg. 22, line 14 through pg. 24, line 9). Zhao particularly provides detailed description wherein the conjugated compound is Semaxanib (pg. 34, lines 1-9). Specific examples taught by Zhao include compounds 25a, 25b, 25c, and 25d (Figure 8):
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compounds 27a, 27b, 27c, and 27d (Figure 9):
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and compounds 50a and 50b (Figure 14):
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.
Regarding claim 1, each of compounds 25a, 25b, 25c, 25d, 27a, 27b, 27c, 27d, 50a, and 50b of Zhao anticipate the conjugate of claim 1. In each of these structures, D is a pi-electron-pair-donating heteroaromatic N-comprising moiety of a drug D-H (Semaxanib) attached to an -L1- moiety by the pi-electron-pair-donating nitrogen. Additionally, each structure can be considered to contain an -L1- group wherein =X1 is =O; -X3- is -N(R7)C(O)- [this -X3- moiety can be present in either orientation within the scope of claim 1 – see Claim Interpretation section above] wherein -R7 is either -H or C1 alkyl; -R3 is C1 alkyl; -R2 and -R2a are -H; -R1 and -R1a are either both -H or one is -H and the other is C1 alkyl. Additionally, in each of these structures, Z is a PEG polymeric moiety, and -L2- is a spacer moiety and interpreted to be substituting -L1-.
In compounds 25a, 25b, 25c, 25d, 27a, 27b, 27c, and 27d, -X2- is -N(R5)- wherein -R5 is either -H or C1 alkyl; whereas in compounds 50a and 50b, -X2- is -O-. Compounds 25b, 25d, 27b, 27d, and 50a, read on the conjugate of claim 1 wherein n is 2. Furthermore, Compounds 25a and 27a read on the conjugate of claim 1 wherein n is 1; and Compounds 25c, 27c, and 50b read on the conjugate of claim 1 wherein n is 3.
As -X2- is -N(R5)- in compounds 25a, 25b, 25c, 25d, 27a, 27b, 27c, and 27d, to read on claim 1, the distance in atoms between the carbon attached to X1 and X2 and the nitrogen in X3 must be 5-7, including these atoms. In compounds 25b, 25d, 27b, and 27d, the distance is 6. In compounds 25a and 27a, the distance is 5. In compounds 25c and 27c, the distance is 7.
Therefore, each of the above described compounds anticipate the conjugate of claim 1.
Regarding claims 2 and 3, in each of compounds 25a, 25b, 25c, 25d, 27a, 27b, 27c, 27d, 50a, and 50b of Zhao, -D is Semaxanib, which is described as a tyrosine kinase inhibitor (pg. 34, lines 1-9; and pg. 68, lines 3-6). The examiner interprets this to be a small molecule drug moiety.
Regarding claim 4, each of the above compounds is conjugated to a Z group that is a PEG-based polymeric moiety (Figures 8, 9, and 14).
Regarding claim 11, Zhao teaches that the polymers of the invention are preferably water soluble and are preferably PEG (pg. 51, first paragraph; and pg. 57, third paragraph). In view of this, the examiner interprets the PEG taught in the above structures to be a water-soluble polymeric moiety.
Regarding claim 12, compounds 50a and 50b of Zhao read on the conjugate of claim 1 wherein =X1 is =O and -X2- is -O- (Figure 14).
Regarding claim 13, compounds 25a, 25b, 25c, 25d, 27a, 27b, 27c, and 27d of Zhao read on the conjugate of claim 1 wherein =X1 is =O and -X2- is -N(R5)- (Figures 8 and 9).
Regarding claim 14, compounds 25a, 25b, 25c, 25d, 27a, 27b, 27c, 27d, 50a, and 50b of Zhao read on the conjugate of claim 1 wherein -L2- is a spacer moiety (Figures 8, 9, and 14).
Regarding claims 15 and 16, compounds 50a and 50b of Zhao are interpreted to read on the conjugate of claim 1 wherein -R3 is C1 alkyl and -L2- is -O- (Figure 14). The molecular weight of oxygen is 16 g/mol, which is a specific value within the range of 14 g/mol to 750 g/mol, therefore anticipating the claimed range (MPEP § 2131.03).
Regarding claim 17, as described above, compounds 50a and 50b of Zhao (Figure 14) are interpreted by the examiner to read on the conjugate of claim 1 wherein -R3 is C1 alkyl and -L2- is -O-. In such an instance, it is interpreted that in the absence of the -L2- group, the -R3 C1 alkyl attached to the -X3- group would be -CH3; while in the presence of the interpreted -L2- group, substituted -R3 is instead -C(H2)-L2-. Therefore, the examiner interprets this to be an embodiment in which one hydrogen given by -R3 is replaced by -L2-.
Regarding claim 18, Zhao teaches that the linker structures permitted in the invention result in stable compounds (pg. 50, lines 15-18). Furthermore, per Table 1 (pg. 98), compounds 25d and 27d possess hydrolysis rate half-lives over 72 hours in plasma and compounds 25d, 27d, and 50b possess hydrolysis rate half-lives over 72 hours in PBS. Zhao describes all the compounds of Example 45 to be stable in PBS (pg. 98, lines 4-5). Therefore, the examiner interprets this to mean that the linkage between Z and -L2- is stable.
Regarding claim 22, Zhao teaches pharmaceutical compositions of the compounds including compounds 25a, 25b, 25c, 25d, 27a, 27b, 27c, 27d, 50a, and 50b (pg. 77-78). More specifically, Zhao teaches that such compositions may be formulated with one or more physiologically acceptable carriers comprising excipients and auxiliaries (pg. 77, lines 2-9).
Regarding claim 25, Zhao teaches that the compounds of the invention may be used for the treatment of tyrosine kinase-dependent diseases or conditions. The method comprises administering a polymer-drug conjugate to a patient in need thereof wherein D is a tyrosine kinase inhibitor, preferable Semaxanib (pg. 80, lines 20-24). Each of the above described compounds 25a, 25b, 25c, 25d, 27a, 27b, 27c, 27d, 50a, and 50b contain Semaxanib as the D group. As these conjugates contain a tyrosine kinase inhibitor and the method is for the treatment of tyrosine kinase-dependent diseases or conditions, the examiner interprets this to be a method of treating a patient suffering from a disease that can be treated with a drug comprising administering an effective amount of the conjugate to the patient.
Regarding claim 26, Zhao teaches a method of treating a patient having a malignant tumor or cancer comprising administering an effective amount of a pharmaceutical composition containing the compounds of the invention (pg. 79, lines 23-25). Zhao also states that SU5416 is a potent inhibitor of tumor angiogenesis (pg. 81, lines 15-16). Therefore, the examiner interprets the treatment of cancer using the aforementioned SU5416 (Semaxanib)-containing polymer conjugates to be a method of treating a disease in a patient suffering from a disease that can be treated with the D-H compound.
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.
The factual inquiries 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 5-10 are rejected under 35 U.S.C. 103 as being unpatentable over Zhao (WO 2011/082368 A2 – provided by applicant in IDS submitted September 19, 2022), as applied to claims 1-4, 11-18, 22, 25 and 26 above, and further in view of Vetter (US 2015/0290337 A1 – cited in previous office action).
As described above, Zhao teaches polymeric conjugates of biologically active agents containing reversibly releasable linkers (Abstract). The conjugates of Zhao are described by the following formula:
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wherein D is an amine-linked biologically active moiety or a hydroxyl-linked biologically active moiety; Y1 is O, S, or NR5; R5 may be hydrogen or C1-6 alkyl; R1 is hydrogen, C1-6 alkyl, or aryl; T1 is selected from structures including hydrogen, alkyl, alkenyl, alkynyl, and amide groups; T2 is selected from structures including hydrogen, alkyl, alkenyl, and alkynyl groups; (a), (b), (c), and (d) are independently zero or one and the sum of which is one, two, three, or four; and D is attached to its connecting carbon by an amine (pg. 2, line 1 through pg. 3, line 12). Zhao teaches that an advantage of the invention is a means for improving the pharmacokinetic properties of tyrosine kinase inhibitors, including through the means of conjugation to water soluble polymers (pg. 5, second paragraph). Zhao discloses several polymers which may be used in the conjugates (pg. 17-18). Zhao teaches that the biologically active agents that can be conjugated to the polymer include aromatic amine-containing structures such as those containing indolinone, indole, purine, or pyrimidine groups and indicates several nitrogens which can be linked to the linker of the invention (pg. 22, line 14 through pg. 24, line 9). Zhao particularly provides detailed description wherein the conjugated compound is Semaxanib (pg. 34, lines 1-9). Specific examples taught by Zhao include compounds 25a, 25b, 25c, and 25d (Figure 8); 27a, 27b, 27c, and 27d (Figure 9); and 50a and 50b (Figure 14).
Zhao does not teach a conjugate wherein the polymeric moiety is a water-insoluble hydrogel.
Vetter teaches polymeric prodrug compositions (pg. 1, [0013]). More specifically, such prodrug compositions comprise a polymeric carrier reversibly attached to a drug through a linker moiety (pg. 7, [0109]-[0111]). Vetter teaches that the polymeric carrier may be a water-insoluble polymeric carrier, preferably in the form a hyaluronic acid-based hydrogel or PEG-based hydrogel (pg. 7, [0120]). Vetter teaches that such polymeric prodrug compositions enable extended release of a drug at therapeutically effective concentrations, avoiding overconcentration (pg. 1, [0017]). Vetter teaches that the carrier-linked prodrug possesses improved pharmacokinetic and physicochemical properties (pg. 6, [0093]).
A person of ordinary skill in the art would recognize that the inventions of both Zhao and Vetter relate to conjugates of drugs connected to polymer groups by a reversible bond on a linker moiety. It would also be recognized that Vetter teaches that conjugation of a drug to a hydrogel carrier can improve pharmacokinetic properties of the drug.
It would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the drug-polymer conjugate of Zhao by substituting the water-soluble PEG moiety for the water-insoluble hydrogels of Vetter because these polymer groups perform the same function in drug conjugates, modifying pharmacokinetic properties of the drug moiety (MPEP § 2143(I)(B)). This combination would have yielded the predictable outcome of a hydrogel-linked drug conjugate.
A person of ordinary skill in the art would have had a reasonable expectation of success in making this modification because both Zhao and Vetter teach several means for attaching drugs to polymer groups through various linkers and spacer groups. Additionally, the branched PEG polymer of Zhao and the PEG-based hydrogel of Vetter have significant structural similarities due to both being primarily PEG. Thus, the same chemistry that can be used to attach drugs in one system would predictably also apply to the other.
The skilled artisan would have been motivated to make this modification because Vetter teaches that the hydrogel attachment improves pharmacokinetic and physicochemical properties (pg. 6, [0093]).
Regarding claims 5 and 7-10, as described above, Zhao teaches drug-polymer conjugates wherein a polymer group (Z) is attached to a drug (Semaxanib, D) by a linker group. Specifically, conjugates 25a, 25b, 25c, 25d, 27a, 27b, 27c, 27d, 50a, and 50b of Zhao anticipate claim 1 and possess linker structures that read on the claimed -L1-L2- moiety (Figures 8, 9, and 14). Furthermore, Vetter teaches conjugates of hydrogels and drugs (pg. 40, [0508]; pg. 78, Examples 11 and 12; and pg. 82, Example 20). Vetter teaches that the polymeric carrier of the prodrug may be a water-insoluble polymeric carrier, preferably in the form a hyaluronic acid-based hydrogel or PEG-based hydrogel (pg. 7, [0120]). Therefore, the combined teachings of Zhao and Vetter render claims 5 and 7-10 obvious.
Regarding claim 6, Vetter teaches that the polymeric moiety preferably comprises PEG (poly(ethylene oxide)) or hyaluronic acid (pg. 7, [0120]). Furthermore, Vetter teaches that the polymeric carrier may also comprise, among other polymers, poly(acrylic acids), poly(acrylates), poly(acrylamides), poly(esters), cellulose, chitosan, and dextrin (pg. 7, [0118]). Therefore, the combined teachings of Zhao and Vetter render claim 6 obvious.
Allowable Subject Matter
Claims 19-21 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.
The examiner considers the Zhao reference detailed above (WO 2011/082368 A2) to be the closest prior art reference for claims 19-21. As described above, Zhao teaches conjugates 25a, 25b, 25c, 25d, 27a, 27b, 27c, 27d, 50a, and 50b that anticipate the conjugate of claim 1 (Figures 8, 9, and 14). Claim 19 is drawn to a narrower embodiment of claim 1 wherein -L1- has a more specific structure described by formula (1x). This structure can be considered to be that of claim 1 wherein -X2- is -N(R5)- and -X3- is -C(O)N(H)- in a single specific orientation such that the amide nitrogen is further from the -D moiety than the carbonyl carbon. Conjugates 25a, 25b, 25c, 25d, 27a, 27b, 27c, and 27d of Zhao are similar in that in the -L1- portion of these structures, -X2- is -N(R5)- and in that -X3- is -C(O)N(H)-, but different in the orientation of the -X3- amide. The examiner notes that Zhao does not teach a structure in which an equivalent -X3- amide is present in the same orientation required by claim 19.
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It is also noted that the inclusion of the -X3- amide nitrogen on the -L1- portion closer to -D is a critical feature to the invention of Zhao, as it keeps the nitrogen on the product with -D after cleavage of the amide, enabling the removal of the rest of the linker from the -D moiety through an intramolecular cyclization reaction (pg. 64, lines 2-13).
As additional pertinent art, the examiner cites Rau (WO 2016/196124 A2 – provided by applicant in IDS filed September 19, 2022). Rau teaches prodrugs of primary or secondary amine-comprising drugs (pg. 1, lines 8-10). Such prodrugs involve a conjugation of a drug to a carrier through a reversible linker (pg. 1, lines 30-34). The conjugates of Rau are prepared by connecting a drug to a polymeric carrier by a linker of formula (I)
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wherein the dashed line indicates the point of attachment of the linker to the primary or secondary amine of the drug (pg. 3, lines 1-5). Rau further teaches that the carrier of such prodrugs may be PEG-based hydrogels or hyaluronic acid-based hydrogels (pg. 49, lines 11-16). Rau teaches that a preferred linker embodiment includes the structure of formula (I’c) (pg. 47, lines 5-11).
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The examiner notes that the invention of Rau is similar to that of both the instant application and Zhao in that it involves a drug conjugated to a polymeric material via a linker connecting group that attaches reversibly to the drug on a nitrogen. However, the nitrogen of Rau is a primary or secondary amine, not a pi electron donating aromatic nitrogen. Additionally, the examiner notes that the linker of formula (I’c) of Rau is similar to that of Zhao depicted above and claim 19 of the instant application in that there is an amide carbon attached to a nitrogen of a drug (forming a carbamide), a short alkyl chain, then an amide group (when reading from right to left, starting at the -D attachment point). The amide of Rau in which the nitrogen connects to R4 and R4a is in the reversed orientation of what Zhao teaches and in the same orientation required in instant claim 19. However, the full linker of Rau containing formula (I’c) does not read fully on that of claim 19, as Rau requires one of the carbons in the short alkyl chain between the amides to be substituted with a nitrogen, which is not permitted in instant claims 1 or 19. While a whole linker from one reference may potentially be substitutable into the structure of another reference, neither Zhao nor Rau teach linkers being so modular that any set of atoms of one can be exchanged with those of another. Thus, there is no specific teaching or suggestion to specifically only substitute the amide of the flipped orientation of Rau for that of Zhao.
For these reasons, the examiner considers claims 19-21 to be drawn to allowable subject matter in view of the prior art.
Response to Arguments
First, Applicant asserts that the compounds disclosed by Zhao do not anticipate the claimed invention. Applicant puts forth that Zhao requires a nucleophilic amine to be present in the -L1- portion of the conjugate. Applicant states that the pending claims have been amended to no longer allow for an amine to interrupt or substitute -L1- between the carbon with the asterisk and -X3-. It is put forth that the amended claim does not allow for the formation of a nucleophilic amine moiety in 5, 6, or 7 atom distance to the asterisk carbon of -L1-.
Second, Applicant asserts that the difference between Zhao and the claimed invention is that Zhao requires an intramolecular cyclization reaction to be initiated by an amine functional group whereas the claimed invention initiates the release of the drug by an amide functional group and the claimed linker structure does not allow for the presence of other more nucleophilic groups such as amines. Applicant puts forth that Zhao teaches that the amine functional group is essential to the function of the conjugate. Applicant states that where Zhao teaches an amide may be present in the linker, that the amide is cleaved to form an amine and that the amide in the linker of Zhao does not participate in the cyclization reaction.
Third, Applicant asserts that the difference between Zhao and the claimed invention is the extended half-lives of the claimed drug conjugates achieved by the linker moiety of formula (I). Applicant states that in Example 45, Table 1 of Zhao, that drug release half-lives of up to >72 hours at 37°C can be inferred to be a time period not significantly longer than 3 days. Applicant puts forth that the present application claims conjugates with half-lives beyond three days compared to those reported by Zhao, which is beneficial to be of interest in therapy.
Fourth, Applicant asserts that there is no guidance in Zhao towards the use of amide functional groups. It is further argued that a skilled person would not have a reason for substituting the essential amine functional group of Zhao with an amide functional group based on the common knowledge.
Fifth, Applicant asserts that Rau 2012 (Rau; et al., US 2012/0156259 A1, herein after referred to as Rau 2012, cited in previous action, *different from the Rau reference cited above as pertinent art) does not teach a method to transiently conjugate a drug moiety -D to a pi electron-pair-donating heteroaromatic N-comprising moiety of a drug to a moiety Z. It is argued that the skilled artisan would not be inclined to consider the teaching of Rau 2012, as it would be expected that such drugs linked to a linker of Rau would be cleaved off too rapidly to provide for a meaningful half-life of the resulting conjugate. It is also argued that the combination of Zhao and Rau fails to teach the use of an amide functional group over an amine functional group as a nucleophilic moiety for triggering the release of the unmodified drug.
Sixth, Applicant asserts that a person skilled in the art would consider the linker structures of Zhao and Vetter as incompatible and would not be inclined to consider a combination of Vetter’s linker structures with the transient linkers as reported by Zhao. It is argued that the linkers of the present invention are specifically adapted to accommodate the unique chemical properties of conjugating a drug through a pi electron pair donating heteroaromatic N-comprising moiety. It is put forth that the linkers of Vetter are adapted to connect to a moiety through an aromatic hydroxy group, aliphatic amine group, aromatic amine group, carboxyl group, phosphate group, hydroxyl group, or mercapto group.
Seventh, Applicant asserts that even if a person skilled in the art would have combined Zhao with Vetter, they would not have arrived at the presently claimed subject matter, as the linkers of Vetter do not allow for a selection of the variable -X2- as permitted in the scope of the amended claims. Additionally, it is put forth that Vetter does not disclose or suggest a positive effect on conjugate half-life achieved by an amide functional group situated in 5, 6, or 7 atom distance from the asterisk carbon of -L1-.
First, respectfully, this argument is not persuasive in full. While it appears that the Zhao structures (i), (ii), and (iii) as defined in the Applicant’s response filed July 10, 2025 (pg. 14) applied in the previous office action include primary or secondary amine groups that are not within the scope of amended claim 1, the examiner still considers the teachings of Zhao to anticipate the claimed structure of formula (I). As described in the above rejections, conjugates 25a, 25b, 25c, 25d, 27a, 27b, 27c, 27d, 50a, and 50b of Zhao anticipate the conjugate of claim 1 (Figures 8, 9, and 14). The use of different embodiments of Zhao in the rejection of claim 1 was necessitated by the change in scope of the structure of -L1- in the amended claim and is thus proper. Furthermore, the examiner disagrees with the assertion that the conjugates of Zhao require a nucleophilic amine to be present in the -L1- portion of the conjugate. As depicted in the structures of Figures 8, 9, and 14 of Zhao, some embodiments of Zhao include an amide group rather than a nucleophilic primary or secondary amine. This is within the scope of the general structure of Formula (I) of Zhao wherein T1 contains a C=Y2 group (pg. 2, lines 2-19).
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As Applicant requires within the scope of amended claim 1 that -X3- is -N*(R7)-C(=O)- and Applicant defines in the specification (pg. 10, lines 6-15) that recitation of such amide structures includes the scope of both orientations (i.e., both -N*(R7)-C(=O)- and -C(=O)-N*(R7)- structures), the structures of Zhao are considered to anticipate the conjugates of claim 1 wherein the -X3- amide within -L1- has an orientation such that the asterisk amide nitrogen is closer to the asterisk carbon of -L1- than the carbonyl carbon of the -X3- group (which is within the scope of the structure of claim 1 – see Claim Interpretation). Furthermore, as described above, these structures of Zhao also read on the limitation that the two asterisked atoms have a distance of 5, 6, or 7 atoms between them (including those atoms, as is within the scope – see Claim Interpretation).
Second, respectfully, this argument is not persuasive. While the examiner agrees that Zhao describes the mechanism by which the conjugates of Zhao release drug moieties includes an intramolecular cyclization reaction initiated by an amine functional group and that linkers may contain amide groups such that the amide group is cleaved to form such an amine group, the examiner notes that the pending claims are drawn to a conjugate or a pharmaceutically acceptable salt thereof, which is considered to be a composition of matter. The patentability of such claims depends on the required structural features, not the properties or functions of the composition. Per MPEP 2112.01, when the structure recited in a reference is identical to the claimed structure, a prima facie case of anticipation has been established. Additionally, if a composition is physically the same, it must have the same properties.
Thus, even if Zhao teaches release of the drug moiety initiated by an amine and the present invention releases the drug moiety in a reaction initiated by an amide, it is the claimed structure of the molecule that determines patentability. As described above, Applicant includes in the scope of the amide structure of -X3- in claim 1 amides with either possible orientation relative to the groups to which it attaches. Therefore, amended claim 1 includes in its scope amide structures that if cleaved would result in a nucleophilic amine group on the remaining -L1- structure attached to the -D moiety.
Third, respectfully, this argument is not persuasive. As described above, the patentability of the pending claims relies on the claimed structures of the conjugates. Per MPEP 2112.01, when the structure recited in the reference is substantially identical to that of the claims, claimed properties or functions are presumed to be inherent. While Applicant argues that the instant application pertains to an invention possessing a longer half-life of drug release, the examiner notes that this is a property of the conjugate. As the structures of Zhao anticipate pending claims 1-4, 11-18 drawn to conjugates of specific claimed structures, the observation of extended drug release half-lives may amount to the recognition of an additional advantage or latent property present but not recognized in the prior art. It is also noted that while both the teachings of the instant application and Zhao teach attachment of a linker to a pi electron donating heteroaromatic nitrogen on a drug moiety, different drug moieties are used in the specific examples. This difference in drug identity could be sufficient to account for any differences in the observed drug release half-lives. Furthermore, the structures of linkers resulting in extended drug release half lives in the instant disclosure are a narrow subset of structures within the scope of the pending claims.
Fourth, respectfully, this argument is not persuasive. The claims are drawn to polymer-drug conjugates, and the patentability of which depends on the claimed structures of said conjugates. The claims are not drawn to a mechanism by which drug release occurs. Thus, Zhao is applied for the teaching of polymer-drug conjugates that anticipate the claimed structures, not for teachings of a mechanism of amide-initiated drug release. As described above, the linker structures of the conjugates of Zhao anticipate embodiments within the scope of amended claim 1. Zhao indeed does teach linker structures including amides. Additionally, the above rejection does not require the substitution of an amine group in the structures of Zhao for an amide group, so this argument is moot.
Fifth, this argument has been considered but is rendered moot because the new ground of rejection does not rely on Rau 2012 as applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Sixth, this argument is considered but is rendered moot because the new ground of rejection does not rely on the incorporation of any of the linker structures of Vetter into the prodrug conjugates of Zhao. The change in the rejection was necessitated by the change in the scope of the claims with the amendment further limiting the scope of possible -X2- structures to exclude carbon-based groups. Instead, as described above, the Vetter reference is applied for its teachings of the hydrogel carrier groups. As the above arguments solely relate to the linkers of Vetter and not the hydrogel carrier groups, they are not pertinent to the above rejections.
Seventh, this argument is considered but is rendered moot because the new ground of rejection does not rely on the incorporation of any of the linker structures of Vetter into the prodrug conjugates of Zhao. Vetter not disclosing or suggesting a positive effect on conjugate half-life achieved by an amide functional group is not relevant as it is the linker of Zhao that reads on the linker of the pending claims and the rejection provided above does not rely on the linker of Vetter to read on claim limitations (but relies on the hydrogel carrier groups instead).
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new grounds 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.
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/E.P.M./Examiner, Art Unit 1612
/SAHANA S KAUP/Supervisory Primary Examiner, Art Unit 1612
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