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 .
Priority
The present application, filed February 25, 2023, is a national stage application of PCT/CN2021/114474, filed August 25, 2021, which claims priority to foreign priority application CN202010862995.8, filed August 25, 2020.
Status of the Application
Applicant’s amendment, received October 22, 2025, wherein claims 1-2, 4-12, 14, and 17 are amended, claims 3 and 18 are canceled, and new claims 19 and 20 are added, is acknowledged.
Claims 1-2, 4-17, and 19-20 are pending and examined on the merits herein.
Withdrawn Rejections
Applicant’s amendment, received October 22, 2025, with respect to the rejection of claim 18 under 35 USC § 112(a) for lacking enablement to practice claim 18 with the full scope of pharmaceutically active agents recited in claim 8, has been fully considered and to be persuasive to remove the rejection because claim 18 is canceled and new claim 20 claims a method of method of treating a tumor in a subject using the macromolecule according to claim 2 wherein the pharmaceutically active agent is an oncology drug, which is enabled by the specification. Therefore the rejection is withdrawn.
Applicant’s arguments, received October 22, 2025, with respect to the rejection of claims 1-18 under 35 USC § 112(b) as indefinite over the term residue A thereof, has been fully considered and to be persuasive to remove the rejection because Applicant points to the specification which states: "[t]he pharmaceutically active agent or its residue, pharmaceutically active agent, and pharmaceutically active agent or its residue A are used interchangeably in the present disclosure and all refer to a molecule or group with pharmaceutical activity" (p. 26, [0088]). Accordingly, residue A thereof is defined by the specification as referring to a molecule or group with pharmaceutical activity is interpreted herein consistent with that definition. Therefore the rejection is withdrawn.
The following are new objection in response to amendment to claim 7 and addition of claim 19.
Claim Objections
Claims 7 and 19 are objected to because of the following informalities:
Claim 7 recites several structures that appear to be underlined, although the structures are present in the claims received April 5, 2024. If these structures are intended to be removed from the claim, as the examiner believes is intended by the amendment to claim 7, then these structures must be clearly struck through.
It is noted that if these structures are included in claim 7, then claim 7 would be rejected under 35 U.S.C. 112(d) for failing to include all limitations of the claim upon which it depends.
Claim 19 recites: “The macromolecule according to claim 2, wherein the pharmaceutically active agent is oncology drug.” Please amend claim 19 to recite: “The macromolecule according to claim 2, wherein the pharmaceutically active agent is an oncology drug.
Appropriate correction is required.
The following are new and/or modified grounds of rejection in response to Applicant’s amendments, received October 22, 2025, wherein claims 1-2, 4-12, 14, and 17 are amended.
Applicant’s arguments with respect the previous rejection over Owen in view of Bapat and evidence of non-obviousness related to the present invention are discussed following these rejections.
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 (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.
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 1-2, 4-17, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Owen (U.S. pre-grant publication no. US 20140171375 A1; cited in previous office action) in view of Bapat (U.S. pre-grant publication no. US 20140364595 A1; cited in previous office action).
Claims 1 and 2 claim a macromolecule comprising a dendrimer D, a first terminal group which is a pharmaceutically active agent, and a second terminal group which is a pharmacokinetic modifier, and wherein the wherein the first terminal group is covalently linked to a surface amino group of the dendrimer by a linker -X1-L-X2- as described in the claim. Claims 4-5 depend from claim 2 and further narrow the alkylene linker, claim 6 requires the linear or branched C1-10 alkylene is linear or branched C1-6 alkylene, and claim 7 requires the linker -X1-L-X2- is a structure shown in the claim.
Claim 8 depends from claim 1 and requires the pharmaceutically active agent is selected from the group recited in the claim, claims 9-11 further limit the pharmaceutically active agent, claim 12 requires the pharmacokinetic modifier is selected from the group recited in the claim, and claim 13 further limits the size of the pharmacokinetic modifier polyethylene glycol. Claim 14 limits the dendrimer D to a group recited in the claim, and claims 15-16 further limit dendrimer D. Claim 17 claims a pharmaceutical composition comprising the macromolecule
according to claim 1 and a pharmaceutically acceptable carrier.
Claim 19 depends from claim 2 and requires the pharmaceutically active agent is an oncology drug. Claim 20 claims a method of treating a tumor in a subject in need thereof, the method comprising: administering an effective amount of the macromolecule according to claim 8 to the subject.
Owen teaches a macromolecule comprising a dendrimer having surface amino groups to which at least two different terminal groups are attached including a pharmaceutically active agent and a pharmacokinetic modifying agent, the pharmaceutically active agent comprising a
hydroxyl group and being attached to the surface amino group of the dendrimer through a diacid linker (cover page, Abstract, lines 1-7). Owen teaches that these macromolecules may allow high drug loading, improved solubility and controlled release of the pharmaceutically active agent (p. 1, [0011], lines 1-10).
As one example, Owen teaches the macromolecule BHALys[Lys]32 α-Glu-DTX]32[ε-PEG1100]32 (p. 24, structure in [0221]; structure reproduced below).
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This is a macromolecule with terminal amine groups attached to the pharmaceutically active agent docetaxel using a C3 alkylene diacid linker (docetaxel abbreviated as DTX; see p. 17, [0194]). Docetaxel satisfies the limitations of the pharmaceutically active agent of claims 1 and 2, is reasonably considered an oncology drug as recited in claims 8 and 19, a taxane as recited in claim 9, and is recited as one of the pharmaceutically active agents in claims 10 and 11.
This macromolecule is also attached to the pharmacokinetic modifying agent polyethylene glycol, with a molecular weight of approximately 1100 Da. This satisfies the limitations of the pharmacokinetic modifier of claims 1, 2, 12, and 13.
The dendrimer of this macromolecule comprises polylysine as recited in claim 14, includes a polylysine core and 4 generations of lysine, as recited in claim 15, and is BHALys[Lys]32, as recited in claim 16.
Owen further teaches their invention includes a pharmaceutical composition comprising the macromolecule of the invention and a pharmaceutically acceptable carrier, as required by claim 17 (p. 2, [0025], lines 1-3).
In addition, Owen teaches their invention includes a method of treating or suppressing the growth of a cancer comprising administering an effective amount of a macromolecule or pharmaceutical composition of the invention in which the pharmaceutically active agent of the first terminal group is an oncology drug (p. 2, [0027]), and further teaches tumors may be primary or metastatic tumors of prostate, testes, lung, colon, pancreas, kidney, bone, spleen, brain, head and/or neck, breast, gastrointestinal tract, skin or ovary (p. 2, [0028], lines 1-4). Therefore, one of ordinary skill in the art would have recognized that the macromolecules taught by Owen may be used to treat a tumor in a subject in need thereof, as required by claim 20. Therefore, Owen teaches a macromolecule that satisfies all limitations of the present claims 1-2, 4-16, and 19, except for the linker structure comprising L substituted with NR1R2, as required by independent claims 1 and 2. In addition, Owen teaches a pharmaceutical composition of said macromolecule with a pharmaceutically acceptable carrier, as required by claim 17, and a method of treating a tumor by administering an effective amount of the macromolecule according to claim 19 to the subject, as required by claim 20.
Owen further teaches other diacid linkers that may be used to link the pharmaceutically active agent to the dendrimer, including, for example, -C(O)-CH2CH2-C(O)-, -C(O)-CH2OCH2-C(O)-, -C(O)-CH2SCH2-C(O)-, -C(O)CH2NHCH2-C(O)-, -C(O)-CH2N(CH3)CH2-C(O)-, and -C(O)-CH2N+(CH3)2CH2-C(O)- (p. 5, [0089], lines 1-7). These include alkylene linkers and heteroalkylene linkers.
More generally, Owen teaches the importance of the linker structure for controlling drug release. Owen teaches that the rate of release of the drug can be controlled by the selection of the diacid linker, and that diacid linkers with one or more oxygen atoms or with a cationic nitrogen atom, tend to release drug at a rapid rate. Owen teaches that the relative rate of drug release is summarized as shown in Owen, wherein diacid linkers with heteroatoms release drug more rapidly than alkyl or heterocyclyl linkers (p. 7, [0093], lines 1-13).
Owen does not teach a macromolecule that includes the substituted linker structure recited by independent claims 1 and 2.
Bapat teaches conjugate-based antifungal or antibacterial prodrugs formed by coupling at least one anti-fungal agent or antibacterial agent with at least one linker and/or carrier (cover page, Abstract, lines 1-4). Bapat teaches antifungal agent-carrier conjugates as prodrugs wherein an antifungal agent with a hydroxyl group is conjugated via a linker to a polymer (document p. 30, Figure 12A). Bapat teaches example linkers include diacid PEG groups, diacid alkyl groups, as well as diacid substituted alkyl groups, including the specific structures shown below (document p. 31, Figure 12A cont.).
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The two linkers substituted with the amino groups shown above satisfy the linker requirements of the present claims 1-6, wherein L is a linear C2 or C3 alkylene group substituted with -NR1R2, wherein R1 and R2 are each hydrogen. In addition, the C3 alkylene linker above satisfies the linker requirements of the C3 alkylene group substituted with the amino linker as shown in claim 7.
Bapat further teaches their conjugated prodrugs can provide sustained release of the antifungal or antibacterial agent, thus providing better pharmacokinetics (p. 3, [0055], lines 11-13).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to substitute the glutaric acid linker structure in the macromolecule taught by Owen with a substituted linker structure taught by Bapat. One of ordinary skill in the art would have been motivated to substitute the glutaric acid linker structure in the macromolecule above taught by Owen for the linker structure taught by Bapat because Owen teaches their macromolecules for improving the formulation of drugs by conjugation to a carrier, teaches several linker structures that may be used for conjugating the prodrug to the carrier, and teaches that the linker structure composition affects the rate of drug release, and because Bapat similarly teaches conjugates of alternative antifungal and antibacterial drugs conjugated to a carrier, providing the exemplary amino-substituted C2 and C3 alkylene linker groups shown above, and further provides that their conjugates may provide sustained release of the pharmaceutical agents.
In this instance, the rationale “simple substitution of one known element for another to obtain predictable results” would apply. Because Owen teaches many different linker compounds that may be useful for conjugation of a drug to a carrier, and because Bapat teaches the alternative linker structures shown above for conjugation of a drug to a carrier, one of ordinary skill in the art would have contemplated substituting the glutaric acid linker taught by Owen in the embodiment above with the amino substituted succinic acid or glutaric acid linkers of Bapat, because each of these groups are known in the art for linking pharmaceutical agents to polymers for the purposes of drug delivery. In addition, because Owen teaches that heteroatom substitutions may modify the rate of drug release from the polymer and Bapat teaches their conjugates provide superior pharmacokinetic properties than the unconjugated pharmaceutical agent, one of ordinary skill in the art would have recognized that the linkers taught by Bapat, including the amino-substituted linkers shown above, may similarly improve the pharmacokinetic properties of the pharmaceutical agents delivered using the macromolecule of Owen.
One of ordinary skill in the art would have had a reasonable expectation of success substituting the glutaric acid linker structure in the macromolecule of Owen above with an amino-substituted linker taught by Bapat because Owen teaches embodiments with many diacid linker structures as alternatives to the glutaric acid linker above, which suggests the linker used to conjugate the drug to dendrimer the macromolecule may be modified, and because Bapat teaches alternative diacid linkers used for conjugation of drugs to polymers for the purposes of drug delivery that are substituted with amino groups. Therefore, one of ordinary skill in the art would have considered the linkers of Bapat for use in the macromolecules taught by Owen with a reasonable expectation that use of the linkers of Bapat in the macromolecule taught by Owen would successfully deliver pharmaceutical agents, such as docetaxel, for the purposes of treating tumors.
Therefore the invention taken as a whole is prima facie obvious.
Claims 1-2, 4-17, and 19-20 are rejected under 35 U.S.C. 103 as being unpatentable over Owen (U.S. pre-grant publication no. US 20140171375 A1; cited in previous office action) in view of Rau (U.S. pre-grant publication no. US 20120156260 A1; cited in PTO-892).
Claims 1 and 2 claim a macromolecule comprising a dendrimer D, a first terminal group which is a pharmaceutically active agent, and a second terminal group which is a pharmacokinetic modifier, and wherein the wherein the first terminal group is covalently linked to a surface amino group of the dendrimer by a linker -X1-L-X2- as described in the claim. Claims 4-5 depend from claim 2 and further narrow the alkylene linker, claim 6 requires the linear or branched C1-10 alkylene is linear or branched C1-6 alkylene, and claim 7 requires the linker -X1-L-X2- is a structure shown in the claim.
Claim 8 depends from claim 1 and requires the pharmaceutically active agent is selected from the group recited in the claim, claims 9-11 further limit the pharmaceutically active agent, claim 12 requires the pharmacokinetic modifier is selected from the group recited in the claim, claim 13 further limits the size of the pharmacokinetic modifier polyethylene glycol. Claims 14 limits the dendrimer D to a group recited in the claim, and claims 15-16 further limit dendrimer D. Claim 17 claims a pharmaceutical composition, comprising the macromolecule
according to claim 1 and a pharmaceutically acceptable carrier. Claim 18 claims a method of treating a tumor in a subject in need thereof, the method comprising: administering an effective amount of the macromolecule according to claim 8 to the subject.
Owen teaches as described in the above rejection under 35 U.S.C. 103.
Owen does not teach a macromolecule that includes the substituted linker structure recited by independent claims 1 and 2.
Rau teaches that to enhance physicochemical or pharmacokinetic properties of a drug in vivo, such drug can be conjugated with a carrier (p. 1, [0002], lines 1-3). Rau teaches that if the drug is chemically bound to a carrier and/or a linker, such systems are commonly considered as prodrugs (p. 1, [0002], lines 3-4).
Rau teaches that a backbone moiety may comprise a spacer moiety which at one end is connected to the backbone moiety and on the other side to the crosslinking moiety (p. 5, [0071], lines 1-3).
Rau teaches that a preferred backbone reagent that may be used in the invention is the structure shown below, which is a polylysine dendrimer structure comprising a PEG group (wherein n=28) (p. 18, [0238]; structure reproduced below). Therefore, because Rau teaches their prodrugs may include backbones like the polylysine dendrimer structure, one of ordinary skill in the art would have reasonably applied the teachings of Rau to the macromolecules disclosed by Owen, because the backbone of Rau has the same structure as the dendrimer of Owen.
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Finally, Rau teaches and claims a prodrug or a pharmaceutically acceptable salt thereof
comprising a drug linker conjugate D-L, wherein D is an aromatic amine containing biologically active moiety; and L is a non-biologically active linker containing i) a moiety L1 represented by formula (I) as shown, and a moiety L2, which is a chemical bond or a spacer, and L2 is bound to a polymeric carrier group Z, wherein L1 is substituted with one to four L2 moieties, provided that the hydrogen marked with the asterisk in formula (I) is not replaced by L2 (p. 33, claim 20).
Rau claims additional L1 groups, including the structures shown below (p. 33, claim 22, structures (i), (ii), and (iii) shown below), wherein R5 is C(O)R6, R1, R1a, R2, R3, and R6 are independently C1-4 alkyl, and L1 is substituted with one L2 moiety, preferably R2 is substituted with one L2 moiety (p. 34, claim 22). In addition, Rau claims the prodrug according claim 20, wherein L2 is a chemical bond (p. 35, claim 24).
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Linkers (ii) or (iii) above with R5 as C(O) R6 and R6 as C1 alkyl and R2 substituted with L2 would give a linker structure that satisfies the requirements of L as defined by present claims 1-6, 8-17, and 19-20. In addition, a linker wherein R2 is substituted with one L2 moiety, wherein L2 is a chemical bond, would provide the linker structure required by independent claims 1 and 2.
Rau further teaches linkers (ii) or (iii) above with R5 as C(O) R6 and R6 as C1-4 alkyl and R2 substituted with L2 as preferable embodiments of their invention (p. 9, [0101]) (emphasis added).
Rau further teaches the general formula (I) of their linker structures (p. 2, [0024]; structure shown below), and specifies that X2 may be, for example, as chemical bond and C(R3R3a)-C(R4R4a) group (p. 2, [0028]). Accordingly, one of ordinary skill in the art would have considered derivatives of (ii) and (iii) above with 1 and 3 carbon alkylene groups, and thus would render obvious the C3-alkylene N-acetylated linkers of claim 7.
Rau claims aromatic amine containing biologically active moiety that may be part of their prodrugs, including the anticancer therapeutics methotrexate and mitomycin, which are interpreted herein as exemplary oncology drugs (p. 36, left column, lines 22-23, part of claim 27).
Finally, Rau teaches that prodrugs comprising a drug linker conjugate D-L containing a linker moiety L1, as defined above, exhibit therapeutically useful autohydrolysis (autocatalytic cleavage) if linked to an aniline derivative or another type of aromatic amine through an anilide bond or an amide bond, respectively (p. 3, [0039], lines 1-6). Rau teaches that their prodrugs show the beneficial effect of a controlled release rate in respect of the (cleaved) drug D-H, including showing a sustained release rate (p. 3, [0040], lines 1-4).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to substitute the glutaric acid linker and pharmaceutical agent disclosed in the macromolecule of Owen for a linker structure and pharmaceutical agent taught by Rau. One of ordinary skill in the art would have been motivated to substitute the glutaric acid linker and pharmaceutical agent in the compound of Owen for the linker structure taught by Rau because Owen teaches embodiments with diacid linker structures as alternatives to the glutaric acid linker above, which suggests the linker used to conjugate the drug to dendrimer the macromolecule is variable, and teaches that the rate of release of the pharmaceutical agent depends on the linker structure, and because Rau teaches alternative diacid-derived linker structures that are substituted with various amino groups that are used for drug release of biologically active moieties comprising aromatic amides. Accordingly, one of ordinary skill in the art would have considered the linkers of Rau for use in the macromolecules taught by Owen with a reasonable expectation that use of the linkers of Rau would be effective in the macromolecule taught by Owen and would successfully deliver a pharmaceutical agent for the purposes of treating tumors with beneficial pharmacokinetic properties.
In addition, it would have been prima facie obvious to one of ordinary skill in the art to substitute the glutaric acid linker in the compound of Owen for linker (ii) or (iii) taught by Rau. One of ordinary skill in the art would have been motivated to substitute the glutaric acid linker in the compound of Owen for the linker (ii) or (iii) taught by Rau because Owen teaches embodiments with many diacid linker structures as alternatives to the glutaric acid linker above, suggests the linker used to conjugate the drug to dendrimer the macromolecule is variable, and teaches that the linker has an effect on the rate of drug release from the macromolecule, and because Rau teaches alternative diacid-derived linker structures that are substituted with various amino groups used for drug release. Accordingly, one of ordinary skill in the art would have considered the linkers of Rau for use in the macromolecules taught by Owen with a reasonable expectation that use of the linkers of Rau in the macromolecule taught by Owen would successfully deliver a drug (for example, the oncology agent methotrexate or mitomycin) for the purposes of treating tumors with beneficial pharmacokinetic properties.
Regarding the specific aromatic amine drugs recited by Rau, Rau appears to require the aromatic amine because such drugs exhibit therapeutically useful autohydrolysis (autocatalytic cleavage) if linked to an aniline derivative or another type of aromatic amine through an anilide bond or an amide bond (p. 3, [0039], lines 1-6). Owen teaches attachment of their drug via a hydroxyl group, forming an ester bond with the linker (for example, see p. 4, [0063]). Because Rau teaches the their conjugates require an aromatic amine because the amides formed from said aromatic amines undergo autohydrolysis, and because Owen teaches that their release rate is dependent on the choice of diacid linker and teaches the release rate of ester-linked docetaxel in plasma, one of ordinary skill in the art would have recognized that both the aromatic amide and ester linkages undergo autohydrolysis under biological conditions, and thus one of ordinary skill in the art would have recognized that the specific linker structures of Rau would reasonably extend to the conjugates taught by Owen, and also be effective in delivering the pharmaceutical agents taught by Owen, such as docetaxel, because both esters and aromatic amides may undergo autohydrolysis.
Regarding the structure of present claim 7, because Rau teaches in their general formula that variable group X2, for example, may be a C(R3R3a)-C(R4R4a) group, one of ordinary skill in the art would have recognized the linkers of Rau, such as structure (ii) or (iii) may include a three carbon substituted alkylene group, and thus would render obvious the C3-alkylene N-acetylated structures of claim 7.
Therefore the invention taken as a whole is prima facie obvious.
Response to Applicant’s Arguments: With respect to the previous rejection of the present claims over Owen in view of Bapat, Applicant presents the following arguments:
1. Applicant argues that there would be no motivation to combine the cited references to
arrive at the claimed compound. The present invention discloses that L is a linear or branched
C1-10 alkylene, wherein the linear or branched C1-10 alkylene is substituted with one or more-NR1R2. Applicant argues that there is no suggestion that X as disclosed by Owen is substituted with -NR1R2.. Alternatively, Applicant argues that Owen provides examples of diacid linkers, which do not involve -NR1R2 substitution. Furthermore, the specification does not disclose molecules with substituents on the alkylene group, nor does it suggest that-NR1R2 substitution could provide better results.
Applicant further argues that Bapat discloses an antifungal conjugate in which the linker connecting the drug and the carrier can be selected from a dicarboxylic acid or -C(O)-L'-C(O)-, wherein L' is an alkyl group that optionally substituted with heteroatoms, and the carrier can be a polymer. Figure 12A of Bapat shows a fragment of an alkyl group substituted with -NH2. However, Bapat only exemplifies the conjugates of two antibacterial agents containing -NH2, and does not disclose molecules whose carriers are dendrimers. Applicant argues that based on Bapat, a person skilled in the art would not choose an alkyl group substituted with -NR1R2 in combination with Owen to obtain a new molecule. Finally, Applicant argues that Bapat discloses the in vitro biological activity of the conjugate but not its pharmacokinetics, and therefore those skilled in the art would not expect that conjugates containing -NR1R2 substitutions would have better pharmacokinetics.
2. Applicant argues that the presently claimed molecules exhibit surprisingly improved properties. Applicant states that Examples 1, 2, and 4 of the present invention demonstrate that the macromolecule containing -NR1R2 substitution has a higher exposure level, a lower drug clearance rate, and a significant sustained-release effect compared to the single drug active agent, or the macromolecule corresponding to L without substitution or L comprising by N(CH3) and S as part of a heteroalkylene linker. Applicant argues that additionally, Example 3 demonstrates that the macromolecule presently claimed exhibited better efficacy and lower toxicity at half the dose, Example 5 demonstrates the higher safety of the macromolecule of the present invention, and Example 6 demonstrates that the macromolecule of the present invention has a higher tumor suppression effect. Applicant concludes that all the above Examples clearly demonstrate that the macromolecule of the present invention has superior pharmacokinetic and pharmacodynamic properties compared to the prior art, and is highly safe, representing significant progress.
Applicant’s arguments have been fully considered but they are not found persuasive with respect to the full scope of R1 and R2 groups recited in independent claims 1 and 2.
With respect to Applicant’s first argument about the combination of the Owen and Bapat, because Owen discloses macromolecules comprising dendrimers for the delivery of pharmaceutically acceptable agents, and Bapat teaches pharmaceutical agents covalently linked to carriers for delivery, one of ordinary skill in the art would have reasonably contemplated the linkers of Bapat as applicable to the macromolecules of Owen, because each may be used for the delivery of pharmaceutical agents. In addition, because Owen teaches the importance of the linker for controlling the release rate of the pharmaceutical agents, one of ordinary skill in the art would have appreciated that new linkers may provide altered pharmaceutical release properties not provided by the linkers disclosed by Owen.
With respect to Applicant’s second argument regarding the unexpected superior results achieved with the presently claimed macromolecule with L as NR1R2, the examiner agrees with Applicant’s claims to the unexpectedly superior results, however the examiner maintains that the unexpected results are not commensurate with the scope of the claims.
MPEP 716.02(d) at I states: “The nonobviousness of a broader claimed range can be supported by evidence based on unexpected results from testing a narrower range if one of ordinary skill in the art would be able to determine a trend in the exemplified data which would allow the artisan to reasonably extend the probative value thereof. In re Kollman, 595 F.2d 48, 201 USPQ 193 (CCPA 1979).
In this instance, Applicant provides evidence of superior pharmacokinetics achieved with the presently claimed macromolecule using the pharmaceutically active agent docetaxel and with L substituted with N(CH3)2 adjacent to the pharmaceutical agent (abbreviated as 1-Z00-J in the specification), L as N(CH3)2 adjacent to the dendrimer (1-Z00-K), and L as N(CH2CH2CH3)2 adjacent to the pharmaceutical agent (1-Z00-M). These are compared with free docetaxel, the macromolecule with docetaxel, with the macromolecule comprising L as CH2-N(CH3)-CH-2 (1-Z00), and with the macromolecule with docetaxel and L as (CH2)3 (1-C00).
The specification provides that 1-Z00-J, 1-Z00-K, and 1-Z00-M provide greater maximum drug exposure and lower drug clearance than free docetaxel, 1-Z00, or 1-C00 (pp. 73-74, Table 2), and that 1-Z00-J provides superior antitumor activity in mice compared with 1-Z00 and free docetaxel (pp. 80-81, Tables 8 and 9). The closest prior art is 1-Z00 and 1-C00, each disclosed by Owen, and thus Applicant’s demonstration of superior pharmacokinetic properties is persuasive evidence of non-obviousness for the claimed macromolecules comprising linker L wherein R-1 and R2 are C1-6 alkyl.
In addition, the instant specification provides examples of superior pharmacokinetics and antitumor activity with dendrimers derivatized with compound 3 recited in claims 10 and 11. The specification provides that macromolecule with L substituted with N(CH3)2 adjacent to the pharmaceutical agent (3-L00), L substituted with N(CH3)2 adjacent to the dendrimer (3-M00), L substituted with N(CH2CH3)2 adjacent to the pharmaceutical agent (3-N00), L substituted with N(CH2CH2CH3)2 adjacent to the pharmaceutical agent (3-O00), and with L substituted with N(CH3)(CHCH3CH3) adjacent to the pharmaceutical agent (3-R00) all show superior pharmacokinetics and tumor growth inhibition in beagles compared with 3-T00 (which lacks the L substituent) (results on p. 84, Table 12 and p. 87, Table 16). Similarly, this is considered as persuasive evidence for the claimed macromolecules comprising L wherein R-1 and R2 are C1-6 alkyl.
This demonstration of superior pharmacokinetic properties is limited to the subset of compounds wherein both R1 and R2 are C1-C3 alkyl. The specification does not demonstrate their unexpected results extend to other R1 or R2 groups, and one of ordinary skill in the art would have recognized that alternative R1 or R2 groups may not provide the same benefit of unexpectedly superior results. For example, Applicant has not demonstrated that a superior release of drug occurs when L is substituted with NH2 and NAc, which are represented in the above rejections.
One of ordinary skill in the art would recognize that, for example, the acetylated amino substitution on linker L may exhibit significantly different physical properties, because the acetylated would lack the formal positive charge provided by the dialkyl amino substituent at physiological pH. Similarly, the NH2 substituent may participate in hydrogen bonding interactions that may not occur in the dialkyl amino substituent at physiological pH. In addition, because both Bapat and Rau suggest that their conjugates, which would encompass said linkers, provide sustained release of the pharmaceutical agents, one of ordinary skill in the art would have reasonably expected a sustained release effect, absent evidence to the contrary.
Therefore, Applicant’s evidence of nonobviousness would be persuasive evidence of nonobviousness wherein R1 and R2 are C1-6 alkyl, but is not commensurate with the full scope of R1 and R2 groups recited in independent claims 1 and 2.
Accordingly, for the reasons stated above, the present rejections of claims 1-2, 4-17, and 19-20 as unpatentable over Owen in view of Bapat and over Owen in view of Rau are maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to BENJAMIN BRANDSEN whose telephone number is (703)756-4780. The examiner can normally be reached Monday - Friday from 9:00 am to 5:00 pm.
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/B.M.B./Examiner, Art Unit 1693
/ANDREA OLSON/Primary Examiner, Art Unit 1693