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 .
Withdrawn Objections/Rejections
The objection to the specification is withdrawn in view of the amendments to the specification.
The objection to claim 43 is withdrawn in view of the claim amendments.
The objections to claim 52 are withdrawn in view of the cancellation of the claim.
The rejections of claims 29-30, 35, 50, and 52 are withdrawn in view of the cancellation of the claim.
The previous rejections claims 1, 31-32, 34, 36-37, 43, and 49 under 35 USC § 112(b) are withdrawn in view of the claim amendments.
Claim Status
Applicants' amendments and arguments filed 11/24/2025 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Rejections and/or objections not reiterated from previous office actions are hereby withdrawn.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.
Claims 2-30, 33, 35, 38-40, 42, 44, 46, 48, and 50-60 are cancelled.
Claims 61-68 are newly added.
Claims 45 and 47 are withdrawn.
Claims 1, 31-32, 34, 36-37, 41, 43, 49, and 61-68 are under current examination. The claims were read in view of the rejoined species election as detailed in the Office Action mailed 05/23/2025.
Claim Objections
Claim 1 is objected to because of the following informalities: it is suggested that “wherein the dendrimer selected from” in lines 16-17 should read “wherein the dendrimer is selected from”.
Claim 65 is objected to because of the following informalities: it is suggested that “N3” in line 13 should read “N3”.
Appropriate correction is required.
New Rejections Necessitated by Claim Amendments
Claim Rejections - 35 USC § 112(a)-New Matter
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.
Claim 37 is rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim 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, at the time the application was filed, had possession of the claimed invention.
Claim 37 recites “…to achieve a mass percent of about 5 to about 80 mass % relative to the mass of the star polymer”. The specification-as-filed describes a mass percent of about 10 to about 80 mass % (paragraphs [0034] and [0048]), and suggests that the mass % of the drug is driven by the mass of the polymer arm (paragraphs [00378]-[00381]). The specification does not provide support for a mass percent of about 5 to about 80 mass % relative to the mass of the star polymer; accordingly, the instant claim introduces new matter.
Claim Rejections – 35 USC § 112(b)
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.
Claims 1, 31-32, 34, 36-37, 41, 43, 49, and 61-68 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 1 recites the limitation “Z is a linker molecule between the end of the polymer arm;”. From this, is unclear what (if anything) Z is linked between, rendering the metes and bounds of the claim uncertain.
Claims 31-32, 34, 36-37, 41, 43, 49, and 61-68 are rejected under 35 U.S.C. 112(b) by virtue of their dependence on claim 1 and failure to cure the deficiency noted above.
Claim 36 recites “the Ds” in line 1 and “the As” in line 2, understood to be the plural forms of “D” and “A”. There is insufficient antecedent basis for these limitations in the claim as claim 1, from which claim 36 depends, recites “D” and “A” in the singular. The metes and bounds of the instant claim are uncertain as it is unclear if the claim requires the presence of multiple different drugs and multiple different polymer arms or not. It is suggested that Applicant can recite “the D is arrayed along the A at a density…” in lines 1-2.
Claim 37 recites “the Ds” in lines 1 and 2, respectively, and “the As” in line 3, understood to be the plural forms of “D” and “A”. There is insufficient antecedent basis for these limitations in the claim as claim 1, from which claim 37 ultimately depends, recites “A” and “D” in the singular. The metes and bounds of the instant claim are uncertain as it is unclear if the claim requires the presence of multiple different drugs and multiple different polymer arms or not. It is suggested that Applicant can recite “the D has a molecular weight…” in lines 1-2 and “the D is arrayed along the A at a density…” in lines 2-3.
Claim 61 recites “the charged monomer are selected from…(latent) amine”. It is unclear if the recitation of “latent” in parentheses is a required feature of the claim or not. If Applicant intends for this to be a required limitation, it is recommended that the parentheses be removed.
The use of the terms “proximal” and “distal” throughout claim 64 render the scope of the claimed polymer architectures uncertain. “Proximal to O” is understood as “closer to O” while “distal to O” is interpreted as “farther from O”. However, these are relative terms, and the claim does not define a reference point that the position of the blocks are compared to in order to determine if they considered “proximal” or “distal”. This is particularly unclear as “b” and “e” are both defined as integers of repeating units “proximal” to O, while “c” is defined as an integer number of repeating units on a block “distal” to O; in the recited polymer architecture -(B)b-(C)c-(E(D))e-, it is unclear how both the b and e blocks can be proximal to O while the c block is distal.
Claim 65 recites the limitation "wherein (E) is selected from…” in line 1. There is insufficient antecedent basis for this limitation in the claim, as no component “(E)” is recited in claims 63 or 1, from which claim 65 depends. For purposes of examination and applying prior art, “(E)” is interpreted to refer to a reactive monomer attached to D, as set forth in instant claim 64, and it is interpreted that the polymer arm of the elected species meets the limitation of the instant claim.
Claim 66 recites that the A comprises one of the recited structures. The structures include variables (b, e, c, b1, b2, c1, and c2) which are not defined by the claim, nor are they defined in claims 63 or 1, from which claim 66 depends. This renders the scope of the claimed copolymer structures uncertain. For purposes of examination and applying prior art, it is interpreted that the polymer arm of the elected species meets the limitation of the instant claim.
Claim 67 recites that the A(D) comprises a copolymer selected from one of the recited structures. The structures include variables (b1, e, b, b2, c, R7, and R8) which are not defined by the claim, nor are they defined in claim 1, from which claim 67 depends. This renders the scope of the claimed copolymer structures uncertain. For purposes of examination and applying prior art, it is interpreted that the polymer arm of the elected species meets the limitation of the instant claim.
Claim 68 recites the limitation "wherein (E) is between 10 and 50 mol%" in line 1. There is insufficient antecedent basis for this limitation in the claim, as no component “(E)” is recited in claims 63 or 1, from which claim 68 depends. For purposes of examination and applying prior art, “(E)” is interpreted to refer to a reactive monomer attached to D, as set forth in instant claim 64.
Rejections Maintained, Modified to Address Claim Amendments and Newly Added Claims 61-68
Claim Rejections-Improper Markush Grouping
Claims 1, 31-32, 34, 36-37, 41, 43, 49, and 61-68 are rejected on the basis that they contain an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claims 1, 31-32, 34, 36-37, 41, 43, 49, and 61-68 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use. Claim 1 is directed to a compound of formula O-([X]-A(D)-[Z]-[L])n where “A” is any polymer arm comprising hydrophilic monomers and charged monomers comprising negatively charged functional groups, “X” and “Z” are any linker molecules, L is any ligand comprising any pharmaceutically active compound that acts extracellularly, and D is any drug comprising a pharmaceutically active compound that acts intracellularly. Each of these elements have an almost unlimited number of possible identities from multiple physical and chemical classes, and do not necessarily share any substantial structural feature. Several components (i.e., linker molecules, compounds that act extracellularly or intracellularly) are defined solely by their function and thus do not share a single structural similarity. The claimed compounds cannot be said to share both a substantial structural feature and a common use that flows from the substantial structural feature. No dependent claim limits the scope of the claimed compounds to a proper Markush group.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112(a)-Written Description
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.
Claims 1, 31-32, 34, 36-37, 41, 43, 49, and 61-68 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claims contain 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 at the time the application was filed, had possession of the claimed invention.
The instant application does not sufficiently describe the invention as it relates to “a ligand comprising a pharmaceutically active compound that acts extracellularly” or “a drug comprising a pharmaceutically active compound that acts intracellularly” (instant claim 1).
In Regents of the University of California v. Eli Lilly & Co. 43 USPQ2d 1398, the court stated:
A written description of an invention involving a chemical genus, like a description of a chemical
species, “requires a precise definition, such as by structure, formula, [or] chemical name,” of the
claimed subject matter sufficient to distinguish it from other materials. Fiers , 984 F.2d at 1171,
25 USPQ2d at 1606; In re Smythe, 480 F.2d 1376, 1383, 178 USPQ 279, 284-85 (CCPA 1973) (“In
other cases, particularly but not necessarily, chemical cases, where there is unpredictability in
performance of certain species or subcombinations other than those specifically enumerated,
one skilled in the art may be found not to have been placed in possession of a genus. . . .”).
Further, MPEP 2163 requires a known or disclosed correlation between function and structure
to show that the invention was in possession of the claimed invention. Per MPEP 2163 (emphasis added)
“An applicant may also show that an invention is complete by disclosure of sufficiently detailed, relevant
identifying characteristics which provide evidence that inventor was in possession of the claimed
invention, i.e., complete or partial structure, other physical and/or chemical properties, functional
characteristics when coupled with a known or disclosed correlation between function and structure, or
some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613 (quoting
the Written Description Guidelines, 66 Fed. Reg. at 1106, n. 49, stating that "if the art has established a
strong correlation between structure and function, one skilled in the art would be able to predict with a
reasonable degree of confidence the structure of the claimed invention from a recitation of its
function".)." Thus, the written description requirement may be satisfied through disclosure of function and minimal structure when there is a well-established correlation between structure and function." Id.”
Here, the claims recite functional characteristics, i.e., the inclusion of a ligand comprising a pharmaceutically active compound that act extracellularly and the inclusion of a drug comprising a pharmaceutically active compound that acts intracellularly. The claims lack written description because there is no disclosure in the specification of a correlation between function and structure of a ligand comprising a pharmaceutically active compound that acts extracellularly or a drug comprising a pharmaceutically active compound that acts intracellularly, nor evidence of strong correlation established in the art. In addition, based on the functional characteristics recited by the instant claims, the instant claims would include compounds discovered at a later date. Given the potentially limitless scope of the compounds encompassed by the instant claims, Applicant cannot reasonably be said to have been in possession of each and every compound encompassed by the generic claim. Accordingly, the present specification fails to provide adequate written description for the genus of the claims and does not reasonably convey to one skilled in the relevant art that the inventor, at the time the application was filed, had possession of the entire scope of the claimed invention.
Claim Rejections – 35 USC § 112(b)
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.
Claim 41 is rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention.
Claim 41 recites “The star polymer of claim 1 wherein the length of the A is selected to:
a) increase the size of the star polymer as a means to increase the persistence of activity of the star polymer in selected tissues; or
b) control the hydrodynamic radius of the star polymer; or
c) increase the size of the star polymer as a means to increase the persistence of activity of the star polymer in selected tissues and control the hydrodynamic radius of the star polymer.”
This is indefinite as it is unclear what structural effect the selection of the length of A has on the star polymer of claim 1, from which claim 41 depends. In parts a) and c), what is the size of the polymer increased relative to? In parts b) and c), how is a controlled hydrodynamic radius structurally different than the star polymer of claim 1?
Claim Rejections - 35 USC § 112(d)
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.
Claim 41 is rejected under 35 U.S.C. 112(d) 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 41 recites that the arm length of the A is selected to achieve an effect of increasing the size of the star polymer as a means to increase the persistence of activity of the star polymer in selected tissues, control the hydrodynamic radius of the star polymer, or both. Selection of a polymer arm length to achieve a certain effect does not structurally limit the star polymer of claim 1, from which claim 41 depends. Claim 1 recites a star polymer having the formula O-([X]-A(D)-[Z]-[L])n, with A being a polymer arm (as defined in claim 1); thus, a polymer arm length must be selected in the star polymer of claim 1. Claim 41 does not recite any structural limitations on the polymer arm length to differentiate it from the polymer arm length of claim 1, and thus fails to further limit the subject matter of claim 1.
Applicant may cancel the claim, amend the claim to place the claim in proper dependent form, rewrite the claim in independent form, or present a sufficient showing that the dependent claim complies with the statutory requirements.
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 1, 31-32, 34, 36-37, 41, 43, 49, and 61-68 are rejected under 35 U.S.C. 103 as being unpatentable over Lidický et al. (“Anti-Lymphoma Efficacy Comparison of Anti-CD20 Monoclonal Antibody-Targeted and Non-Targeted Star-Shaped Polymer-Prodrug Conjugates” Molecules 2015, 20, 19849-19864; included on IDS submitted 05/25/2022), hereafter “Lidický”, as evidenced by NIH (“Doxorubicin” https://pubchem.ncbi.nlm.nih.gov/compound/Doxorubicin; of record), in view of Wiss et al. (“Facilitating Polymer Conjugation via Combination of RAFT Polymerization and Activated Ester Chemistry” Journal of Polymer Chemistry: Part A: Polymer Chemistry 2010, 48(21), 4758-4767; of record), hereafter “Wiss”, and Ulbrich et al. (US 2006/0057099 A1, published March 16, 2006; included on IDS submitted 05/25/2022).
Regarding instant claims 1 and 64-67, Lidický teaches star-shaped polymer-doxorubicin conjugates (see abstract and Figures 1 and 2) with a PAMAM dendrimer core with amine functional groups (component O) and nine (an integer greater than 2, n) HPMA-based polymer arms (component A) attached to the anticancer drug doxorubicin (component D). The polymer arms of Lidický comprise HPMA monomers proximal to the polymer core, consistent with elected polymer arm A; per the instant specification, HPMA is an example of a neutral hydrophilic monomer (paragraph [00192]). The polymer arms of Lidický further comprise the following monomers linked to the drug doxorubicin via a linkage comprising an amide (abstract, Figure 1):
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while the polymer arm of the elected species comprises the following drug-linked reactive monomers:
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.
The monomers of Lidický differ from those of the elected species in the addition of three successive -CH2- groups in the polymer side chain, and are considered to be homologous to the monomers of the elected species. Per MPEP 2144.09 II, “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).”
The polymer precursors of Lidický are grafted to the PAMAM dendrimer which results in the polymer covalently linked through the linking group (component X) shown in Figure 2 (a portion of which is reproduced below).
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Regarding instant claim 31, as noted above, the compounds of Lidický comprise nine polymer arms, or greater than 5.
Regarding instant claim 32, Lidický teaches that the hydrazide content (hydrazide groups being used for doxorubicin attachment) of the polymer precursor for dendrimer-based polymers is 4.8 mol% (Table 1; pg. 19859, “3.2 Synthesis of Polymer Precursors and Polymer-Drug Conjugates”), indicating that the majority of the monomer units of the polymer arm are HPMA. Per the instant specification, HPMA is an example of a neutral hydrophilic monomer (paragraph [00192]).
Regarding instant claim 36, as noted above, Lidický teaches that the hydrazide content of the polymer precursor for dendrimer-based polymers is 4.8 mol%, and that hydrazide groups are used for doxorubicin attachment (Table 1; pg. 19859, “3.2 Synthesis of Polymer Precursors and Polymer-Drug Conjugates”). It is therefore interpreted that the drugs are arrayed along the polymer arms at a density of 4.8 mol%, or greater than 3%.
Regarding instant claim 37, as noted above, Lidický teaches that the hydrazide content of the polymer precursor for dendrimer-based polymers is 4.8 mol%, and that hydrazide groups are used for doxorubicin attachment (Table 1; pg. 19859, “3.2 Synthesis of Polymer Precursors and Polymer-Drug Conjugates”). It is therefore interpreted that the drugs are arrayed along the polymer arms at a density of 4.8 mol%, or between about 4 to about 50 mol%. As evidenced by NIH, the molecular weight of doxorubicin is 543.5 g/mol (pg. 1, “Molecular Weight”). As Lidický teaches a drug that satisfies the recited molecular weight and a density along the polymer arm consistent with the instant claim, it is interpreted that it will also satisfy the limitation of a mass percent of about 5 to about 80% relative to the mass of the star polymer (see instant specification paragraphs [0034] and [0048] which indicate a connection between these properties).
Regarding instant claim 41, it is interpreted that the polymer arm length of the polymers of Lidický will control the hydrodynamic radius of the star polymer. Lidický further suggests that a higher radius can enable prolonged circulation of star-like polymer conjugates relative to lower molecular weight linear polymers (pg. 19853, paragraph 3), suggesting that selecting a polymer arm length capable of achieving such a higher radius is desirable.
Regarding instant claim 43, Lidický teaches that the star polymers have a hydrodynamic radius of 13.2 nm (pg. 19853, paragraph 3).
Regarding instant claim 49, as noted above, the polymer arms of Lidický comprise monomers of HPMA, a methacrylamide, noted in the specification to be hydrophilic (paragraph [00192]).
Regarding instant claim 63, Lidický shows polymer arms linked to the dendrimer through an amide linking group (see Figure 2, a portion of which is reproduced above).
Lidický does not teach the presence of linker Z with the structure
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, as required by the elected species wherein Z comprises an amide or a triazole (instant claim 63).
Wiss teaches polymers with adjustable functional end-groups for polymer conjugation which allow for flexible functionalization (abstract). They teach that a crucial step on the way toward more efficient and versatile polymer conjugation strategies is a flexible and reliable endgroup functionalization that enables the incorporation of diverse reactive groups and thus allows for high combinatory flexibility (pg. 4759, “Results and Discussion”). Wiss teaches the incorporation of an alkyne α-end-group consistent with those of the elected species (Scheme 1; pg. 4760-4761, “Synthesis of Polymers with an Alkyne α-End-Group”).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to incorporate the alkyne end group of the elected species to the polymer conjugates of Lidický, as suggested by Wiss. One of ordinary skill would have been motivated to do so with a reasonable expectation of success in order to introduce a functional group to a well-defined polymer which allows for high combinatory flexibility in polymer synthesis, which can be highly valuable in the case of materials for pharmaceutical use (Wiss, “Introduction”, paragraph 2; “pg. 4759, “Results and Discussion”; pg. 4766, “Conclusions”). There is a reasonable expectation of success as the polymer conjugates of Lidický are taught to be used in anti-lymphoma treatment strategies (pg. 19857, “2.7 In Vivo Experimental Therapy”).
Lidický does not teach that the polymer arm comprises charged monomers comprising negatively charged functional groups (instant claim 1), 1 to 20 mol% charged monomers comprising negatively charged functional groups (instant claim 34) or that the co-monomers are the MA-b-Ala-COOH of the elected species (instant claims 61-62, and 64 and 66-67). Lidický does not teach that the reactive monomer is between 10 and 50 mol% (instant claim 68).
Ulbrich teaches a conjugate comprising monomer units linked to form a polymeric chain with units of N-(2-hydroxypropyl)-methacrylamide (HPMA), 1 to 25% of units of methacryloylated hydrazones of α-amino acids, ε -amino acids, aromatic amino acids or oligopeptides terminated with a molecule of an anthracycline cancerostatic, and 0.5 to 15% methacryloylated α-amino acids, ε-amino acids, aromatic amino acids or oligopeptides or their sodium salts (claim 1). The anthracycline cancerostatic is further taught to be doxorubicin (claims 4 and 5), and the amino acids are chosen from the group including β-alanine (claim 7). See particularly claim 5 and Fig. 1 which exemplify monomer units
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wherein X is the amino acid β-alanine (paragraph [0025]), consistent with the charged monomers of the elected species.
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant invention to modify the polymer arms of Lidický to include 0.5 to 15 mol % MA-b-Ala-COOH monomer units (overlapping the claimed range) and 1 to 25 mol% of reactive drug-linked monomer units (overlapping the claimed range), as suggested by Ulbrich.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success in order to achieve a polymeric carrier with prolonged circulation that is capable of releasing a drug in response to pH change (paragraphs [0005]-[0006]) and that has targeted transfer and drug release after penetration to target tumor cells (paragraph [0009]). There is a reasonable expectation of success as the polymer conjugates of Lidický similarly comprise HPMA and monomer units comprising doxorubicin linked via hydrazone bonds (abstract) and are taught to be used in anti-lymphoma treatment strategies (pg. 19857, “2.7 In Vivo Experimental Therapy”). Further, per MPEP 2144.05 I, “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
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Claims 1, 31-32, 34, 36-37, 41, 43, 49, and 61-68 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 73-74, 81-82, and 85-88 of copending Application No. 18/032,538 in view of Lidický et al. (“Anti-Lymphoma Efficacy Comparison of Anti-CD20 Monoclonal Antibody-Targeted and Non-Targeted Star-Shaped Polymer-Prodrug Conjugates” Molecules 2015, 20, 19849-19864; included on IDS submitted 05/25/2022), hereafter “Lidický”, as evidenced by NIH (“Doxorubicin” https://pubchem.ncbi.nlm.nih.gov/compound/Doxorubicin; of record), Wiss et al. (“Facilitating Polymer Conjugation via Combination of RAFT Polymerization and Activated Ester Chemistry” Journal of Polymer Chemistry: Part A: Polymer Chemistry 2010, 48(21), 4758-4767; of record), hereafter “Wiss”, and Ulbrich et al. (US 2006/0057099 A1, published March 16, 2006; included on IDS submitted 05/25/2022).
Claims 1, 31-32, 34, 36-37, 41, 43, 49, and 61-68 are directed to an invention not patentably distinct from claims 73-74, 81-82, and 85-88 of commonly assigned copending Application No. 18/032,538.
Both the instant claims and those of copending Application No. 18/032,538 recite a star polymer having the same formula (compare formula O-([X]-A(D)-[Z]-[L])n of the instant claims to formula O[D1]-([X]-A(D2)-[Z]-[D3])n of copending claim 73) of a core, a polymer arm attached to the core, linker molecules, and drug molecules (compounds that extracellularly or intracellularly). The polymer arm of both sets of claims comprises charged monomers and a drug at the same density on the polymer arm. The star polymer of both sets of claims recite a value of n greater than 5 and overlapping molecular weights of the polymer arm. Both sets of claims recite a PAMAM dendrimer core. The D2 drug of copending Application No. 18/032,538 is recited to be selected from immunostimulants or chemotherapeutics.
Regarding the elected species, the claims of copending Application No. 18/032,538 do not recite the specific drug (or that the drug has a molecular weight of between about 200-1,000 Da resulting in a mass percent of about 10 to about 80 mass%), polymer arm monomer units and mol%, or linker Z of the elected compound.
Lidický teaches star-shaped polymer-doxorubicin conjugates (see abstract and Figures 1 and 2) with a PAMAM dendrimer core with amine functional groups (component O) and nine (an integer, n) HPMA-based polymer arms (component A) attached to the anticancer drug doxorubicin (component P2). The polymer arms of Lidický comprise HPMA monomers proximal to the core, consistent with elected polymer arm A. The polymer arms of Lidický comprise the following monomers linked to the drug doxorubicin via a hydrazone linkage (abstract, Figure 1):
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while the polymer arm of the elected species comprises the following drug-linked monomers:
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.
The monomers of Lidický differ from those of the elected species in the addition of three successive -CH2- groups in the polymer side chain, and are considered to be homologous to the monomers of the elected species. Per MPEP 2144.09 II, “Compounds which are position isomers (compounds having the same radicals in physically different positions on the same nucleus) or homologs (compounds differing regularly by the successive addition of the same chemical group, e.g., by -CH2- groups) are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977).”
Lidický teaches that the hydrazide content of the polymer precursor for dendrimer-based polymers is 4.8 mol%, and that hydrazide groups are used for doxorubicin attachment (Table 1; pg. 19859, “3.2 Synthesis of Polymer Precursors and Polymer-Drug Conjugates”), indicating that the majority of the monomer units of the polymer arm are HPMA (a neutral hydrophilic monomer per the instant specification at paragraph [00192]). As evidenced by NIH, the molecular weight of doxorubicin is 543.5 g/mol (pg. 1, “Molecular Weight”). As Lidický teaches a drug that satisfies the recited molecular weight and a density along the polymer arm consistent with the instant claim, it is interpreted that it will also satisfy the limitation of a mass percent of about 5 to about 80% relative to the mass of the star polymer (see instant specification paragraphs [0034] and [0048] which indicate a connection between these properties).
Wiss teaches polymers with adjustable functional end-groups for polymer conjugation which allow for flexible functionalization (abstract). They teach that a crucial step on the way toward more efficient and versatile polymer conjugation strategies is a flexible and reliable endgroup functionalization that enables the incorporation of diverse reactive groups and thus allows for high combinatory flexibility (pg. 4759, “Results and Discussion”). Wiss teaches the incorporation of an alkyne α-end-group consistent with those of the elected species (Scheme 1; pg. 4760-4761, “Synthesis of Polymers with an Alkyne α-End-Group”).
Ulbrich teaches a conjugate comprising monomer units linked to form a polymeric chain with units of N-(2-hydroxypropyl)-methacrylamide (HPMA), 1 to 25% of units of methacryloylated hydrazones of α-amino acids, ε -amino acids, aromatic amino acids or oligopeptides terminated with a molecule of an anthracycline cancerostatic, and 0.5 to 15% methacryloylated α-amino acids, ε-amino acids, aromatic amino acids or oligopeptides or their sodium salts (claim 1). The anthracycline cancerostatic is further taught to be doxorubicin (claims 4 and 5), and the amino acids are chosen from the group including β-alanine (claim 7). See particularly claim 5 and Fig. 1 which exemplify monomer units
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wherein X is the amino acid β-alanine (paragraph [0025]), consistent with the charged monomers of the elected species.
It would have been prima facie obvious to one of ordinary skill in the art to modify the star polymer of copending Application No. 18/032,538 with monomer units and doxorubicin as suggested by Lidický. One of ordinary skill in the art would have been motivated to do so in order to achieve a dendrimer star polymer that can be used in anti-lymphoma treatment strategies (pg. 19857, “2.7 In Vivo Experimental Therapy”) and which can release an anticancer drug readily in mildly acidic environments (abstract).
It would further have been prima facie obvious to one of ordinary skill in the art to incorporate the alkyne end group of the elected species to the star polymer of copending Application No. 18/032,538, as suggested by Wiss. One of ordinary skill would have been motivated to do so in order to introduce a functional group to a well-defined polymer which allows for high combinatory flexibility in polymer synthesis, which can be highly valuable in the case of materials for pharmaceutical use (Wiss, “Introduction”, paragraph 2; “pg. 4759, “Results and Discussion”; pg. 4766, “Conclusions”).
It would further have been prima facie obvious to one of ordinary skill in the art to modify the polymer arms of copending Application No. 18/032,538 to include 0.5 to 15 mol % MA-b-Ala-COOH monomer units (overlapping the claimed range) and 1 to 25 mol% of reactive drug-linked monomer units (overlapping the claimed range), as suggested by Ulrich. One of ordinary skill in the art would have been motivated to do so in order to achieve a polymeric carrier with prolonged circulation that is capable of releasing a drug in response to pH change (paragraphs [0005]-[0006]) and that has targeted transfer and drug release after penetration to target tumor cells (paragraph [0009]). Further, per MPEP 2144.05 I, “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990)”.
This is a provisional nonstatutory double patenting rejection.
The U.S. Patent and Trademark Office may not institute a derivation proceeding in the absence of a timely filed petition. The USPTO normally will not institute a derivation proceeding between applications or a patent and an application having common ownership (see 37 CFR 42.411). Commonly assigned copending Application No. 18/032,538, discussed above, may form the basis for a rejection of the noted claims under 35 U.S.C. 102 or 103 if the commonly assigned case qualifies as prior art under 35 U.S.C. 102(a)(2) and the patentably indistinct inventions were not commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention.
In order for the examiner to resolve this issue the applicant or patent owner can provide a statement under 35 U.S.C. 102(b)(2)(C) and 37 CFR 1.104(c)(4)(i) to the effect that the subject matter and the claimed invention, not later than the effective filing date of the claimed invention, were owned by the same person or subject to an obligation of assignment to the same person. Alternatively, the applicant or patent owner can provide a statement under 35 U.S.C. 102(c) and 37 CFR 1.104(c)(4)(ii) to the effect that the subject matter was developed and the claimed invention was made by or on behalf of one or more parties to a joint research agreement that was in effect on or before the effective filing date of the claimed invention, and the claimed invention was made as a result of activities undertaken within the scope of the joint research agreement; the application must also be amended to disclose the names of the parties to the joint research agreement.
A showing that the inventions were commonly owned or deemed to be commonly owned not later than the effective filing date under 35 U.S.C. 100(i) of the claimed invention will preclude a rejection under 35 U.S.C. 102 or 103 based upon the commonly assigned case. Alternatively, applicant may take action to amend or cancel claims such that the applications, or the patent and the application, no longer contain claims directed to patentably indistinct inventions.
Response to Arguments
Applicants’ arguments filed 11/24/2025 have been fully considered.
Regarding the claim rejections as containing an improper Markush grouping of alternatives, Applicant argues that the amended claims, which restrict the definitions of O, A, L, and D, share a single structural similarity and a common use that flows from the structural similarity, namely, displaying and/or delivering pharmaceutically active compounds.
These arguments are unpersuasive. The Examiner respectfully maintains, as detailed in the above rejections, that the claimed compounds cannot be said to share both a substantial structural feature and a common use that flows from the substantial structural feature, and no dependent claim limits the scope of the claimed compounds to a proper Markush group. In particular, Claim 1 is directed to a compound of formula O-([X]-A(D)-[Z]-[L])n where “A” is any polymer arm comprising hydrophilic monomers and charged monomers comprising negatively charged functional groups, “X” and “Z” are any linker molecules, L is any ligand comprising any pharmaceutically active compound that acts extracellularly, and D is any drug comprising a pharmaceutically active compound that acts intracellularly. Each of these elements have an almost unlimited number of possible identities from multiple physical and chemical classes, and do not necessarily share any substantial structural feature. Several components (i.e., linker molecules, compounds that act extracellularly or intracellularly) are defined solely by their function and thus do not share a single structural similarity.
Regarding the claim rejections under 35 U.S.C. § 112(a), Written Description, Applicant argues that the specification, citing specifically to paragraphs [0512]-[0528], provides ample disclosure on star polymers as presently claimed.
These arguments are unpersuasive. The Examiner respectfully maintains that the present specification fails to provide adequate written description for the genus of the claims, with particular emphasis on the invention as it relates to “a ligand comprising a pharmaceutically active compound that acts extracellularly” or “a drug comprising a pharmaceutically active compound that acts intracellularly” (instant claim 1). As detailed in the above rejections, the claims recite functional characteristics, but lack written description because there is no disclosure in the specification of a correlation between function and structure of a ligand comprising a pharmaceutically active compound that acts extracellularly or a drug comprising a pharmaceutically active compound that acts intracellularly, nor evidence of strong correlation established in the art (see MPEP 2163). Additionally, based on the functional characteristics recited by the instant claims, the instant claims would include compounds discovered at a later date. Given the potentially limitless scope of the compounds encompassed by the instant claims, Applicant cannot reasonably be said to have been in possession of each and every compound encompassed by the generic claim.
Regarding the claim rejections under 35 U.S.C. § 112(b), Indefiniteness, Applicant argues that the amendments to the claims have overcome the rejections.
In response, as noted above, the previous rejections of claims 1, 31-32, 34, 36-37, 43, and 49 under 35 U.S.C. § 112(b) have been withdrawn. New rejections necessitated by claim amendments are set forth above.
Regarding instant claim 41, the Examiner maintains that the claim is indefinite as it is unclear what structural effect the selection of the length of A has on the star polymer of claim 1, from which claim 41 depends. In parts a) and c), what is the size of the polymer increased relative to? In parts b) and c), how is a controlled hydrodynamic radius structurally different than the star polymer of claim 1?
Regarding the rejection of claim 41 under 35 U.S.C. § 112(d), Improper Dependent Claim, Applicant argues that claim 41 has been amended to be dependent from claim 1 and requests reconsideration and withdrawal of the rejection.
In response, the Examiner maintains that Claim 41 fails to further limit the subject matter of the claim from which it depends. Selection of a polymer arm length to achieve a certain effect, as recited in claim 41, does not structurally limit the star polymer of claim 1, from which claim 41 depends. Claim 1 recites a star polymer having the formula O-([X]-A(D)-[Z]-[L])n, with A being a polymer arm (as defined in claim 1); thus, a polymer arm length must be selected in the star polymer of claim 1. Claim 41 does not recite any structural limitations on the polymer arm length to differentiate it from the polymer arm length of claim 1, and thus fails to further limit the subject matter of claim 1.
Regarding the claim rejections under 35 U.S.C. § 103, Applicant argues that the inventors of the present application unexpectedly discovered that incorporation of charged monomers on the polymer arms led to increased tissue retention in vivo and reduced antibody induction against the ligands or drugs displayed on the star polymer (citing to paragraph [0184] of the specification). Applicant argues that Lidický does not teach or suggest polymer arms containing charged monomers with negatively charged functional groups, let alone polymer arms conferring increased tissue retention and reduced ligand- or drug-induced antibodies in vivo. Applicant argues that neither Wiss nor Ulbrich fails to remedy the deficiencies of Lidický; Applicant further argues that Ulbrich describes linear polymers, not star polymers with multiple arms radiating from a central core. A person of ordinary skill in the art would not have been motivated to combine the linear polymer conjugates of Ulbrich with the star polymers of Lidický, and such a combination would require non-trivial reengineering of polymer initiation and architecture to convert a linear system into a star configuration. Even assuming, arguendo, that such a combination were attempted, there would be no reasonable expectation of success in achieving star polymers suitable for displaying and/or delivering therapeutic agents that exhibit the observed enhanced tissue retention and reduced antibody induction in vivo.
These arguments are unpersuasive. Regarding the argument that neither Lidický nor it’s combination with Wiss and Ulbrich teach star polymers with polymer arms conferring increased tissue retention and reduced ligand- or drug-induced antibodies in vivo and there is no reasonable expectation of success in achieving this effect, the Examiner notes that the features upon which applicant relies (i.e., enhanced tissue retention and reduced antibody induction in vivo ) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
The Examiner further notes, per MPEP 2144 IV., “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006)”. Further, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
Regarding the argument that the instant invention achieves unexpected results, per 716.02(d), unexpected results must be commensurate in scope with the claimed invention. The evidence of record does not establish that incorporation of charged monomers on the polymer arms of the claimed star polymer increases tissue retention in vivo and reduces antibody induction against the ligands or drugs displayed commensurate with the full scope of claimed star polymer of formula O-([X]-A(D)-[Z]-[L])n. Particularly, the evidence of record does not demonstrate that any charged monomers comprising negatively charged functional groups demonstrates unexpected results for any drug, D, comprising a pharmaceutically active compound that acts intracellularly and any ligand, L, comprising a pharmaceutically active compound that acts extracellularly.
Regarding the arguments that Ulbrich describes linear polymer and not star polymers, and that a person of ordinary skill in the art would not have been motivated to combine the linear polymer conjugates of Ulbrich with the star polymer of Lidický, the Examiner notes that the test for obviousness is not whether the features of a secondary reference may be bodily incorporated into the structure of the primary reference; nor is it that the claimed invention must be expressly suggested in any one or all of the references. Rather, the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). From the combined teaching of the prior art, modification of the HPMA-based polymer arm on the star polymer on Lidický with the elected MA-b-Ala-COOH monomer units suggested by Ulbrich for use in HPMA-based polymers for drug delivery would predictably result in a polymeric carrier with prolonged circulation that is capable of releasing a drug in response to pH change and that has targeted transfer and drug release after penetration to target tumor cells (see Ulbrich, paragraphs [0005]-[0006] and [0009]), providing motivation to the skilled artisan for the modification. Further, Lidický teaches that star polymers are prepared by grafting HPMA polymer precursors to PAMAM dendrimers (see Figure 2), and one of ordinary skill in the art would expect that that the modified polymer arms suggested by Ulbrich could similarly be grafted to form the claimed star polymer.
Regarding the nonstatutory double patenting rejections, Applicant requests the rejections be held in abeyance until patentable subject matter is identified.
In response, the Examiner notes that a request to hold a rejection in abeyance is not a proper response to a rejection. Rather, a request to hold a matter in abeyance may only be made in response to an OBJECTION or REQUIREMENTS AS TO FORM (see MPEP 37 CFR 1.111(b) and 714.02). As set forth above, the instant claims remain rejected on the ground of obvious-type nonstatutory double patenting as being unpatentable over the co-pending claims of Application No. 18/032,538 in view Lidický, as evidenced by NIH, Wiss, and Ulbrich.
Conclusion
Applicant's amendment necessitated the new ground(s) 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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/BETHANY P BARHAM/Supervisory Patent Examiner, Art Unit 1611
/J.M.K./Examiner, Art Unit 1611