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 .
Election/Restrictions
Applicant’s election without traverse of Group I and species of the polymer conjugate C005D shown in Figure 4 in the reply filed on July 20, 2026 is acknowledged. Because the elected species C005D lacks an ionophore moiety, the species does not read on any pending claims. Consequently, search and examination have been expanded to encompass the full scope of claim 7.
Claim Rejections - 35 USC § 112 Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 7-9, 11, and 12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claim 7, the phrase "d is, when present, approximately 1” lacks an objective boundary and structural clarity. Although the specification defines “approximately” as “greater than or less than” (PGPub of the instant application, ¶ 91), it provides no specific quantitative limits or numerical ranges to define the upper and lower bounds of variable “d.” Additionally, it is unclear whether “approximately 1” includes 1, because “greater than or less than 1” literally excludes 1. Furthermore, the phrase “approximately 1” is not a well-understood term of art with an established industry standard in the relevant technical field. Because neither the specification nor the prior art establishes an industry standard or conventional understanding for “approximately 1” in the context of the claimed polymer conjugate, a person of ordinary skill in the art would not be able to determine with reasonable certainty the precise metes and bounds of the claim scope (the specific variance or deviation allowed from 1). It is suggested that claim 7 be amended to replace “approximately 1” with a clear numerical range supported by the specification. Mainly, it is unclear if “approximately 1” encompasses 0, or other numbers such as 2, 3, etc.
The dependent claims fall therewith.
Clarification and/or amendment is required.
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, 2, 5-9, 11, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Chung (WO 2019 245458) in view of Kang et al. (WO 2020 082057).
Regarding claims 1 and 7, Chung discloses zinc(II) agents comprising zinc(II)/polyglutamic acid (PGA) complex conjugated to tumor-targeting moieties and charge-carrying moieties for treating cancer patients (abstract; claim 25). Chung discloses that the polymer backbone comprising PGA is formed by a peptide bond (page 17, ¶ 2-3). Chung discloses that tumor-targeting moieties such as folic acid, which binds to folate receptor expressed in many human tumors (page 19, ¶ 3) can be covalently bonded to PGA (page 19, ¶ 2). Chung discloses that charge-modifying moieties can be used as sites for chelating Zn(II) ions, and the charge-modification will also affect transport and solubility of the Zn/PGA complexes, as such, they can be used to tune the pharmaceutical effects of the carrier and the Zn/PGA complexes (page 21, ¶ 2). The charge-modification moieties read on the ionophore moieties of instant claims, as the specification of the instant application defines that ionophores are molecules that reversibly bind with a metal ion and aid the transport of the metal ion across a biological membrane (PGPub of the instant application, ¶ 64). Chung discloses that the moieties can be conjugated to PGA via a spacer group (linker moiety) such as polyethylene glycol (PEG) amine (page 20, ¶ 4). Regarding claim 2, Chung discloses that different targeting moieties can be covalently joined to PGA in any combination and ratio to form complexes (page 19, ¶ 2). Chung discloses the Zn(II) agent C005D comprising folate-PEG4-NH2 (first receptor-targeting moieties with first linker moieties) and cRGDfK (cyclo(-Arg-Gly-Asp-D-Phe-Lys-))-PEG4-NH2 (second receptor-targeting moieties with second linker moieties) pendant from a monomer unit in the polymer backbone (page 38, ¶ 5; FIGURE 1). The structure of C005D of Chung is similar to that of a zinc(II) complex of the polymer conjugate according to Formula IV in instant claim 7, except for the ionophore moieties. Regarding claims 5 and 11, Chung discloses that a ratio of zinc to glutamic acid units can be 1:10, and that an appropriate balance between the dosage amount (zinc) and amount of non-zinc component can be determined by one of ordinary skill in the art (page 22, ¶ 2). Chung discloses the preparation of Zn(II) agent C005D (page 38, Example 2). Chung discloses that 45 kDa y-PGA can be conjugated to targeting moieties such as folate-PEG4-NH2 and cRGDfK-PEG4-NH2 at 1:3:3 ratio, and that zinc can be bound at a molar ratio of zinc:glutamate monomer 1:4.5 (page 39, ¶ 1). If molecular weights for y-PGA monomer, Folate-PEG4-NH2, cRGDfK-PEG4-NH2, and zinc are 129.11, 659.7, 850, and 65.38 g/mol, respectively, the weight of the conjugate backbone accounting for condensation loss of water (18.02 g/mol) can be about 49,421 g/mol (45,000 + (659.7 X 3) + (850 X 3) - (18.02X6)). The number of monomers per chain would be about 348.5 (45,000 / 129.11), and the mass of bound zinc would be about 5,063 g (65.38 X (348.5/4.5)). Including the bound zinc, the total weight of the zinc-polymer conjugate is about 54.484 g/mol (49.421 + 5.063). Thus, the weight ratio would be about 1:11 (5,063:54,484). Regarding claims 6 and 12, the number of zinc(II) ions per polymer conjugate of C005D can be about 77 (348.5/4.5). Regarding claim 8, Chung discloses that the PGA polymer is combined with a zinc salt in buffered aqueous solution and suitably processed for preparing a pharmaceutically acceptable formulated composition (page 23, ¶ 2). Chung discloses that a liquid solution formulation may be prepared with suitable carriers, diluents, buffers, preservatives, or other excipients suitably selected with regard to the form of administration (page 24, ¶ 4). Regarding claim 9, Chung discloses that the liquid solutions can be administered by injection (parenteral administration) (page 24, ¶ 2).
Chung does not disclose that the ionophore moieties are covalently bonded to the polymer backbone via cleavable linker moiety.
Kang discloses interleukin-10 polypeptide conjugates comprising a cytotoxic agent such as ionophores (abstract, ¶ 120). Kang discloses that the cytotoxic agent can be linked to the conjugate via a cleavable linker (¶ 28).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the conjugate of Chung to use a cleavable linker to conjugate ionophore moieties to the polymer backbone in order to improve stability, controlled release, and targeted delivery. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Kang teaches that a cleavable linker can be used to link an ionophore to the conjugate. Further, a person of ordinary skill in the art would have been motivated to utilize a cleavable linker for the ionophore to enable the ionophore moiety to separate from the polymer backbone and form a complex with the therapeutically active metal ion under certain conditions. A person of ordinary skill in the art would have been motivated to optimize the linker length and cleavable terminal site position as a matter of design choice according to the specific requirements of the target applications. Similarly, a person of ordinary skill in the art would have been motivated to optimize the number and order of targeting moieties and ionophore moieties as a matter of design choice according to the specific requirements of the target applications. Such design parameters are result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the parameters for achieving the desired conjugate characteristics.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Chung and Kang as applied to claims 1, 2, 5-9, 11, and 12 above, and further in view of Yang et al. (Theranostics, 2017; cited on PTO-892).
Chung and Kang are discussed above.
Neither Chung nor Kang discloses that the zinc(II) complex of the polymer conjugate further comprises a plurality of labeling moieties via a label-linker moiety.
Yang discloses the use of a near-infrared fluorophore, Cy5.5 conjugated with hyaluronic acid (HA) for in vivo imaging (abstract). Yang discloses that the Cy5.5 can be conjugated to HA via a linker moiety (page 155, Figure 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the conjugate of Chung and Kang to include labeling moieties such as Cy5.5 via a linker moiety for targeted diagnostics. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Yang teaches that a labeling moiety such as Cy5.5 can be bound to a polymer conjugate via a linker for in vivo imaging analysis. Further, a person of ordinary skill in the art would have been motivated to utilize a labeling moiety in addition to the therapeutic conjugate in order to diagnose and monitor a targeted area and treat the area for theranostic applications. A person of ordinary skill in the art would have been motivated to optimize the linker length and the number and order of labeling moieties as a matter of design choice according to the specific requirements of the target applications. Such a design parameter is a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the parameters for achieving the desired conjugate characteristics. Accordingly, applying the teachings of Yang to the conjugate of Chung and Kang constitutes no more than the predictable use of prior art elements according to their established functions and therefore renders claim 3 obvious.
Claims 1, 2, and 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over Chung (WO 2018 084806; cited on PTO-892; hereinafter “Chung 2018”) in view of Kang et al. (WO 2020 082057).
Regarding claims 1 and 7, Chung 2018 discloses a complex of the Zn(II) ion with y-PGA, a tumor-targeting moiety, and a charge-modifying moiety for treating tumors in patients (abstract; claim 15). Chung 2018 discloses that the PGA polymer backbone comprising PGA is formed by a peptide bond (page 14, ¶ 4). Chung 2018 discloses that tumor-targeting moieties can be covalently bonded to PGA (page 18, ¶ 2). Chung 2018 discloses that charge-modifying moieties can be used as sites for chelating Zn(II) ions, and the charge-modification will also affect transport and solubility of the Zn/PGA complexes, and as such, they can be used to tune the pharmaceutical effects of the carrier and the Zn/PGA complexes (page 20, ¶ 1). The charge-modification moieties read on the ionophore moieties of instant claims, as the specification of the instant application defines that ionophores are molecules that reversibly bind with a metal ion and aid the transport of the metal ion across a biological membrane (PGPub of the instant application, ¶ 64). Chung 2018 discloses that the moieties can be conjugated to PGA via a spacer group (linker moiety) such as PEG amine (page 19, ¶ 2). Regarding claim 2, Chung 2018 discloses that any combination of various targeting moieties such as folic acid and RGD peptide can be covalently joined to y-PGA (page 9, ¶ 6). It can be expected that the conjugation can comprise a second targeting moieties. Regarding claim 8, Chung 2018 discloses that the zinc salt and y-PGA carrier are combined with excipients suitable for use in a pharmaceutical product (page 27, ¶ 2). Chung 2018 discloses that a liquid solution formulation may be prepared with suitable carriers, diluents, buffers, preservatives, or other excipients suitably selected with regard to the form of administration (page 21, ¶ 4). Regarding claim 9, Chung 2018 discloses that the liquid solutions can be administered by injection (parenteral administration) (page 21, ¶ 2).
Chung 2018 does not disclose the ionophore moieties are covalently bonded to the polymer backbone via a cleavable linker moiety.
As discussed above, Kang discloses interleukin-10 polypeptide conjugates comprising cytotoxic agent such as ionophores (abstract, ¶ 120). Kang discloses that the cytotoxic agent can be linked to the conjugate via a cleavable linker (¶ 28).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the conjugate of Chung 2018 to use a cleavable linker to conjugate ionophore moieties to the polymer backbone in order to improve stability, controlled release, and targeted delivery. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Kang teaches that a cleavable linker can be used to link an ionophore to the conjugate. Further, a person of ordinary skill in the art would have been motivated to utilize a cleavable linker for the ionophore to enable the ionophore moiety to separate from the polymer backbone and form a complex with the therapeutically active metal ion under certain conditions. A person of ordinary skill in the art would have been motivated to optimize the linker length and cleavable terminal site position as a matter of design choice according to the specific requirements of the target applications. Similarly, a person of ordinary skill in the art would have been motivated to optimize the number and order of targeting moieties and ionophore moieties as a matter of design choice according to the specific requirements of the target applications. Such design parameters are result effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the parameters for achieving the desired conjugate characteristics.
Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Chung 2018 and Kang as applied to claims 1, 2, and 7-9 above, and further in view of Yang et al. (Theranostics, 2017; cited on PTO-892).
Chung 2018 and Kang are discussed above.
Neither Chung 2018 nor Kang discloses that the zinc(II) complex of the polymer conjugate further comprise a plurality of labeling moieties via a label-linker moiety.
Yang discloses the use of a near-infrared fluorophore, Cy5.5 conjugated with HA for in vivo imaging (abstract). Yang discloses that Cy5.5 can be conjugated to the HA via a linker moiety (page 155, Figure 1).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the conjugate of Chung 2018 and Kang to include labeling moieties such as Cy5.5 via a linker moiety for targeted diagnostics. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Yang teaches that a labeling moiety such as Cy5.5 can be bound to a polymer conjugate via a linker for in vivo imaging analysis. Further, a person of ordinary skill in the art would have been motivated to utilize a labeling moiety in addition to the therapeutic conjugate in order to diagnose and monitor a targeted area and treat the area for theranostic applications. A person of ordinary skill in the art would have been motivated to optimize the linker length and the number and order of labeling moieties as a matter of design choice according to the specific requirements of the target applications. Such a design parameter is a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the parameters for achieving the desired conjugate characteristics. Accordingly, applying the teachings of Yang to the conjugate of Chung 2018 and Kang constitutes no more than the predictable use of prior art elements according to their established functions and therefore renders claim 3 obvious.
Claims 5, 6, 11, and 12 are rejected under 35 U.S.C. 103 as being unpatentable over Chung 2018 and Kang as applied to claims 1, 2, and 7-9 above, and further in view of Chung (WO 2019 245458).
Chung 2018 and Kang are discussed above.
Neither Chung 2018 nor Kang discloses that the weight-to-weight ratio of zinc(II) to the polymer conjugate is in the range of 1:5 to 1:20, and that the number of zinc(II) ions per polymer conjugate on average is at least 20.
As discussed above, Chung discloses zinc(II) agents comprising zinc(II)/PGA complex conjugated to tumor-targeting moieties and charge-carrying moieties for treating cancer patients (abstract; claim 25). Regarding claims 5 and 6, Chung discloses that a ratio of zinc to glutamic acid units can be 1:10, and that an appropriate balance between the dosage amount (zinc) and amount of non-zinc component can be determined by one of ordinary skill in the art (page 22, ¶ 2). Chung discloses the preparation of Zn(II) agent C005D (page 38, Example 2). Chung discloses that 45 kDa y-PGA can be conjugated to targeting moieties such as folate-PEG4-NH2 and cRGDfK-PEG4-NH2 at 1:3:3 ratio, and that zinc can be bound at a molar ratio of zinc:glutamate monomer of 1:4.5 (page 39, ¶ 1). If molecular weights for y-PGA monomer, Folate-PEG4-NH2, cRGDfK-PEG4-NH2, and zinc are 129.11, 659.7, 850, and 65.38 g/mol, respectively, the weight of the conjugate backbone accounting for condensation loss of water (18.02 g/mol) can be about 49,421 g/mol (45,000 + (659.7 X 3) + (850 X 3) - (18.02X6)). The number of monomers per chain would be about 348.5 (45,000 / 129.11), and the mass of bound zinc would be about 5,063 g (65.38 X (348.5/4.5)). Including the bound zinc, the total weight of the zinc-polymer conjugate is about 54.484 g/mol (49.421 + 5.063). Thus, the weight ratio would be about 1:11 (5,063:54,484). Regarding claims 6 and 12, the number of zinc(II) ions per polymer conjugate of C005D can be about 77 (348.5/4.5).
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use zinc(II) having a weight ratio to the conjugate of about 1:11 and a number of zinc ions per the conjugate of about 77 for the conjugate of Chung 2018. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Chung teaches that zinc can have a weight ratio to the conjugate of about 1:11 and about 77 ions per conjugate. Further, a person of ordinary skill in the art would have been motivated to optimize the weight ratio and number of zinc ions in the conjugate as a matter of design choice according to the specific requirements of the target applications. The weight ratio and number of zinc ions are result effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the amount of zinc in the conjugate for achieving the desired conjugate characteristics as taught by Chung.
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.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-3, 5-9, 11, and 12 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 19/008,446 in view of Chung (WO 2019 245458), Kang et al. (WO 2020 082057), and Yang et al. (Theranostics, 2017; cited on PTO-892).
Regarding claims 1 and 7, claim 1 of the ‘446 recites a zinc(II) agent comprising Zn(II)/y-PGA conjugated to a tumor-targeting moiety and/or a charge-carrying moiety. Claims of the ‘446 do not recite linker moieties. As discussed above, Chung discloses zinc(II) agents comprising a zinc(II)/ PGA complex conjugated to tumor-targeting moieties and charge-carrying moieties for treating cancer patients (abstract; claim 25). Chung discloses that the polymer backbone comprising PGA is formed by a peptide bond (page 17, ¶ 2-3). Chung discloses that tumor-targeting moieties such as folic acid, which binds to folate receptors expressed in many human tumors (page 19, ¶ 3) can be covalently bonded to PGA (page 19, ¶ 2). Chung discloses that charge-modifying moieties can be used as sites for chelating Zn(II) ions, and the charge-modification will also affect transport and solubility of the Zn/PGA complexes, and as such can be used to tune the pharmaceutical effects of the carrier and the Zn/PGA complexes (page 21, ¶ 2). The charge-modification moieties read on the ionophore moieties of instant claims as the specification of the instant application defines that ionophores are molecules that reversibly bind with a metal ion and aid the transport of the metal ion across a biological membrane (PGPub of the instant application, ¶ 64). Chung discloses that the moieties can be conjugated to PGA via a spacer group (linker moiety) such as PEG amine (page 20, ¶ 4). As discussed above, Kang discloses interleukin-10 polypeptide conjugates comprising a cytotoxic agent such as ionophores (abstract, ¶ 120). Kang discloses that the cytotoxic agent can be linked to the conjugate via a cleavable linker (¶ 28). It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the conjugate of the ‘446 to use linkers as taught by Chung and Kang to conjugate functional moieties to the polymer backbone. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Chung and Kang teach that a cleavable or non-cleavable linker can be used to improve conjugation. Further, a person of ordinary skill in the art would have been motivated to use linkers in a polymer-drug conjugate in order to improve stability, controlled release, and targeted delivery. Especially, a person of ordinary skill in the art would have been motivated to utilize a cleavable linker for the ionophore to enable the ionophore moiety to separate from the polymer backbone and form a complex with the therapeutically active metal ion under certain conditions. A person of ordinary skill in the art would have been motivated to optimize the linker length and cleavable terminal site position as a matter of design choice according to the specific requirements of the target applications. Similarly, a person of ordinary skill in the art would have been motivated to optimize the number and order of targeting moieties and ionophore moieties as a matter of design choice according to the specific requirements of the target applications. Such design parameters are result effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the parameters for achieving the desired conjugate characteristics.
Regarding claim 2, claims of the ‘446 do not recite a plurality of second receptor. As discussed above, Chung discloses that different targeting moieties can be covalently joined to PGA in any combination and ratio to form complexes (page 19, ¶ 2). Chung discloses the Zn(II) agent C005D comprising folate-PEG4-NH2 (first receptor-targeting moieties with first linker moieties) and cRGDfK-PEG4-NH2 (second receptor-targeting moieties with second linker moieties) pendant from a monomer unit in the polymer backbone (page 38, ¶ 5; FIGURE 1). It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the conjugate of the ‘446 to add second targeting moieties in order to improve binding specificity. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Chung teaches that the conjugate can have dual-targeting moieties. Further, a person of ordinary skill in the art would have been motivated to utilize a dual targeting conjugation system in order to overcome tumor heterogeneity and increase binding specificity and cellular uptake at disease sites.
Regarding claim 3, claims of the ‘446 do not recite a plurality of labeling moieties. As discussed above, Yang discloses the use of a near-infrared fluorophore, Cy5.5 conjugated with HA for in vivo imaging (abstract). Yang discloses that Cy5.5 can be conjugated to the HA via a linker moiety (page 155, Figure 1). It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to modify the conjugate of Chung to include labeling moieties such as Cy5.5 via a linker moiety for targeted diagnostics. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Yang teaches that a labeling moiety such as Cy5.5 can be bound to the conjugate via a linker for in vivo imaging analysis. Further, a person of ordinary skill in the art would have been motivated to utilize a labeling moieties in addition to the therapeutic conjugate in order to diagnose and monitor a targeted area and treat the area for theranostic applications. A person of ordinary skill in the art would have been motivated to optimize the linker length and the number and order of labeling moieties as a matter of design choice according to the specific requirements of the target applications. Such a design parameter is a result effective parameter that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the parameters for achieving the desired conjugate characteristics.
Regarding claims 5, 6, 11, and 12, claims of the ‘446 do not recite that the weight-to-weight ratio of zinc(II) to the polymer conjugate is in the range of 1:5 to 1:20, and that the number of zinc(II) ions per polymer conjugate on average is at least 20. As discussed above, Chung discloses zinc(II) agents comprising a zinc(II)/PGA complex conjugated to tumor-targeting moieties and charge-carrying moieties for treating cancer patients (abstract; claim 25). Chung discloses that a ratio of zinc to glutamic acid units can be 1:10, and that an appropriate balance between the dosage amount (zinc) and amount of non-zinc component can be determined by one of ordinary skill in the art (page 22, ¶ 2). Chung discloses the preparation of Zn(II) agent C005D (page 38, Example 2). Chung discloses that 45 kDa y-PGA can be conjugated to targeting moieties such as folate-PEG4-NH2 and cRGDfK-PEG4-NH2 at a 1:3:3 ratio, and that zinc can be bound at a molar ratio of zinc:glutamate monomer of 1:4.5 (page 39, ¶ 1). If molecular weights for y-PGA monomer, Folate-PEG4-NH2, cRGDfK-PEG4-NH2, and zinc are 129.11, 659.7, 850, and 65.38 g/mol, respectively, the weight of the conjugate backbone accounting for condensation loss of water (18.02 g/mol) can be about 49,421 g/mol (45,000 + (659.7 X 3) + (850 X 3) - (18.02X6)). The number of monomers per chain would be about 348.5 (45,000 / 129.11), and the mass of bound zinc would be about 5,063 g (65.38 X (348.5/4.5)). Including the bound zinc, the total weight of the zinc-polymer conjugate is about 54.484 g/mol (49.421 + 5.063). Thus, the weight ratio would be about 1:11 (5,063:54,484). Regarding claims 6 and 12, the number of zinc(II) ions per polymer conjugate of C005D can be about 77 (348.5/4.5). It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use zinc(II) having a weight ratio to the conjugate of about 1:11 and a number of zinc ions per the conjugate is of 77 for the conjugate of the ‘446. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Chung teaches that zinc can have a weight ratio to the conjugate of about 1:11 and about 77 ions per conjugate. Further, a person of ordinary skill in the art would have been motivated to optimize the weight ratio or number of zinc ions in the conjugate as a matter of design choice according to the specific requirements of the target applications. The weight ratio and number of zinc ions are result effective parameters that a person of ordinary skill in the art would routinely optimize. Optimization of parameters is a routine practice that would be obvious for a person of ordinary skill in the art to employ and reasonably would expect success. It would have been customary for an artisan of ordinary skill to determine the amount of zinc in the conjugate for achieving the desired conjugate characteristics as taught by Chung.
Regarding claim 8, claims of the ‘446 do not recite a pharmaceutical composition comprising a polymer conjugate and a pharmaceutically-acceptable diluent, carrier, buffer, vehicle, or any combination thereof. As discussed above, Chung discloses that the PGA polymer is combined with a zinc salt in buffered aqueous solution and suitably processed for preparing a pharmaceutically acceptable formulated composition (page 23, ¶ 2). Chung discloses that a liquid solution formulation may be prepared with suitable carriers, diluents, buffers, preservatives, or other excipients suitably selected with regard to the form of administration (page 24, ¶ 4). It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the conjugate of the ‘446 for a pharmaceutical composition comprising the polymer conjugate and a pharmaceutically-acceptable carrier for pharmaceutical applications. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Chung teaches a pharmaceutical composition comprising such a conjugate and a pharmaceutically acceptable carrier for applications. Further, a person of ordinary skill in the art would have been motivated to utilize the conjugate for a pharmaceutical composition in order to expand the applications of the conjugate.
Regarding claim 9, claims of the ‘446 do not recite that the pharmaceutical composition formulated for parenteral administration. As discussed above, Chung discloses that the liquid solutions can be administered by injection (parenteral administration) (page 24, ¶ 2). It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to use the conjugate of the ‘446 for a pharmaceutical composition formulated for parenteral administration. A person of ordinary skill in the art would have been motivated to make these modifications and reasonably would have expected success because Chung teaches that a pharmaceutical composition comprising such a conjugate can be used for parenteral administration. Further, a person of ordinary skill in the art would have been motivated to utilize the conjugate for a pharmaceutical composition for parenteral administration in order to achieve a rapid onset of action, an enhanced drug bioavailability, and a reliable delivery.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
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/JONG HWAN BAEK/Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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