DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
The present application, filed January 13, 2023, is a national stage application of PCT/CN2021/105899, filed July 13, 2021, and claims priority to foreign priority application PCT/CN2020/102115, filed July 15, 2020.
Status of the Application
Applicant’s preliminary amendment, received January 13, 2023, wherein claims 2-62 are canceled and new claims 63-81 are added, is acknowledged.
1 and 63-81 are pending and examined on the merits herein.
Information Disclosure Statement
The information disclosure statement filed March 13, 2025 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. Specifically, no explanations of relevance for NPL documents 1, 2, 5, 6, and 7 are included. These documents have been placed in the application file, but the information referred to therein has not been considered.
Claim Interpretation
The limitation “for locally delivering a therapeutic agent at a controlled rate” is interpreted herein as an intended use of the drug delivery system recited in claim 1.
MPEP 2111.02 at II states: “During examination, statements in the preamble reciting the purpose or intended use of the claimed invention must be evaluated to determine whether or not the recited purpose or intended use results in a structural difference (or, in the case of process claims, manipulative difference) between the claimed invention and the prior art. If so, the recitation serves to limit the claim. …To satisfy an intended use limitation which is limiting, a prior art structure which is capable of performing the intended use as recited in the preamble meets the claim.” In this instance, claim 1 interpreted as satisfied by a drug delivery system that satisfies the structural limitations recited in claim 1, even if that drug delivery system is not expressly used for locally delivering a therapeutic agent at a controlled rate.
Claim Objections
Claims 1, 78, and 79 are objected to because of the following informalities:
Claim 1 recites “a therapeutic agent comprising at least a second binding group BG2 selected from the group consisting of hydroxyl group, carboxylic group, amino group,
amide group, amine group and a combination thereof”. The amino and amine groups are believed to refer to the same functional group. Please remove one of these terms from this limitation.
Claim 78 includes several structures that have text denoting functional groups which overlap with other text on the structure. For example, in the second structure of claim 78, the C3-OH overlaps with the C4-O group above it in the structure. Similarly, the C4-OH overlaps with a bond on the other saccharide structure in the figure. These types of issues are present in structures on pp. 11, 12, 13, 14, 17, 22, and 23.
In addition, some of the structures of claim 78 are of sufficiently low resolution that they are difficult to interpret. For example, at least some of the structures on pp. 11, 12, 13, 14, 15, 16, 17, 18, 19, and 22 are low resolution. Please replace these figures with higher resolution structures.
Claim 79 recites: “The drug delivery system of claim 1, wherein the drug delivery system is locally administrated to a subject in need thereof via injection, oral dosage form, inhalation. implant, or topical application.” The examiner believes this to be a typographical error and should read: “The drug delivery system of claim 1, wherein the drug delivery system is
locally administered to a subject in need thereof via injection, oral dosage form, inhalation. implant, or topical application.”
Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claim 78 is 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.
Claim 78 recites the structures that are shown in the claims. These structures have brackets around the disaccharide unit and shows the group “n.” However, claim 78 does not define group n. Moreover, group n is defined in claim 1 as an integer from 1 to 4, and refers to the values of subscript n as shown in claim 1. It is not clear if n as defined in claim 1 is intended to apply to both claim 1 and claim 78, or if this n shown in claim 78 has different values than in claim 1.
In addition, some structures in claim 78 show asterisks at the ends of the disaccharide unit (for example, see the last three structures on p. 14). It is not clear if and how these asterisks are intended to limit the claim.
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.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], 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.
Claims 65 and 79 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, 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 65 depends from claim 1 and recites wherein (ii) BG2 is carboxylic group and V is -O- or a direct bond, such that an ester linkage is formed, or BG2 is hydroxyl group and V is -C(=O)-, such that an ester linkage is formed.
However, claim 1 requires that variable group V is connected to the therapeutic agent through BG2 such that at least one linkage selected from the group consisting of amide, urea, thiourea, carbamate, thiocarbamate, phosphoramidate, aza-acetal and combination thereof is formed. Therefore, claim 1 does not appear to permit that V be connected to the therapeutic agent through BG2 via an ester bond. In addition, claim 1 does not permit V as -O-. Therefore, claim 65 fails to include all the limitations of the claim upon which it depends.
For the purposes of expedited prosecution, claim 65 is interpreted as not reciting (ii) and (iii) above, and instead is limited to (i), which does include all limitations of claim 1.
Claim 79 depends from claim 1 and requires the drug delivery system is locally administered to a subject in need thereof via injection, oral dosage form, inhalation, implant, or topical application. However, claim 1 is directed to a product, and thus the requirement that the drug delivery system is locally administered to a subject is interpreted as an intended use of the drug delivery system of claim 1 and does not limit the structure of the claim. The claim does not recite a limitation that further limits the structure of the drug delivery system of claim 1, such as being formulated for local administration.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 63, 65, 66, 67, 68, 69, 71, 74, and 80 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yousefpour (Yousefpour, P.; et al. International Journal of Nanomedicine 2011, vol. 6, pp. 1977-1990; cited in PTO-892).
Yousefpour recites the structure shown below, which is a conjugate formed between doxorubicin and chitosan with a succinyl group as a linker (p. 1979, Figure 1). The structure presented in Figure 1 and reproduced below omits a carbonyl oxygen from doxorubicin. However, the doxorubicin staring material shows this carbonyl oxygen, and the examiner is interpreting the missing carbonyl oxygen to be an inadvertent error by Yousefpour.
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In this instance, chitosan is a biopolymer comprising an amino group as BG1, and doxorubicin is a therapeutic agent comprising an amino group as BG2. The succinyl linker has U as -C(=O)-, A as C2 alkyl, B as direct bond, C as direct bond, D as direct bond, and V as -C(=O)-, and wherein U is connected to BG1 via an amide bond and V is connected to BG2 via an amide bond. Alternatively, this linker can also be interpreted as having A as direct bond and B as C2 alkyl. Finally, the succinyl linker has the structure of group Ia in claim 68 with q as 2. This structure satisfies the limitations of present claims 1, 63, 65, 66, 67, 68, 71, and 74, where doxorubicin is an anticancer drug.
Yousefpour further teaches that the cytotoxicity of conjugates comprising the above structures (e.g. CS-DOX-2, CS-DOX-mAb) and free doxorubicin against SKOV-3 cells was evaluated using a tetrazolium-based colorimetric assay, and that the tested concentrations were 8, 40, and 200 nM doxorubicin equivalents (p. 1981, right column, In vitro cytotoxicity assay section, lines 1-6). Because these conjugates are tested in cell culture, and because Yousefpour teaches a concentration measurement for doxorubicin equivalents, they are reasonably interpreted as present in solution with a pharmaceutically acceptable excipient, as recited in claim 80.
Thus Yousefpour anticipates claims 1, 63, 65, 66, 67, 68, 71, 74, and 80.
Regarding the rejection of claim 69, claim 69 depends from claim 68 and further limits variable group M, which is only included in some structures recited in claim 68. Because claim 69 further limits structures in claim 68 that include group M, and because Yousefpour anticipates an alternative structure of claim 68 that does not include group M, claim 69 is also anticipated by Yousefpour.
Claims 1, 63, 65, 66, 67, 68, 69, 71, 74, and 79-81 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kato (Kato, Y.; et al. Biomaterials 2004, vol. 25, pp. 907-915; cited in PTO-892).
Kato teaches examples of N-succinyl-chitosan conjugated to the amino group of mitomycin C (p. 909, Figure 1; structure shown below).
In this instance, chitosan is a biopolymer comprising an amino group as BG1, and mitomycin C is a therapeutic agent comprising an amino group as BG2. The succinyl linker has U as -C(=O)-, A as C2 alkyl, B as direct bond, C as direct bond, D as direct bond, and V as -C(=O)-, and wherein U is connected to BG1 via an amide bond and V is connected to BG2 via an amide bond. Alternatively, this linker can also be interpreted as having A as direct bond and B as C2 alkyl. Finally, the succinyl linker has the structure of group Ia in claim 68 with q as 2. This structure satisfies the limitations of present claims 1, 63, 65, 66, 67, 68, 71, and 74, wherein mitomycin is an anticancer drug.
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Kato teaches that for Suc-Chi-MMC, the suspensions were administered subcutaneously, intratumorally or intraperitoneally after the conjugates were homogenized in saline (p. 910, Section 3.2, lines 1-4). Saline is interpreted as a pharmaceutically acceptable carrier, and thus these compositions satisfy the requirements for claims 79 and 80.
Kato further teaches administering Suc-Chi-MMC and Suc(II)-Chi-MMC conjugates to tumor-bearing mice by i.p. or i.v. injection and for all tumors, resulted in an increased life span, indicating administration of these conjugates as effective for treating cancer (p. 912, Table 1). These compounds are therefore used in a method for treating cancer, as required by claim 81.
Thus Kato anticipates claims 1, 63, 65, 66, 67, 68, 71, 74, and 79-81.
Regarding the rejection of claim 69, claim 69 depends from claim 68 and further limits variable group M, which is only included in some structures recited in claim 68. Because claim 69 further limits structures in claim 68 that include group M, and because Kato anticipates an alternative structure of claim 68 that does not include group M, claim 69 is also anticipated by Kato.
Claims 1, 63, 65-70, 74, and 79-81 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Harada (Harada, M.; et al. Journal of Controlled Release 2000, vol. 69, pp. 399-412; cited in PTO-892).
Harada teaches conjugates comprising a camptothecin analogue conjugated to dextran (p. 399, Title).
Harada teaches the conjugate has the structure as shown below, with various amino acid combinations as linkers (p. 401, Figure 1). In this structure with glycine as the linker, the camptothecin analogue T2513 (p. 401, Figure 1) is considered as the therapeutic agent, dextran is the biopolymer which includes a carboxylic group, U is NR1 with R1 as hydrogen, A is C1 alkyl, B, C, and D are direct bond, and V is -C(=O)-. This structure has each of BG1 linked to U and V linked to BG2 by amide bonds. Alternatively, this linker can also be interpreted as having A as direct bond and B as C2 alkyl. Finally, the glycine linker has the structure of group Ia in claim 68 with q as 1. In addition, the glycine linker has the structure
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recited in claim 70 with q as 1.
This structure, with glycine as the linker, satisfies the limitations of present claims 1, 63, 65, 66, 67, 68, 70, and 74, where T2513 is an anticancer drug.
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Harada further teaches the antitumor activity of the conjugates against MX-1 human mammary carcinoma (p. 403, right column, section 2.8, lines 1-2). Harada teaches that MX-1 tumor fragments (3×3×3 mm), harvested from subcutaneous growing tumors in nude mice hosts, was implanted subcutaneously, and that a single intravenous injection of conjugates at a dose equivalent to 2.5 mg/kg of T-2513 or vehicle (saline) with 5 mice/group was performed when the tumor volume was 100–250 mm3 (p. 403, right column, section 2.8, lines 5-13). Harada discloses that each of the conjugates slowed tumor growth compared with the control sample (p. 410, Figure 9a). Because the camptothecin analogue T2513 is used to treat cancer, it is considered as an anti-cancer drug as recited in claim 74.
Furthermore, Because Harada discloses injection of conjugates, the examiner asserts that formulation of these conjugates for injection necessitates a pharmaceutically acceptable carrier, and thus would form a composition as described in claim 80. Moreover, Harada discloses injection of a vehicle of saline, which further implies the vehicle of the conjugates is saline, and further supports formulation with a pharmaceutically acceptable carrier, absent evidence to the contrary.
Thus Harada anticipates claims 1, 63, 65, 66, 67, 68, 70, 74, and 79-81.
Regarding the rejection of claim 69, claim 69 depends from claim 68 and further limits variable group M, which is only included in some structures recited in claim 68. Because claim 69 further limits structures in claim 68 that include group M, and because Harada anticipates an alternative structure of claim 68 that does not include group M, claim 69 is also anticipated by Harada.
Claims 1, 65, 66, 68, 69, 71, 72, 74, and 79-81 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Lin (Publication no. WO 2015028172 A1; cited in PTO-892).
Lin teaches a conjugate of hyaluronan and the anti-cancer compound gemcitabine (document p. 46, Figure 10; structure shown below).
This structure has gemcitabine as the therapeutic agent an amino group as BG2, dextran as the biopolymer with a carboxylic group as BG1, U, A, B, C, D, and V each as direct bond, and U connected to the biopolymer through BG1 and V connected to the biopolymer through BG2 via an amide bond. Gemcitabine is reasonably considered as an anti-cancer compound, as recited 74. In addition, this structure satisfies the requirements for linker (Ia) of claim 68 with q as 0.
This structure satisfies the limitations of present claims 1, 65, 66, 68, 71, 72, and 74.
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In addition, Lin claims a pharmaceutical composition comprising at least one conjugate
from a glycosaminoglycan and an active compound according to one of the claims 1 to 7, which includes the above HA-Gem conjugate, in combination with at least one excipient and/or diluent (p. 29, claim 12), and further claims the composition is for treating cancer (p. 29, claim 13).
Finally, Lin teaches that the preferred embodiment of the formulation or dosage form of their invention includes an excipient to formulate a dosage form for eye, ear, oral, nose, respiratory tract, gastrointestinal tract, circulation system or topical use (pp. 15, lines 8-10).
Thus Lin anticipates 1, 65, 66, 68, 71, 72, 74, and 79-81.
Regarding the rejection of claim 69, claim 69 depends from claim 68 and further limits variable group M, which is only included in some structures recited in claim 68. Because claim 69 further limits structures in claim 68 that include group M, and because Lin anticipates an alternative structure of claim 68 that does not include group M, claim 69 is also anticipated by Lin.
Claims 1, 66, 68, 69, 71, 72, 74, and 80 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Norbedo (U.S. pre-grant publication no. US 20090253651 A1; cited in IDS received June 11, 2025).
Norbedo teaches a conjugate of hyaluronic acid and the anti-cancer compound methotrexate (document p. 7, Figure 6; structure shown below).
This structure has methotrexate as the therapeutic agent with a carboxylic group as BG2, hyaluronic acid as is the biopolymer with an amino group as BG1, and U, A, B, C, D, and V each as direct bond. In this instance, U is connected to the biopolymer through BG1 and V is connected to the biopolymer through BG2 via an amide. Methotrexate is reasonably considered as an anti-cancer compound, as recited 74. In addition, this structure satisfies the requirements for linker (Ia) of claim 68 with q as 0.
This structure satisfies the limitations of present claims 1, 66, 68, 71, 72, and 74.
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Norbedo further teaches and claims a pharmaceutical composition comprising the drug delivery system (abbreviated as DDS) of claim 1, which would include the above conjugate, in admixture with pharmaceutically acceptable excipients and/or diluents (p. 18, claim 13).
Thus Norbedo anticipates claims 1, 66, 68, 71, 72, 74, and 80.
Regarding the rejection of claim 69, claim 69 depends from claim 68 and further limits variable group M, which is only included in some structures recited in claim 68. Because claim 69 further limits structures in claim 68 that include group M, and because Norbedo anticipates an alternative structure of claim 68 that does not include group M, claim 69 is also anticipated by Norbedo.
Claims 1, 66, 68, 69, 71, 73, 74, and 79-81 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Liu (Liu, P.; et al. Carbohydrate Polymers 2019, vol. 213, pp. 17-26; cited in PTO-892).
Liu teaches preparation of a chondroitin sulphate-doxorubicin conjugate (p. 17, Abstract, line 3; structure shown on p. 18, Figure 1 and reproduced below).
This structure has doxorubicin as the therapeutic agent with an amino group as BG2, chondroitin sulfate as the biopolymer a carboxyl group as BG1, and U, A, B, C, D, and V each as direct bond. In this instance, U is connected to the biopolymer through BG1 and V is connected to the biopolymer through BG2 via an amide. Doxorubicin is reasonably considered as an anti-cancer compound, as recited 74. In addition, this structure satisfies the requirements for linker (Ia) of claim 68 with q as 0.
This structure satisfies the limitations of present claims 1, 66, 68, 71, 73, and 74.
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In addition, Liu teaches preparation of PLGA nanoparticles comprising CS-DOX and PLGA (p. 18, Section 2.3, first paragraph lines 1-10), and further teaches that after evaporation of the dichloromethane solvent used when preparing the nanoparticle emulsion, deionized water is added to the nanoparticle composition (p. 18, Section 2.3, first paragraph lines 10-11). Deionized water is a pharmaceutically acceptable solvent, and thus the nanoparticles taught by Liu satisfy the requirements of present claim 80.
Liu further teaches administration of the CS-DOX-PLGA nanoparticles were
intravenously administered by tail vein injection into normal mice to study their biodistribution in vivo (p. 19, right column, section 2.10, lines 1-4), which would require formulation for injection as recited in claim 79.
Finally, Liu teaches administration of these CS-DOX-PLGA nanoparticles to mice for treating xenograft tumors of U251 cells (p. 19, right column, section 2.11, lines 1-4). Liu teaches that the CS-DOX-PLGA nanoparticles slowed tumor growth more effectively than doxorubicin alone (p. 25, Figure 8b). This is interpreted as a method of treating cancer, as recited in claim 81.
Thus Liu anticipates claims 1, 66, 68, 71, 73, 74, and 79-81.
Regarding the rejection of claim 69, claim 69 depends from claim 68 and further limits variable group M, which is only included in some structures recited in claim 68. Because claim 69 further limits structures in claim 68 that include group M, and because Liu anticipates an alternative structure of claim 68 that does not include group M, claim 69 is also anticipated by Liu.
Claims 1, 63, 65-69, 74, 75, and 77 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Gardner (U.S. pre-grant publication no. US 20150337054 A1; cited in PTO-892).
Gardner teaches conjugates that include tofacitinib (cover page, Abstract, line 1). As one example, Gardner teaches tofacitinib conjugated to the protein bovine serum albumin (p. 1, [0011]; structure reproduced below).
This structure has tofacitinib as the therapeutic agent, which includes an amino group as BG2, and the protein BSA as the biopolymer, which includes an amino group as BG1. This structure’s succinic acid linker has U as -C(=O)-, A as C2 alkyl, B as direct bond, C as direct bond, D as direct bond, and V as -C(=O)-, and wherein U is connected to BG1 via an amide bond and V is connected to BG2 via an amide bond. Alternatively, this linker can also be interpreted as having A as direct bond and B as C2 alkyl. Finally, the succinic acid linker has the structure of group Ia in claim 68 with q as 2.
This structure satisfies the limitations of present claims 1, 63, 65, 66, 67, 68, 74, 75, and 77.
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Thus Gardner anticipates present claims 1, 63, 65, 66, 67, 68, 74, 75, and 77.
Regarding the rejection of claim 69, claim 69 depends from claim 68 and further limits variable group M, which is only included in some structures recited in claim 68. Because claim 69 further limits structures in claim 68 that include group M, and because Gardner anticipates an alternative structure of claim 68 that does not include group M, claim 69 is also anticipated by Gardner.
Claims 1, 63, 66, 67, 68, 69, 70, 74, 75, 76, and 80 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Karnthaler-Benbakka (Karnthaler-Benbakka, C; et al. Chemistry and Biodiversity 2019, vol. 16, e1800520; cited in PTO-892).
Karnthaler-Benbakka teaches a cathepsin B-cleavable prodrug of the VEGFR inhibitor sunitinib (cover page, Abstract, line 5).
As one example, Karnthaler-Benbakka teaches compound 8 (p. 4, Scheme 1; structure shown below). Compound 8 has the therapeutic agent sunitinib with an amide as BG2 and the biopolymer glycine-phenylalanine-lysine with a carboxylic group as BG1. This structure’s linker has U as -N(R1)- with R1 as hydrogen, A as direct bond, B as aryl, C as direct bond, D as C1 alkyl, and V as -OC(=O)-, and wherein U is connected to BG1 via an amide bond and V is connected to BG2 via a carbamate. The examiner notes that although the glycine amino group in the biopolymer of compound 8 is further derivatized with a group not part of a typical biopolymer, because claim 1 recites the inclusive transitional phrase “comprising”, this additional derivatization would be permitted as part of the biopolymer of claim 1.
This compound satisfies the limitations of claims 1, 63, 66, 67, 68 (structure Ik with q as 0, u as 1, and M as aryl), 69 (with M as phenyl), 70 (structure
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with q as 0 and u as 1), 74, 75, and 76.
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Karnthaler-Benbakka further teaches compound 8 was dissolved in 10 mM sodium phosphate buffer (pH 7.4, 37°C) to assay its stability. Sodium phosphate buffer is a pharmaceutically acceptable carrier, and thus this composition satisfies the limitations of claim 80.
Thus Karnthaler-Benbakka anticipates claims 1, 63, 66, 67, 68, 69, 70, 74, 75, 76, and 80.
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, 63, 65-68, 71, 72, 74, 75, 77, and 79-81 are rejected under 35 U.S.C. 103 as being unpatentable over Wei (Wei, X.; et al. Molecular Pharmaceutics 2018, vol. 15, pp. 3456-3467; cited in IDS received June 11, 2025) Ikeya (U.S. pre-grant publication no. US 20070197465 A1; cited in IDS received March 17, 2025).
Wei teaches that although the Janus kinase (JAK) inhibitor, Tofacitinib (abbreviated as Tofa), is highly effective in treating rheumatoid arthritis (RA), it has dose-dependent toxicities that limit its clinical application (p. 3456, Abstract, lines 1-4). Wei teaches a prodrug design that targets arthritic joints to enhance Tofa’s therapeutic efficacy, which may provide an opportunity for future development of safer Tofa dosing regimens (p. 3456, Abstract, lines 4-8).
Wei teaches their prodrug is a conjugate of Tofa with HPMA via an acid-cleavable carbamate linker (p. 3456, Abstract, lines 8-11; structure shown on p. 3457, Scheme 1 and reproduced below). Wei further teaches the prodrug activation data demonstrates the carbamate linkage is cleaved under acidic environments (such as during inflammatory acidosis or at lysosomal pH values) (p. 3465, left column, first paragraph, lines 1-8).
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Wei further teaches that the therapeutic efficacy of a single dose of P-Tofa was compared to the dose-equivalent daily oral administration of Tofa in an adjuvant-induced arthritis (AA) rat model. Wei teaches that saline treated AA rats and age-matched healthy rats were used as controls, and observational analyses support the superior and sustained efficacy of a single dose P-Tofa treatment compared to the dose-equivalent daily Tofa administration in ameliorating joint inflammation (p. 3456, Abstract, lines 10-14). This is interpreted as treating inflammation associated with arthritis.
Wei concludes by stating that an HPMA-based nanoscale prodrug of P-Tofa has the potential to enhance the therapeutic efficacy and widen the therapeutic window of Tofa therapy in rheumatoid arthritis (p. 3456, Abstract, lines 19-21).
Wei does not teach the drug delivery system of the present claims that includes a biopolymer, as required by claim 1.
Ikeya teaches a hyaluronic acid (HA)-methotrexate conjugate useful as a therapeutic drug for joint diseases (cover page, Abstract, lines 1-3). Ikeya teaches that HA preparations are becoming more useful as a safer intra-articular injection alternative to steroid preparations for locally treating osteoarthritis (p. 1, [0003], lines 14-16). Ikeya further teaches that a high molecular weight type HA preparation having a molecular weight close to that of HA present in normal synovial fluid is approved in Japan with regard to an indication for the elimination of knee pain associated with rheumatoid arthritis (p. 1, [0005], lines 5-10).
Ikeya teaches that it is generally thought that HA preparations reverse the impaired viscosity and elasticity of synovial fluid resulting from the pathologic condition of osteoarthritis or rheumatoid arthritis to eliminate pain (p. 1, [0006], lines 1-4).
Finally, Ikeya teaches that methotrexate (abbreviated as MTX) is a drug that has the advantage of having excellent potency and relatively short time before the exertion of its effect. However, MTX is known to cause, in regions other than joint which is to be treated, serious side effects (p. 1, [0009], lines 4-9). Ikeya further teaches that a means for lessening the systemic side effects of MTX or a means for enabling MTX to exert its action only in the region where the development of the beneficial effect of MTX is required would provide a safer rheumatoid arthritis therapy (p. 2, left column, lines 2-7). Ikeya teaches a large number of HA-MTX conjugates with a variety of linker structures between HA and MTX (e.g., see examples summarized in Table 1, pp. 26-28), and teaches administering them to reduce join swelling in a collagen-induced arthritis model (p. 32, Table 4).
Finally, Ikeya teaches that the HA-MTX conjugate of their invention may be used in the form of a pharmaceutical composition by properly adding, to an effective amount thereof, a pharmaceutically acceptable carrier (p. 8, [0073], lines 1-4).
It would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the present application to substitute the HPMA polymer in the tofacitinib conjugate disclosed by Wei with the hyaluronic acid polymer disclosed by Ikeya. One of ordinary skill in the art would have been motivated to substitute the HPMA polymer in the tofacitinib conjugate disclosed by Wei with the hyaluronic acid polymer disclosed by Ikeya because Ikeya teaches that hyaluronic acid injections reverse the impaired viscosity and elasticity of synovial fluid resulting from the pathologic condition of osteoarthritis or rheumatoid arthritis to eliminate pain, and that injections of hyaluronic acid into the knee joint are widely used as arthritic therapy, and because Wei teaches the HPMA-tofacitinib conjugates as effective for controlling delivery of tofacitinib to arthritic joints. Accordingly, one of ordinary skill in the art would have contemplated substituting the HPMA in the conjugate of Wei for hyaluronic acid, because hyaluronic acid is also known to provide targeted delivery of anti-arthritic agents (e.g., of MTX as taught by Ikeya), and because Ikeya teaches benefits of hyaluronic acid injection for arthritic joints. Therefore, by substituting the HPMA in the conjugate of Wei for hyaluronic acid, one of ordinary skill in the art would have reasonably expected an additional benefit associated with hyaluronic acid injection into arthritic joints when delivering a conjugate comprising tofacitinib.
Regarding the specific functional groups used for conjugation of tofacitinib and hyaluronic acid, because Wei teaches conjugation of the linker structure to tofacitinib through a carbamate, which is cleaved under acidic conditions, and conjugation of the linker to the polymer backbone as an ester, one of ordinary skill in the art would have reasonably considered the same tofacitinib linker structure attached via ester bond to hyaluronic acid. Such a structure would produce a conjugate that satisfies all limitations of claims 1, 63, 65, 66, 67, 68 (wherein q is 2), 71-72, 74, 75, and 77. In addition, one of ordinary skill in the art would have contemplated formulating such a conjugate as an injection, which would satisfy the limitations of the formulation of claim 79 and the pharmaceutical composition of claim 80. Finally, because Wei teaches their conjugate as effective for treating inflammation, administration of this conjugate to treat arthritis-associated inflammation, a disorder recited in claim 81, would also have been obvious.
Therefore the invention taken as a whole is prima facie obvious.
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, 63-73, and 79-81 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 52-54, 57, 59-64 of co-pending U.S. patent application 18692340 (reference application, hereafter ‘340).
The present application and ‘340 are each assigned to Coval Biopharm (Shanghai) Co., Ltd. and include Hao Zhang, Weijiang Zhang, Lichun Feng, Guolong Wu, and Dafeng Li as inventors.
The amended claims received November 8, 2024 are cited in this provisional nonstatutory double patenting rejection.
Claim 1 of ‘340 claims a drug delivery system for locally delivering a therapeutic agent at a controlled rate as described in the claim. Claim 59 of ‘340 depends from claim 1 claims the structures shown below:
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127
320
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(p. 10)
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125
306
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(p. 12)
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118
306
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(p. 12)
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85
315
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(p. 12)
These compounds have the therapeutic agent triamcinolone acetonide conjugated to a polysaccharide via a linker. In the second, third, and fourth structure shown, the polysaccharide is hyaluronic acid.
These compounds anticipate present claims 1, 63, 64, 65, 66, 67, 71, and 72.
In addition, claim 57 of ‘340 claims the biopolymer is chondroitin sulfate, which renders obvious claim 73.
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the hyaluronic acid biopolymer of the structures above for chondroitin sulfate, in view of ‘340 claiming those specific drug delivery system structures, and further claiming their drug delivery system may include chondroitin sulfate as the biopolymer.
Claim 60 of ‘340 claims wherein the drug delivery system is locally administrated to a subject in need thereof, and claim 61 claims wherein the drug delivery system is locally administered to a subject in need thereof via injection, oral dosage form, via inhalation,
implant, or topical application, which anticipates claim
Claim 62 of ‘340 claims a pharmaceutical composition comprising the drug delivery system according to claim 1 and a pharmaceutically acceptable excipient.
Claim 63 of ‘340 claims a method of treating a disorder in a subject in need thereof, the method comprising administering to the subject a therapeutic effective amount of the drug delivery system according to claim 1, wherein the disorder is allergic diseases, autoimmune diseases, or inflammatory diseases, and claim 64 depends from claim 63 and claims the disorder is selected from a group that includes, for example, Neovascular (Wet) Age-Related Macular Degeneration (AMD), Macular Edema Following Retinal Vein Occlusion (RVO), Diabetic Macular Edema (DME), and Diabetic Retinopathy (DR).
In addition, claims 52, 53, and 54 of ‘340 claim additional linker structures as shown, several of which are the same of fall within the genus of present claims 68 (e.g., Ia, wherein the subscript value is 5; Ik with an M groups recited in claim 53 of ‘340), 69 (e.g., the specific M groups listed) and 70 (e.g.,
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81
129
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).
It would therefore have been prima facie obvious to one of ordinary skill in the art to substitute the linker of one of the drug delivery system structures claimed by ‘340 above for an alternative linker recited in claims 52, 53, or 54 of ‘340, because claim 59 of ‘340 claims those specific drug delivery structures, and claims 52-54 of ‘340 further claim their drug delivery system may include one of those linkers of claims 52-54. Accordingly, one of ordinary skill in the art would have contemplated derivatives of the drug delivery specific drug delivery system structures above with the alternative linker structures recited in claims 52-54 of ‘340.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Claims 1, 74, 75, and 77 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 59, and 63-64 of co-pending U.S. patent application 18692340 (reference application, hereafter ‘340) in view of Wei (Wei, X.; et al. Molecular Pharmaceutics 2018, vol. 15, pp. 3456-3467; cited in IDS received June 11, 2025).
Claims 1, 59, and 63-64 of ‘340 claim as described in the above provisional nonstatutory double patenting rejection. In addition, claim 64 claims the disorder is selected from the group that includes osteoarthritis and rheumatism.
The claims of ‘340 do not claim wherein the therapeutic agent is tofacitinib, as recited in present claims 74-75 and required by claim 77.
Wei teaches as described in the above rejection under 35 U.S.C. 103.
It would therefore have been prima facie obvious to substitute the therapeutic agent in a structure recited in claim 59 of ‘340 for tofacitinib because the claims of ‘340 claim a drug delivery system for controlled delivery of a therapeutic agent and a method of treating rheumatism using said agent, and because Wei teaches conjugates comprising tofacitinib covalently linked to another polymer, HPMC, for the purposes of locally treating rheumatoid arthritis. Accordingly, one of ordinary skill in the art would have reasonably contemplated a conjugate claimed by ‘340 with tofacitinib as the active agent for the purposes of locally treating rheumatoid arthritis.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not been patented.
Conclusion
No claims are allowed.
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/B.M.B./ Examiner, Art Unit 1693
/ANDREA OLSON/ Primary Examiner, Art Unit 1693