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 .
DETAILED ACTION
Claims 1-2, 15-19, 23-29, 32-35, 40 and 45 are pending in the instant application.
Claims 35, 40, and 45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/17/2026.
Claims 15 and 32-33 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 4/17/2026.
Restriction Response
Applicant’s election without traverse of Group I drawn to a conjugate or pharmaceutical composition of Formula III (X-Y-Z1)n-(Z2)p-(Z3)q (III) or Formula IIIa (X1-X2-Y-Z1)n-(Z2)p-(Z3)q (IIIa) and a species of Conjugate 21, wherein X1 is SEQ ID NO:91, X2 is SEQ ID NO:21, Y is
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(MP2H), Y’ is
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in the reply filed on 4/17/2026 is acknowledged.
Claims 1-2, 16-19, 23-29, and 34 are pending on the elected species.
Nucleotide and/or Amino Acid Sequence Disclosures
Objections to the Drawings and Specification
Fig. 2 and 4 do not include SEQ ID NOs for the sequences in the figure or the Brief Description of the Drawings.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Amino acid sequences of 4 or more amino acids require a sequence identifier. Fig. 2 and 4 do not include SEQ ID NOs for the sequences in the figure or the Brief Description of the Drawings. Amendment to the Drawings or Brief Description of the Drawings in the specification to include a SEQ ID NO: for the sequences is required.
Claim Rejections – 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
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.
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.
Claims 1-2, 16-19, 23-29, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over WO 2021/003223 (Jackson WM et al. IDS reference), Mojarradi H et al. (Uppsala Universitet Thesis 2010), US 2021/0046181 (Jackson WM et al. IDS reference), WO 2019/028382 (Achmatowicz M et al.), Chen X et al. (Adv Drug Deliv Rev. 2012 65(10):1357–1369).
‘223 taught a conjugate of Formula I: (X-Y)n-Z Formula (I) wherein each X is independently a peptide having a molecular weight of from about 5 kDa to about 200 kDa; each Y is independently a hydrophilic linker; Z is a biocompatible polymer having a molecular weight of from about 0.1 MDa to about 3 MDa; and subscript n is an integer from 10 to 1000 (abstract). A 0.1 MDa to about 3 MDa hyaluronic acid polymer would equal a polymer of about 250 to about 7,000 hyaluronic acid units of one polymer unit of 425.38 g/mol. ‘223 taught a multivalent peptide polymer conjugate comprising an anti-VEGF VHH with a Mal-PEG2-hydrazide (MP2H) linker conjugated to hyaluronic acid (page 57-58, Table 5), which corresponds to a conjugate of X-Y-Z1 and would have a structure of
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, wherein a Y of MP2H has the structure of
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. ‘223 taught the VHH anti-VEGF antibody as SEQ ID NO:17 (page 12, [0069])
‘223 taught a composition comprising a multivalent peptide polymer conjugate comprising an anti-VEGF VHH with a Mal-PEG2-hydrazide linker conjugated to hyaluronic acid and a pharmaceutically acceptable excipient was effective and improved potency (Fig. 5). ‘223 taught conjugation of hyaluronic acid to linkers wherein about 0.9 MDa (852 kDa) hyaluronic acid and the linker Mal-PEG2-hydrazide (MP2H) were mixed in an aqueous solution comprising HOBt and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) for conjugation (page 49, [0189] and Table 1). The 0.9 MDa (852 kDa) hyaluronic acid polymer molecular weight would equal a polymer of about 2,000 hyaluronic acid units wherein the molecular weight of one polymer unit is 425.38 g/mol. Valency values of between 13 and 171 were obtained which equal about 0.4% to 9% (13/2,000 to 171/2,000) with the MP2H linker and hyaluronic acid conjugate (page 50-51, Table 1). ‘223 taught reaction pH or equivalents of hydrazide linker, HOBt or sNHS, and EDC can be altered higher or lower in order to increase or decrease the number of thiol reactive small molecule linkers covalently linked per biopolymer (valency), wherein polymer valency with the MP2H linker were dose-responsive with linker concentration in the reaction (page 49-51, [0189-0190 and Table 1]). ‘223 taught hyaluronic acid conjugates exhibited a dose-responsive Kd value that was dependent on valency of the hyaluronic acid conjugate (Fig. 16). ‘223 taught conjugation of VHH to hyaluronic acid that contained a MP2H linker was not 100% efficient (page 57-58, [0201] and Table 5). Thus, the polymer contained unreacted MP2H linkers.
‘223 did not teach: 1) a Z2 moiety in the structure or a Z3 moiety conjugated to a linker without a peptide conjugate; 2) including a linker comprised of SEQ ID NO:21; or 3) a conjugate of (X-Y-Z1)n-(Z2)p-(Z3)q, but this is obvious in view of Mojarradi, ‘181, ‘382, and Chen.
Mojarradi taught there has been a great interest to attach functional groups to HA and carbodiimides are used (page 3-4, bridging paragraph). Mojarradi taught 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) is the most commonly used carbodiimide (page 4, paragraph 3). Mojarradi taught EDC as a coupling agent for conjugation of compounds to hyaluronic acid
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(page 4-5, Schemes 1-2).
Mojarradi taught HA + EDC yielded compound 3
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(page 5). Mojarradi taught 3 is not stable in solution and can undergo cyclic electronic displacement (N to O displacement), giving the energetically more favored N-acylurea 4, see F. N-acylurea is unreactive towards primary amines and is covalently attached to HA (page 6 last paragraph).
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(page 6). Mojarradi taught changing the concentration of EDC and conjugate moiety increased the HA-N-acylurea moiety and HA-conjugate moiety (page 34-35, Table 8). Mojarradi taught HA-N-acylurea is formed in all reactions, and the highest amount is when high ratios of EDC and conjugate moiety TYR are used, which is necessary to achieve a high degree of substitution (page 34-35, Table 8).
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‘181 taught a hyaluronic acid polymer conjugated to an anti-inflammatory peptide via a thiol (Fig. 1) and that an anti-inflammatory peptide VHH conjugated to a hyaluronic acid polymer had an increased potency (Fig. 4A-D) and half-life (Fig. 5A-B). ‘181 taught peptides were engineered to include a cysteine available for conjugation at either the C-terminus or the N-terminus and that a rigid peptide linker may be included as a part of the anti-inflammatory peptide sequence (page 14-15, [0138]). ‘181 taught a reaction comprising hyaluronic acid, EDC, and a maleimide linker produced a hyaluronic acid conjugate wherein the product of the reaction was polymer with the addition of maleimide reactive groups at 0.5-5% of the available carboxylic acid reactive groups (page 14, [0137]).
‘382 taught methods of conjugation of cysteine antibody conjugation (abstract), wherein peptidyl linkers containing a cysteine residue can be used for conjugation to a maleimide functionalized moiety and wherein the peptidyl linker is a rigid linker with the sequence AEAAAKEAAAKEAAAKAGG (pages 54-55, [0256-0257]).
Chen taught a rigid linker comprising AEAAAKEAAAKA can improve biological activity (page 1360, Table 3).
Regarding instant claims 1-2, 16-19, 23-29, and 34, it would have been obvious for a person having ordinary skill in the art to take the composition of ‘223 comprising a multivalent peptide polymer conjugate comprising an anti-VEGF VHH with a Mal-PEG2-hydrazide linker conjugated to hyaluronic acid and a pharmaceutically acceptable excipient was effective and improved potency, wherein the anti-VEGF VHH comprises ‘223 SEQ ID NO:17, wherein the structure is (X-Y-Z1)n-(Z3)q – and:
Produce a conjugate of (X-Y-Z1)n-(Z2)p-(Z3)q, wherein the molecular weight is from about 0.1 MDa to about 3 MDa; and subscript n is an integer from 10 to 1,000 and q between about 250 to about 7,000, wherein X is the VHH, Y is a Mal-PEG2-hydrazide linker, Z1 is hyaluronic acid, Z2 has the structure
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, and Z3 has the structure
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in view of ‘223 and Mojarradi;
Include a peptide linker in the conjugate to produce a Formula of (X1-X2-Y-Z1)n-(Z2)p-(Z3)q, wherein X1 is the VHH and X2 is a peptide linker with the sequence AEAAAKEAAAKEAAAKAGC in view of ‘181, ‘382, and Chen;
Produce a conjugate wherein the subscript n is an integer from 10 to 1000 and the sum of n, p, and q is between about 250 to about 7,000 in view of ‘223 and n is about 0.4%-9% or 0.5-5% of the sum of n, p, and q in view of ‘223, Mojarradi, and ‘181;
Produce a conjugate wherein the subscript p is an integer from 10 to 1000 and the sum of n, p, and q is between about 250 to about 7,000 in view of ‘223 and n is about 0.4%-9% or 0.5-5% of the sum of n, p, and q in view of ‘223, Mojarradi, and ‘181; and
Produce a conjugate wherein the subscript q is the remainder of and the sum of n and p, wherein q is (about 250 to about 7,000) – (n + p) and the percentage of q is (100%) – (the percentage of n + p) in view of ‘223, Mojarradi, and ‘181.
This is obvious because:
1a) Regarding the structure of Z2, the conjugation of ‘223 comprises a reaction of hyaluronic acid to linkers wherein hyaluronic acid and the linker Mal-PEG2-hydrazide (MP2H) were mixed in an aqueous solution comprising 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) for conjugation, wherein the reaction of hyaluronic acid and EDC was taught by Mojarradi to also produce a hyaluronic acid EDC N-acylurea conjugate within the polymer wherein the structure is
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as taught by Mojarradi;
1b) Regarding the structure of Z3, the structure of
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represents a hyaluronic acid moiety that is conjugated to the MP2H linker and not further conjugated to VHH and was recognized to be within the conjugate of ‘223 wherein ‘223 taught conjugation of VHH to hyaluronic acid that contained a MP2H linker was not 100% efficient. Thus, the polymer contained unreacted MP2H linkers;
2a) ‘181 taught: i) a hyaluronic acid polymer conjugated to an anti-inflammatory peptide via a thiol, wherein an anti-inflammatory peptide VHH conjugated to a hyaluronic acid polymer had an increased potency and half-life; ii) the peptides were engineered to include a cysteine available for conjugation at the C-terminus; and iii) a rigid peptide linker may be included as a part of the anti-inflammatory peptide sequence;
2b) ‘382 taught methods of conjugation of cysteine antibody conjugation, wherein peptidyl linkers containing a cysteine residue can be used for conjugation to a maleimide functionalized moiety and wherein the peptidyl linker is a rigid linker with the sequence -AEAAAKEAAAKEAAAKAGG;
2c) Chen taught a rigid linker comprising AEAAAKEAAAKA can improve biological activity;
2d) Thus, inclusion of a cysteine at the C-terminus of a rigid linker of AEAAAKEAAAKEAAAKAGG would yield a sequence of AEAAAKEAAAKEAAAKAGC, wherein a linker comprising AEAAAKEAAAKA is known to improve biological activity;
3a) Regarding n, ‘223 taught: i) the conjugate with a subscript n is an integer from 10 to 1000 and that higher valency bioconjugate polymers are dose-responsively effective: and ii) valency values of between 13 and 171 were obtained which equal about 0.4% to 9% (13/2,000 to 171/2,000) with the MP2H linker and hyaluronic acid conjugate.
3b) Regarding the sum of n, p, and q, ‘223 taught a 0.1 MDa to about 3 MDa hyaluronic acid polymer which would equal a polymer of about 250 to about 7,000 hyaluronic acid units of one polymer unit of 425.38 g/mol. Thus the total of n, p, and q of 250 to about 7,000 is obvious;
3c) ‘181 taught a reaction comprising hyaluronic acid, EDC, and a maleimide linker produced a hyaluronic acid conjugate wherein the product of the reaction was polymer with the addition of maleimide reactive groups at 0.5-5% of the available carboxylic acid reactive groups, wherein the hyaluronic acid bioconjugates were effective;
4a) Mojarradi taught: i) changing the concentration of EDC and conjugate moiety increased the HA-N-acylurea moiety and HA-conjugate moiety; ii) HA-N-acylurea is formed in all reactions, and the highest amount is when high ratios of EDC and conjugate moiety TYR are used, which is necessary to achieve a high degree of substitution; and iii) varying EDC and amine conjugate moiety concentrations can achieve similar concentrations of conjugate and N-acylurea; and
4b) Altering EDC and MP2H linker concentrations in view of Mojarradi would allow equal n and p values;
5a) ‘223 taught reaction pH or equivalents of hydrazide linker, HOBt or sNHS, and EDC can be altered higher or lower in order to increase or decrease the number of thiol reactive small molecule linkers covalently linked per biopolymer (valency), wherein polymer valency with the MP2H linker were dose-responsive with linker concentration in the reaction. Conjugation of MP2H linkers to a hyaluronic acid polymer that didn’t form the N-acylurea moiety would yield MP2H throughout the polymer that was not attached to the VHH-linker moiety in Z1.
There is a reasonable expectation of success because:
1a) Regarding the structure of Z2, the conjugation of ‘223 comprises a reaction of hyaluronic acid to linkers wherein hyaluronic acid and the linker Mal-PEG2-hydrazide (MP2H) were mixed in an aqueous solution comprising 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) for conjugation, wherein the reaction of hyaluronic acid and EDC was taught by Mojarradi to also produce a hyaluronic acid EDC N-acylurea conjugate within the polymer wherein the structure is
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as taught by Mojarradi;
1b) Regarding the structure of Z3, the structure of
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represents a hyaluronic acid moiety that is conjugated to the MP2H linker and not further conjugated to VHH and was recognized to be within the conjugate of ‘223 wherein ‘223 taught conjugation of VHH to hyaluronic acid that contained a MP2H linker was not 100% efficient. Thus, the polymer contained unreacted MP2H linkers;
2a) ‘181 taught: i) a hyaluronic acid polymer conjugated to an anti-inflammatory peptide via a thiol, wherein an anti-inflammatory peptide VHH conjugated to a hyaluronic acid polymer had an increased potency and half-life; ii) the peptides were engineered to include a cysteine available for conjugation at the C-terminus; and iii) a rigid peptide linker may be included as a part of the anti-inflammatory peptide sequence;
2b) ‘382 taught methods of conjugation of cysteine antibody conjugation, wherein peptidyl linkers containing a cysteine residue can be used for conjugation to a maleimide functionalized moiety and wherein the peptidyl linker is a rigid linker with the sequence AEAAAKEAAAKEAAAKAGG;
2c) Chen taught a rigid linker comprising AEAAAKEAAAKA can improve biological activity;
2d) Thus, inclusion of a cysteine at the C-terminus of a rigid linker of AEAAAKEAAAKEAAAKAGG would yield a sequence of AEAAAKEAAAKEAAAKAGC, wherein a linker comprising AEAAAKEAAAKA is known to improve biological activity;
3a) Regarding n, ‘223 taught: i) the conjugate with a subscript n is an integer from 10 to 1000 and that higher valency bioconjugate polymers are dose-responsively effective: and ii) valency values of between 13 and 171 were obtained which equal about 0.4% to 9% (13/2,000 to 171/2,000) with the MP2H linker and hyaluronic acid conjugate.
3b) Regarding the sum of n, p, and q, ‘223 taught a 0.1 MDa to about 3 MDa hyaluronic acid polymer which would equal a polymer of about 250 to about 7,000 hyaluronic acid units of one polymer unit of 425.38 g/mol, wherein 0.9 MDa hyaluronic acid conjugates were shown to be effective. Thus the total of n, p, and q of 250 to about 7,000 has a reasonable expectation of success;
3c) ‘181 taught a reaction comprising hyaluronic acid, EDC, and a maleimide linker produced a hyaluronic acid conjugate wherein the product of the reaction was polymer with the addition of maleimide reactive groups at 0.5-5% of the available carboxylic acid reactive groups, wherein the hyaluronic acid bioconjugates were effective;
4a) Mojarradi taught: i) changing the concentration of EDC and conjugate moiety increased the HA-N-acylurea moiety and HA-conjugate moiety; ii) HA-N-acylurea is formed in all reactions, and the highest amount is when high ratios of EDC and conjugate moiety TYR are used, which is necessary to achieve a high degree of substitution; and iii) varying EDC and a primary amine conjugate moiety concentrations can achieve similar concentrations of conjugate and N-acylurea; and
4b) Altering EDC and MP2H linker concentrations in view of Mojarradi would allow equal n and p values.
5a) ‘223 taught reaction pH or equivalents of hydrazide linker, HOBt or sNHS, and EDC can be altered higher or lower in order to increase or decrease the number of thiol reactive small molecule linkers covalently linked per biopolymer (valency), wherein polymer valency with the MP2H linker were dose-responsive with linker concentration in the reaction. Conjugation of MP2H linkers to a hyaluronic acid polymer that didn’t form the N-acylurea moiety would yield MP2H throughout the polymer that was not attached to the VHH-linker moiety in Z1.
This would produce a conjugate of (X1-X2-Y-Z1)n-(Z2)p-(Z3)q (instant claims 1-2)of an anti-VEGF VHH (X1) conjugated to a rigid peptide linker (X2) and a Mal-PEG2-hydrazide linker (Y) conjugated to hyaluronic acid and a pharmaceutically acceptable excipient (instant claim 34), wherein the anti-VEGF VHH comprises ‘223 SEQ ID NO:17, which comprises a sequence identical to the elected species of instant SEQ ID NO:91 (instant claim 16), wherein the rigid peptide linker comprises AEAAAKEAAAKEAAAKAGC, which contains an alpha helix and is identical to the elected species of instant SEQ ID NO:21 (instant claim 17), wherein the molecular weight is from about 0.1 MDa to about 3 MDa; and subscript n and p are individually an integer from 10 to 1,000 and q is between about 250 to about 7,000, wherein Y is a Mal-PEG2-hydrazide linker with the structure
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(instant claims 18-19), wherein X1-Y-Z1 has the structure
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, Z2 has the structure
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(instant claims 23-24), and Z3 has the structure
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, wherein the subscript n and p individually are about 0.5-5% or 0.4% to 9% of the sum of n, p, and q, which is less than about 2% to 15% (instant claims 25-29), and wherein q is about 80% to about 99%.
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 1-2, 16-19, 23-29, and 34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of copending Application No. 18/856,982 in view of Mojarradi H et al. (Uppsala Universitet Thesis 2010).
‘982 taught methods of treating uveitis in a subject in need thereof with a polymer in copending claims 1-28, wherein the method used: 1) a composition comprising a hyaluronic acid conjugate of Formula Va (X-Y)n-Z in copending claim 1, wherein the anti-inflammatory peptide conjugate X was a VHH of VEGF of ‘982 SEQ ID NO:91 or anti-TNFa or anti-IL-1b SEQ ID NO:101-106 in copending claim 4; or 2) a composition comprising a hyaluronic acid conjugate of Formula Va (X1-X2-Y)n-Z in copending claim 10, wherein an alpha helix peptide linker X2 of SEQ ID NO:21 was bound to an anti-inflammatory peptide conjugate X1 in copending claim 11.
‘982 taught a conjugate of Formula VI (X-Y-Z1)n-(Z2)p-(Z3)q, having a molecular weight of about 0.1 MDa to about 3 MDa wherein X is independently an anti-TNF-a or anti-IL-1b peptide,
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‘982 did not teach a single embodiment of the elected species, but this is obvious in view of the options of anti-inflammatory peptides and linkers in other copending claims and the EDC N-acylurea conjugate of Mojarradi.
Mojarradi taught there has been a great interest to attach functional groups to HA and carbodiimides are used (page 3-4, bridging paragraph). Mojarradi taught 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) is the most commonly used carbodiimide (page 4, paragraph 3). Mojarradi taught EDC as a coupling agent for conjugation of compounds to hyaluronic acid
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(page 4-5, Schemes 1-2).
Mojarradi taught HA + EDC yielded compound 3
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(page 5). Mojarradi taught 3 is not stable in solution and can undergo cyclic electronic displacement (N to O displacement), giving the energetically more favored N-acylurea 4, see F. N-acylurea is unreactive towards primary amines and is covalently attached to HA (page 6 last paragraph).
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(page 6). Mojarradi taught changing the concentration of EDC and conjugate moiety increased the HA-N-acylurea moiety and HA-conjugate moiety (page 34-35, Table 8). Mojarradi taught HA-N-acylurea is formed in all reactions, and the highest amount is when high ratios of EDC and conjugate moiety TYR are used, which is necessary to achieve a high degree of substitution (page 34-35, Table 8).
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Regarding instant claims 1-2, 16-19, 23-29, and 34, it would have been obvious for a person having ordinary skill in the art to take the composition of ‘982 copending claim 29 – and:
Exchange the anti-TNF-a or anti-IL-1b peptides for an anti-inflammatory peptide of SEQ ID NO:91 in copending claim 4, wherein copending claim 4 further taught anti-TNF-a or anti-IL-1b peptides were anti-inflammatory;
Include an alpha-helix peptide linker of X2 of SEQ ID NO:21 in copending claim 11, wherein copending claim 11 further taught an alpha-helix peptide linker conjugated to an anti-inflammatory peptide;
Produce a Z2 of
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in the conjugate in view of Mojarradi; and
Include a pharmaceutically acceptable excipient in a composition with the conjugate in view of it being used in methods of treatment.
This is obvious because:
copending claim 4 taught anti-TNF-a or anti-IL-1b peptides were anti-inflammatory and could be used in a treatment method so exchange of one anti-inflammatory peptide for another in the conjugate would be obvious;
copending claim 11 taught an alpha-helix peptide linker conjugated to an anti-inflammatory peptide could be used in a treatment method;
the reaction of hyaluronic acid and EDC for conjugation reactions was taught by Mojarradi to also produce a hyaluronic acid EDC N-acylurea conjugate within the polymer wherein the structure is
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as taught by Mojarradi; and
a pharmaceutically acceptable excipient in a composition with the conjugate would allow the conjugate to be used in methods of treatment.
There is a reasonable expectation of success because:
copending claim 4 taught anti-TNF-a or anti-IL-1b peptides were anti-inflammatory and could be used in a treatment method so exchange of one anti-inflammatory peptide for another in the conjugate would have a reasonable expectation of success;
copending claim 11 taught an alpha-helix peptide linker conjugated to an anti-inflammatory peptide could be used in a treatment method; and
the reaction of hyaluronic acid and EDC for conjugation reactions was taught by Mojarradi to also produce a hyaluronic acid EDC N-acylurea conjugate within the polymer wherein the structure is
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as taught by Mojarradi; and
a pharmaceutically acceptable excipient in a composition with the conjugate would allow the conjugate to be used in methods of treatment.
This would produce a conjugate of (X1-X2-Y-Z1)n-(Z2)p-(Z3)q (instant claims 1-2)of an anti-VEGF VHH (X1) conjugated to a rigid peptide linker (X2) and a Mal-PEG2-hydrazide linker (Y) conjugated to hyaluronic acid and a pharmaceutically acceptable excipient (instant claim 34), wherein the anti-VEGF VHH comprises ‘982 SEQ ID NO:91, which comprises a sequence identical to the elected species of instant SEQ ID NO:91 (instant claim 16), wherein the rigid peptide linker comprises AEAAAKEAAAKEAAAKAGC, which contains an alpha helix and is identical to the elected species of instant SEQ ID NO:21 (instant claim 17), wherein the molecular weight is from about 0.1 MDa to about 3 MDa, wherein Y is a Mal-PEG2-hydrazide linker with the structure
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(instant claims 18-19), wherein X1-Y-Z1 has the structure
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, Z2 has the structure
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(instant claims 23-24), and Z3 has the structure
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with an unreacted organic linker, wherein
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(instant claims 25-29), and wherein q is less than about 75% to about 99%.
This is a provisional nonstatutory double patenting rejection.
Claims 1-2, 16-19, 23-29, and 34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 11, 14-18, 22-30, 32, 34-38, and 43 of copending Application No. 18/300,823 in view of WO 2021/003223 (Jackson WM et al. IDS reference) and Mojarradi H et al. (Uppsala Universitet Thesis 2010).
‘823 taught compositions of VHH peptide sequences and a method of preparation which included anti-VEGF VHH peptides in copending claims 1, 11, and 14-16. ‘823 taught biocompatible polymer conjugates in copending claims 17-18, 22-30, 32, 34-38, and 43. ‘823 taught a random polymer conjugate of Formula IIIa (X1-X2-Y-Z1)n-(Z2)p-(Z3)q, having a molecular weight of about 0.8 MDa, wherein
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in copending claim 35. ‘823 taught conjugates in a pharmaceutical composition with a pharmaceutically acceptable excipient in copending claim 37.
‘823 did not teach a single embodiment of the elected species, but this is obvious in view of ‘223 and Mojarradi.
‘223 taught a conjugate of Formula I: (X-Y)n-Z Formula (I) wherein each X is independently a peptide having a molecular weight of from about 5 kDa to about 200 kDa; each Y is independently a hydrophilic linker; Z is a biocompatible polymer having a molecular weight of from about 0.1 MDa to about 3 MDa; and subscript n is an integer from 10 to 1000 (abstract). A 0.1 MDa to about 3 MDa hyaluronic acid polymer would equal a polymer of about 250 to about 7,000 hyaluronic acid units of one polymer unit of 425.38 g/mol. ‘223 taught a multivalent peptide polymer conjugate comprising an anti-VEGF VHH with a Mal-PEG2-hydrazide (MP2H) linker conjugated to hyaluronic acid (page 57-58, Table 5), which corresponds to a conjugate of X-Y-Z1 and would have a structure of
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, wherein a Y of MP2H has the structure of
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. ‘223 taught the VHH anti-VEGF antibody as SEQ ID NO:17 (page 12, [0069])
‘223 taught a composition comprising a multivalent peptide polymer conjugate comprising an anti-VEGF VHH with a Mal-PEG2-hydrazide linker conjugated to hyaluronic acid and a pharmaceutically acceptable excipient was effective and improved potency (Fig. 5). ‘223 taught conjugation of hyaluronic acid to linkers wherein about 0.9 MDa (852 kDa) hyaluronic acid and the linker Mal-PEG2-hydrazide (MP2H) were mixed in an aqueous solution comprising HOBt and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) for conjugation (page 49, [0189] and Table 1). The 0.9 MDa (852 kDa) hyaluronic acid polymer molecular weight would equal a polymer of about 2,000 hyaluronic acid units wherein the molecular weight of one polymer unit is 425.38 g/mol. Valency values of between 13 and 171 were obtained which equal about 0.4% to 9% (13/2,000 to 171/2,000) with the MP2H linker and hyaluronic acid conjugate (page 50-51, Table 1). ‘223 taught reaction pH or equivalents of hydrazide linker, HOBt or sNHS, and EDC can be altered higher or lower in order to increase or decrease the number of thiol reactive small molecule linkers covalently linked per biopolymer (valency), wherein polymer valency with the MP2H linker were dose-responsive with linker concentration in the reaction (page 49-51, [0189-0190 and Table 1]). ‘223 taught hyaluronic acid conjugates exhibited a dose-responsive Kd value that was dependent on valency of the hyaluronic acid conjugate (Fig. 16). ‘223 taught conjugation of VHH to hyaluronic acid that contained a MP2H linker was not 100% efficient (page 57-58, [0201] and Table 5). Thus, the polymer contained unreacted MP2H linkers.
Mojarradi taught there has been a great interest to attach functional groups to HA and carbodiimides are used (page 3-4, bridging paragraph). Mojarradi taught 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide (EDC) is the most commonly used carbodiimide (page 4, paragraph 3). Mojarradi taught EDC as a coupling agent for conjugation of compounds to hyaluronic acid
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(page 4-5, Schemes 1-2).
Mojarradi taught HA + EDC yielded compound 3
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(page 5). Mojarradi taught 3 is not stable in solution and can undergo cyclic electronic displacement (N to O displacement), giving the energetically more favored N-acylurea 4, see F. N-acylurea is unreactive towards primary amines and is covalently attached to HA (page 6 last paragraph).
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(page 6). Mojarradi taught changing the concentration of EDC and conjugate moiety increased the HA-N-acylurea moiety and HA-conjugate moiety (page 34-35, Table 8). Mojarradi taught HA-N-acylurea is formed in all reactions, and the highest amount is when high ratios of EDC and conjugate moiety TYR are used, which is necessary to achieve a high degree of substitution (page 34-35, Table 8).
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Regarding instant claims 1-2, 16-19, 23-29, and 34, it would have been obvious for a person having ordinary skill in the art to take the conjugate of copending claim 35
and a pharmaceutical composition and a pharmaceutically acceptable excipient of copending claim 37 – and:
Exchange the peptide of X1 for an anti-VEGF VHH comprising ‘223 SEQ ID NO:17 wherein ‘223 taught hyaluronic acid conjugates with anti-VEGF VHH were effective and improved potency,
Produce a Z2 of
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in the conjugate in view of Mojarradi; and
Produce a Z3 with unreacted linker Y’ which was taught as an option.
This is obvious because:
‘223 taught an anti-VEGF VHH comprising ‘223 SEQ ID NO:17 and wherein hyaluronic acid conjugates with anti-VEGF VHH were effective and improved potency,
the reaction of hyaluronic acid and EDC for conjugation reactions was taught by Mojarradi to also produce a hyaluronic acid EDC N-acylurea conjugate within the polymer wherein the structure is
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as taught by Mojarradi;; and
Z3 with unreacted linker Y’ which was taught as an option.
There is a reasonable expectation of success because:
‘223 taught an anti-VEGF VHH comprising ‘223 SEQ ID NO:17 and wherein hyaluronic acid conjugates with anti-VEGF VHH were effective and improved potency,
the reaction of hyaluronic acid and EDC for conjugation reactions was taught by Mojarradi to also produce a hyaluronic acid EDC N-acylurea conjugate within the polymer wherein the structure is
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as taught by Mojarradi;; and
Z3 with unreacted linker Y’ which was taught as an option.
This would produce a conjugate of (X1-X2-Y-Z1)n-(Z2)p-(Z3)q (instant claims 1-2) of an anti-VEGF VHH (X1) conjugated to a rigid peptide linker (X2) and a Mal-PEG2-hydrazide linker (Y) conjugated to hyaluronic acid and a pharmaceutically acceptable excipient (instant claim 34), wherein the anti-VEGF VHH comprises ‘223 SEQ ID NO:17, which comprises a sequence identical to the elected species of instant SEQ ID NO:91 (instant claim 16), wherein the rigid peptide linker comprises AEAAAKEAAAKEAAAKAGC, which contains an alpha helix and is identical to the elected species of instant SEQ ID NO:21 (instant claim 17), wherein the molecular weight is about 0.9 MDa, wherein Y is a Mal-PEG2-hydrazide linker with the structure
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(instant claims 18-19), wherein X1-Y-Z1 has the structure
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, Z2 has the structure
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(instant claims 23-24), and Z3 has the structure
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with an unreacted organic linker, wherein
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(instant claims 25-29), and wherein q is less than about 89% to about 99%.
This is a provisional nonstatutory double patenting rejection.
Conclusion
Claims 1-2, 16-19, 23-29, and 34 are rejected.
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/J.J.S./Examiner, Art Unit 1643
/Karen A. Canella/Primary Examiner, Art Unit 1643
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