DETAILED ACTION
Status of claim rejections
The rejections of record under 35 USC 103 are maintained in view of Applicant’s arguments in the response filed 02/20/2026.
The non-statutory double patenting rejections of record are maintained in view of Applicant’s arguments in the response filed 02/20/2026.
Claim Interpretation
Claim 1 requires, inter alia, a compound having a structure of X-Y-Z, wherein X is an extracellular matrix component, Y is a non-releasable linker, and Z is a bone -targeting molecule polypeptide or a pharmaceutically acceptable salt thereof that binds to hydroxyapatite. The claim has been amended to recite “X is an extracellular matrix component or a fragment of an extracellular matrix component comprising an integrin ligand that retains integrin ligand receptor-binding activity without cleavage of Y or from Z”. This claim has been interpreted under broadest reasonable interpretation to mean that X (the ligand) retains functional activity when it is fused to Z directly or when linked to Z through Y. The rejections below reflect this interpretation.
Claim 1 recites, inter alia, that “Y is absent or a non-releasable linker” (emphasis added). The term “non-releasable linker” is not defined in the specification as instantly filed. As such, the examiner has interpreted the limitation under broadest reasonable interpretation (BRI) to encompass (including but not limited to) linkers that do not readily release the drug at the target site, and to exclude linkers such as (but not limited to) protease-sensitive linkers and acid sensitive linkers.
New Claim Rejection - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 20-27, 30-32, 37-38 and 41-42 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See, e.g., Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010); University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 USPQ2d 1398 (Fed. Cir. 1997) at 1406; Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021) ("[T]he written description must lead a person of ordinary skill in the art to understand that the inventor possessed the entire scope of the claimed invention. Ariad, 598 F.3d at 1353–54 ('[T]he purpose of the written description requirement is to ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor's contribution to the field of art as described in the patent specification.' (internal quotation marks omitted).").
A "representative number of species" means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). The issue is whether the skilled artisan would understand inventor to have invented, and been in possession of, the invention as claimed.
Claim 1 requires, inter alia, a compound having a structure of X-Y-Z, wherein X is an extracellular matrix component, Y is a non-releasable linker, and Z is a bone -targeting molecule polypeptide or a pharmaceutically acceptable salt thereof that binds to hydroxyapatite. The claim has been amended to recite “X is an extracellular matrix component or a fragment of an extracellular matrix component comprising an integrin ligand that retains integrin ligand receptor-binding activity without cleavage of Y or from Z”. From the claim language, the phrase “intergrin ligand that retains integrin ligan receptor-binding activity” modifies both the “extracellular matrix component” or “the fragment thereof” as instantly claimed. Thus, the examiner has interpreted the claim to require a broad genus of fragments of integrin ligands that retain their functional binding capacity when used in a peptide conjugate composition. This is problematic because the specification fails to teach an art-recognized correlation between structure and function.
In support of the claimed genus of integrin ligands, the specification discloses the use of, e.g., collagen fragments (chemotactic collagen fragment, para 0224-227; P-15 collagen fragments (example 17; para 0229-34; and DGEA fragment; example 18), SPARC113, P3 (bone sialoprotein), and integrin alpha (ITGA5) ligand (example 19), used in various peptide conjugates linked using 4 miniPEGs (mp4) to observe in vivo fracture healing efficacy of the bone targeting moiety (examples 20-24). The generation of the specific conjugates disclosed in the examples of the specification containing use of specific integrin ligands (full length and fragments) cannot reasonably be extrapolated and applied to support possession of the entire claimed genus of integrin ligand fragments that retain their functional activity when bound directly to or via a noncleavable linker to bone targeting peptides, because no one species, combination, or variant accounts for the variability amongst the claimed genus. As in Ariad, merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species. “A patent is not a hunting license. It is not a reward for the search, but compensation for its successful conclusion.” Brenner v. Manson, 383 U.S. 519, 536 (1966).
There is also no disclosure as to what structure(s) must be present or retained on the fragment of integrin ligands that would result in a functional fragment for use in the conjugate. Applicant has not provided any information or steps as to how one of ordinary skill would obtain a functional fragment of the integrin ligands, or any sufficient distinguishing structure-function relationship with respect to the broad genus as claimed. this data cannot be extrapolated to any and all possible fragments of the integrin ligands. Even with knowledge in the art regarding modification of genes, one of ordinary skill would not reasonably know, based on the disclosure provided, what structures or functions are required for the outcome of creating a functional fragment of any integrin ligand without a recognized correlation between structure and function. Applicant has provided no information as to how a fragment would be considered “functional”, distinguishing characteristics, or the amount of biological activity that is required for the fragment to work. There is no sufficient structure-function relationship with respect to the broad genus as claimed.
The specification, then, is considered devoid of sufficiently detailed, relevant, identifying characteristics demonstrating that Applicant was in possession of the claimed genus of integrin ligand fragments, i.e., additional complete or partial structures, other physical and/or chemical properties, functional characteristics coupled with a known or disclosed correlation between function and structure, or some combination thereof demonstrating possession of the claimed genus.
Maintained Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
First rejection
Claims 20-23, 26, 30-32, 37-38, and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Marie et al. (WO 2010/015938, hereinafter “Marie”; prior art of record) in view of Wang et al. (Bioconjugate, 14:853-859 (2003), IDS-NPL, hereinafter “Wang”; prior art of record), and further in view of Low et al (Bone-targeted acid-sensitive doxorubicin conjugate micelles as potential osteosarcoma therapeutics. Bioconjug Chem. 2014 Nov 19;25(11):2012-20. doi: 10.1021/bc500392x. Epub 2014 Oct 22; hereinafter “Low”; prior art of record).
In view of Applicant’s species election, the prior art was searched for a compound having a structure of X-Y-Z, wherein X is an integrin ligand, Y is a non-releasable linker, and Z is a polypeptide; or a pharmaceutically acceptable salt thereof.
Marie teaches a composition to promote bone repair or regeneration comprising an integrin alpha 5 (ITGA5) agonist in the form of a cyclic peptide ligand having the sequence CRRETAWAC, i.e., RRETAWA comprising terminal cysteines to form a disulfide bridge, which corresponds to at least “ITGaS cys” (i.e., X is an extracellular matrix component as in claim 20; Abstract; page 4, lines 10-21; page 10, lines 33-35; page 11, lines 1-2; claim 1). Marie further teaches that the ligand can be “chemically associated with a bone seeking agent such as calcium, strontium or a bisphosphonate to target the bone tissue” (i.e., Z is a bone targeting agent as in claim 20; page 4, lines 13-15).
Marie does not explicitly teach a bone targeting agent polypeptide, for example, containing glutamic or aspartic acid residues.
However, Wang teaches that drugs can be targeted to bone using aspartic acid or glutamic acid residues (page 853, second column; page 854, Scheme 1, reproduced, in part, below).
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Wang further teaches, e.g., a D-aspartic acid octapeptide used for bone-targeting can be conjugated to a drug through a polyethylene glycol (PEG) linker (page 855, Scheme 2), using fluorescein isothiocyanate (FITC)) (see pg. 855).
One of ordinary skill in the art would have been motivated to modify Marie in view of Wang in order to advantageously target the ligand to bone using D-aspartic acid octapeptide as taught by Wang with a reasonable expectation of success. As the instant claims require a bone-targeting moiety containing aspartic and glutamic residues, one of ordinary skill would have been motivated to perform a simple substitution of one known element (the bone targeting molecules of Marie) with another (the D-aspartic octapeptide of Wang) with a reasonable expectation of successful creation of a drug capable of targeting bone.
Moreover, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of aspartic acid or glutamic acid residues, for use in the compound taught by Marie and Wang with a reasonable expectation of success, especially since the claims contemplates any number of aspartic acid residues and glutamic residues and nothing in the Specification reasonably evidences the criticality or unexpected nature of a particular number of each.
None of the references explicitly teaches the linker Y is non-releasable.
However, Low (in the same or similar field of endeavor of bone targeting therapeutics) teaches the creation of a bone-targeting drug that contains 8-Amino-3,6-dioxaoctanoic acid (miniPEG) (non-releasable linker as in claim 20; 8-amino-3,6-dioxaoctanoic acid units as in claim 42) which was placed between 11-aminoundecanoic acid (AUA) moieties and the D-Asp8 bone-targeting moiety for additional flexibility of the backbone (see scheme 1 and 2; pg. 2013); pg. 2014, col 1, paragraph 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to modify the compound of Marie and Wang and include 8-Amino-3,6-dioxaoctanoic acid (miniPEG) with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Low explicitly teaches that 8-amino-3,6-dioxaoctanoic acid can advantageously be used in bone-targeting therapeutics to increase the flexibility of the drug conjugate backbone.
Moreover, it would have been prima facie obvious to combine the integrin ligand of Marie (i.e., “X” as instantly claimed) to a bone targeting polypeptide such as the D-aspartic acid octapeptide as taught by Wang (i.e., “Z” as instantly claimed) via a non-releasable linker as taught by Low (i.e., “Y” as instantly claimed) with a reasonable expectation of successfully creating a compound that retains functional activity when it is fused to Z directly or when linked to Z through Y as claimed. One of ordinary skill would have been motivated to make the modification because Marie teaches that ITGA5 can be successfully chemically conjugated to a bone seeking agent, Wang teaches suitable bone targeting moieties, and Low teaches miniPEG noncleavable spacer/linker useful for exhibiting high drug loading while retaining covalent bonds between the targeting ligand and the drug (see Scheme 1 and 2; pg. 2013, col 1).
Further regarding claim 42, while Low does not explicitly teach use of four miniPEG units as the linker, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of oxyethylene units, e.g., four, for use in the compound taught by Marie and Wang with a reasonable expectation of success. One of ordinary skill would have been motivated to do so to further increase the flexibility of the backbone of the drug, especially since Low teaches that at least one miniPEG unit adds additional flexibility of the backbone.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Second rejection
Claims 24-25 and 27 are rejected under 35 U.S.C. 103 as being unpatentable over Marie, Wang, and Low as applied to claims 20-23, 26, 30-32, 37-38, and 42 above, and further in view of Kopecek et al (WO 2016/196400, IDS-FOR, hereinafter “Kopecek”).
As discussed above, claims 20-23, 26, 30-32, 37-38, and 42 were rendered prima facie obvious by the teachings of Marie, Wang, and Low. While Wang teaches glutamic acid residues for bone targeting, the references do not explicitly teach D-glutamic acid.
The references also do not explicitly teach a decapeptide of D-glutamic acid or D-aspartic acid.
However, Kopecek teaches that compounds that promote bone growth and/or bone healing can be targeted to bone using acidic oligopeptides of D-aspartic acid or D-glutamic acid, having not less than 4 and not more than 10 amino acids (a decapeptide); 6 or more amino acids; 10 or more amino acids; etc. (Abstract; para 0055-0057, 0093, 0095). One of ordinary skill in the art would have been motivated utilize art-recognized oligopeptide lengths (e.g., 6, 10, etc.) of bone targeting amino acids (e.g., D-glutamic acid or D-aspartic acid), such as those taught by Kopecek, for use in the compound taught by Marie and Wang with a reasonable expectation of success. Indeed, one of ordinary skill in the art would have been motivated to try the oligopeptide lengths taught by Kopecek to determine which oligopeptide lengths of D-glutamic acid or D-aspartic acid would maximize bone targeting while minimizing any effect on ligand function with a reasonable expectation of success.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Third rejection
Claim 40 is rejected under 35 U.S.C. 103 as being unpatentable over Marie, Wang, and Low as applied to claims 20-23, 26, 30-32, 37-38, and 42 above, and further in view of AAPPTEC Peptides ("Peptide modification"; available online 26 Mar 2015; retrieved 16 Dec 2024; https://www.peptide.com/resources/solid-phase-peptide-synthesis/peptide-modification/; hereinafter “AAPPTEC”).
As discussed above, claims 20-23, 26, 30-32, 37-38, and 42 were rendered prima facie obvious by the teachings of Marie, Wang, and Low.
As further discussed above, Marie teaches integrin alpha 5 (ITGA5) agonist in the form of a cyclic peptide ligand having the sequence CRRETAWAC, i.e., RRETAWA comprising terminal cysteines to form a disulfide bridge, which corresponds to at least “ITGaS cys” (Abstract; page 4, lines 10-21; page 10, lines 33-35; page 11, lines 1-2; claim 1).
None of the references explicitly teach that the integrin ligand is ITGA stb-DAPD.
However, AAPPTEC teaches peptide modification that better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application (see pg. 1, para 1). Known modification techniques include cyclization of the peptide, used to impose desired conformation in the protein (see pg. 1, para 2). AAPPTEC further teaches specific cyclization techniques, including sidechain-to-sidechain cyclization via amide formation between an aspartic acid or glutamic acid residue and one of the basic amino acids like lysine (Lys), ornithine (Orn), 2,4-diaminobutyric acid (Dab) and 2,3-diaminopropionic acid (Dap) (i.e., DAP-D) (pg. 2, para 2).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to modify the ITGA of Marie and Wang using art recognized peptide cyclization techniques for use in the compound with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously impose a desired conformation in the peptide, better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application.
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Fourth rejection
Claim 41 is rejected under 35 U.S.C. 103 as being unpatentable over Marie and Wang as applied to claims 20-23, 26, 30-32, 37-38, and 42 above, and further in view of Wang et al (Development of controlled drug delivery systems for bone fracture-targeted therapeutic delivery: A review. European Journal of Pharmaceutics and Biopharmaceutics: Official Journal of Arbeitsgemeinschaft fur Pharmazeutische Verfahrenstechnik e.V; published 2018 Jun;127:223-236. available online 19 Feb 2018, 127:223-236; hereinafter “Wang2”).
As discussed above, claims 20-23, 26, 30-32, 37-38, and 42 were rendered prima facie obvious by the teachings of Marie, Wang, and Low.
None of the references explicitly teach the compound is formulated for systemic administration.
However, Wang2 teaches that systemically delivered, fracture-targeted systems have the advantages of simple dosing control, non-invasive administration, and fewer side-effects, which may make translation of therapeutics more feasible (pg. 15, para 2). Wang also teaches that as active targeting mechanisms, bisphosphonates have been widely explored as effective strategies to target bone due to their high affinity to hydroxyapatite (HAp), which is the main mineral component of bone (see pg. 15, para 2).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to modify the compound of Marie, Wang, and Low by formulating for systemic administration as taught by Wang2 with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously deliver fracture-targeted systems having simple dosing control, non-invasive administration, and fewer side-effects (pg. 15, paragraph 2).
Accordingly, the claimed invention was prima facie obvious to one of ordinary skill in the art at the time of filing especially in the absence of evidence to the contrary.
Maintained/modified 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 20-27, 30-32, and 42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-27 and 29-38 of copending Application No. 17/058,887 (reference application) in view of Low.
Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claims are drawn to an overlapping compound having a structure of X-Y-Z (claim 19). The conflicting claims teach X is an extracellular matrix component, a fragment of an extracellular matrix component, or an agent that activates an extracellular matrix component; e.g., a Src kinase inhibitor (e.g., Dasatinib or E739), a sphingosine-1-phosphate receptor I (S1P1R) agonist, a SIP lyase inhibitor, neuropeptides (e.g., Substance P), etc. (claims 19, 32-38).
The conflicting claims teach that Y is a non-releasable linker comprising: at least one non-releasable linker group, each non-releasable linker group being independently selected from the group consisting of a carbon-carbon bond, ether, and an amide; one or more ethylene glycol unit or 2-8 oxyethylene units (claims 27, 29-31). The conflicting claims teach identical D-glutamic and D-aspartic acid residues as bone-targeting molecules (claims 20-26). The conflicting claims do not teach that the ligand retains receptor-binding activity without cleavage of Y from Z.
However, Low (in the same or similar field of endeavor of bone targeting therapeutics) teaches the creation of a bone-targeting drug that contains 8-Amino-3,6-dioxaoctanoic acid (miniPEG) which was placed between 11-aminoundecanoic acid (AUA) moieties and the D-Asp8 bone-targeting moiety for additional flexibility of the backbone (see scheme 1 and 2; pg. 2013); pg. 2014, col 1, paragraph 1).
It would have been prima facie obvious to combine the ligand of ‘887 (i.e., “X” as instantly claimed) to a bone targeting polypeptide such as the D-aspartic acid octapeptide (i.e., “Z” as instantly claimed) via a non-releasable linker as taught by Low (i.e., “Y” as instantly claimed) with a reasonable expectation of successfully creating a compound that retains functional activity when it is fused to Z directly or when linked to Z through Y as claimed. One of ordinary skill would have been motivated to make the modification because Low teaches miniPEG noncleavable spacer/linker useful for exhibiting high drug loading while retaining covalent bonds between the targeting ligand and the drug (see Scheme 1 and 2; pg. 2013, col 1).
Further regarding claim 42, while Low does not explicitly teach use of four miniPEG units, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of oxyethylene units, e.g., four, for use in the compound taught by the copending claims with a reasonable expectation of success. One of ordinary skill would have been motivated to do so to further increase the flexibility of the backbone of the drug, especially since Low teaches that at least one miniPEG unit adds additional flexibility of the backbone.
As such, the instant claims are not patentably distinct from the conflicting claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 40 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-27 and 29-38 of copending Application No. 17/058,887 (reference application) in view of AAPPTEC.
The rejection of claims 20-27 and 30-32 are set forth above. None of the conflicting claims disclose the integrin ligand is ITGA-DAPD. However, AAPPTEC teaches peptide modification that better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application (see pg. 1, para 1). Known modification techniques include cyclization of the peptide, used to impose desired conformation in the protein (see pg. 1, para 2). AAPPTEC further teaches specific cyclization techniques, including sidechain-to-sidechain cyclization via amide formation between an aspartic acid or glutamic acid residue and one of the basic amino acids like lysine (Lys), ornithine (Orn), 2,4-diaminobutyric acid (Dab) and 2,3-diaminopropionic acid (Dap) (i.e., DAP-D) (pg. 2, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘887 using art recognized peptide cyclization techniques for use in the compound with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously impose a desired conformation in the peptide, better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application.
As such, the instant claims are not patentably distinct from the conflicting claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 41 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 19-27 and 29-38 of copending Application No. 17/058,887 (reference application) in view of Wang2.
The rejection of claims 20-27 and 30-32 is set forth above. The conflicting claims do not disclose formulating for systemic administration. However, Wang2 teaches that systemically delivered, fracture-targeted systems have the advantages of simple dosing control, non-invasive administration, and fewer side-effects, which may make translation of therapeutics more feasible (pg. 15, para 2). Wang also teaches that as active targeting mechanisms, bisphosphonates have been widely explored as effective strategies to target bone due to their high affinity to hydroxyapatite (HAp), which is the main mineral component of bone (see pg. 15, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘887 by formulating for systemic administration as taught by Wang2 with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously deliver fracture-targeted systems having simple dosing control, non-invasive administration, and fewer side-effects.
As such, the instant claims are not patentably distinct from the conflicting claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims
Claims 20-27, 30-32, and 42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 and 16-18 and of copending Application No. 18/074,275 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claims are drawn to an overlapping compound having a structure of X-Y-Z, wherein X comprises a fibroblast growth factor (FGF) receptor targeting sequence , i.e., an integrin ligand agent that activates an extracellular matrix component (claims 1-4). The conflicting claims further disclose identical non-releasable linkers (Y) and D-glutamic/aspartic acid targeting peptides (Z) (claims 5-13, 16-18). The conflicting claims do not teach that the ligand retains receptor-binding activity without cleavage of Y from Z.
However, Low (in the same or similar field of endeavor of bone targeting therapeutics) teaches the creation of a bone-targeting drug that contains 8-Amino-3,6-dioxaoctanoic acid (miniPEG) which was placed between 11-aminoundecanoic acid (AUA) moieties and the D-Asp8 bone-targeting moiety for additional flexibility of the backbone (see scheme 1 and 2; pg. 2013); pg. 2014, col 1, paragraph 1).
It would have been prima facie obvious to combine the ligand of ‘275 (i.e., “X” as instantly claimed) to a bone targeting polypeptide such as the D-aspartic acid octapeptide (i.e., “Z” as instantly claimed) via a non-releasable linker as taught by Low (i.e., “Y” as instantly claimed) with a reasonable expectation of successfully creating a compound that retains functional activity when it is fused to Z directly or when linked to Z through Y as claimed. One of ordinary skill would have been motivated to make the modification because Low teaches miniPEG noncleavable spacer/linker useful for exhibiting high drug loading while retaining covalent bonds between the targeting ligand and the drug (see Scheme 1 and 2; pg. 2013, col 1).
Further regarding claim 42 while Low does not explicitly teach use of four miniPEG units, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of oxyethylene units, e.g., four, for use in the compound taught by ‘275 with a reasonable expectation of success. One of ordinary skill would have been motivated to do so to further increase the flexibility of the backbone of the drug, especially since Low teaches that at least one miniPEG unit adds additional flexibility of the backbone.
As such, the instant claims are not patentably distinct from the conflicting claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 40 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 and 16-18 and of copending Application No. 18/074,275 (reference application) as applied to claims 20-27 and 30-32 above, and further in view of AAPPTEC.
The rejection of claims 20-27 and 30-32 are set forth above. None of the conflicting claims disclose the integrin ligand is ITGA-DAPD. However, AAPPTEC teaches peptide modification that better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application (see pg. 1, para 1). Known modification techniques include cyclization of the peptide, used to impose desired conformation in the protein (see pg. 1, para 2). AAPPTEC further teaches specific cyclization techniques, including sidechain-to-sidechain cyclization via amide formation between an aspartic acid or glutamic acid residue and one of the basic amino acids like lysine (Lys), ornithine (Orn), 2,4-diaminobutyric acid (Dab) and 2,3-diaminopropionic acid (Dap) (i.e., DAP-D) (pg. 2, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘275 using art recognized peptide cyclization techniques for use in the compound with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously impose a desired conformation in the peptide, better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application.
As such, the instant claims are not patentably distinct from the conflicting claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 41 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13 and 16-18 and of copending Application No. 18/074,275 (reference application) as applied to claims 20-27 and 30-32in view of Wang2.
The rejection of claims 20-27 and 30-32 is set forth above. The conflicting claims do not disclose formulating for systemic administration. However, Wang2 teaches that systemically delivered, fracture-targeted systems have the advantages of simple dosing control, non-invasive administration, and fewer side-effects, which may make translation of therapeutics more feasible (pg. 15, para 2). Wang also teaches that as active targeting mechanisms, bisphosphonates have been widely explored as effective strategies to target bone due to their high affinity to hydroxyapatite (HAp), which is the main mineral component of bone (see pg. 15, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘275 by formulating for systemic administration as taught by Wang2 with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously deliver fracture-targeted systems having simple dosing control, non-invasive administration, and fewer side-effects.
As such, the instant claims are not patentably distinct from the conflicting claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 20-23 and 42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, and 8-11 of copending Application No. 17/184,400 (reference application) in view of Low.
Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claims are drawn to an overlapping compound having a structure of X-Y-Z, wherein: X is a bone anabolic agent; Y is a non-releasable linker; and Z is a peptide consisting essentially of glutamic acid residues, aspartic acid residues, or a combination thereof, the peptide having not less than 6 and not more than 40 amino acid residues (claim 1; see also claims 3-4 and 11). The conflicting claims disclose that X is an agonist of parathyroid hormone receptor 1 (PTH1R) or a bone anabolic peptide or fragment thereof (claims 8-10), i.e., integrin ligand agents that activates an extracellular matrix component. The conflicting claims do not teach that the ligand retains receptor-binding activity without cleavage of Y from Z.
However, Low (in the same or similar field of endeavor of bone targeting therapeutics) teaches the creation of a bone-targeting drug that contains 8-Amino-3,6-dioxaoctanoic acid (miniPEG) which was placed between 11-aminoundecanoic acid (AUA) moieties and the D-Asp8 bone-targeting moiety for additional flexibility of the backbone (see scheme 1 and 2; pg. 2013); pg. 2014, col 1, paragraph 1).
It would have been prima facie obvious to combine the ligand of ‘400 (i.e., “X” as instantly claimed) to a bone targeting polypeptide such as the D-aspartic acid octapeptide (i.e., “Z” as instantly claimed) via a non-releasable linker as taught by Low (i.e., “Y” as instantly claimed) with a reasonable expectation of successfully creating a compound that retains functional activity when it is fused to Z directly or when linked to Z through Y as claimed. One of ordinary skill would have been motivated to make the modification because Low teaches miniPEG noncleavable spacer/linker useful for exhibiting high drug loading while retaining covalent bonds between the targeting ligand and the drug (see Scheme 1 and 2; pg. 2013, col 1).
Further regarding claim 42 while Low does not explicitly teach use of four miniPEG units, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of oxyethylene units, e.g., four, for use in the compound taught by ‘275 with a reasonable expectation of success. One of ordinary skill would have been motivated to do so to further increase the flexibility of the backbone of the drug, especially since Low teaches that at least one miniPEG unit adds additional flexibility of the backbone.
As such, the instant claims are not patentably distinct from the conflicting claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 24-27 and 30-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, and 8-11 of copending Application No. 17/184,400 as applied to claims 20-23 and 42 above, and further in view of Wang and Low.
The rejection of claims 20-23 is set forth above. The conflicting claims do not disclose the D-amino acids of claims 24-27 or the linkers of claims 30-32. However, Wang teaches that drugs can be targeted to bone using aspartic or glutamic acid residues (page 853, second column; page 854, Scheme 1, reproduced, in part, below).
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Wang further teaches, e.g., a D-aspartic acid octapeptide used for bone-targeting can be conjugated to a drug through a polyethylene glycol (PEG) linker (page 855, Scheme 2), using fluorescein isothiocyanate (FITC)) (see pg. 855).
One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Wang in order to advantageously target the ligand to bone using D-aspartic acid octapeptide as taught by Wang with a reasonable expectation of success. As the instant claims require a bone-targeting moiety containing aspartic and glutamic residues, one of ordinary skill would have been motivated to perform a simple substitution of one known element (the bone targeting molecules of the conflicting claims) with another (the D-aspartic octapeptide of Wang) with a reasonable expectation of successful creation of a drug capable of targeting bone.
Moreover, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of aspartic acid or glutamic acid residues, for use in the compound taught by the conflicting claims with Wang with a reasonable expectation of success, especially since the claims contemplates any number of aspartic acid residues and glutamic residues and nothing in the Specification reasonably evidences the criticality or unexpected nature of a particular number of each.
As such, the instant claims are not patentably distinct from the conflicting claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 37-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, and 8-11 of copending Application No. 17/184,400 as applied to claims 20-23 and 28 above, and further in view of Marie.
The rejection of claims 20-23 and 28 is set forth above. The conflicting claims do not disclose the integrin ligands of claims 37-38. However, Marie teaches a composition to promote bone repair or regeneration comprising an integrin alpha 5 (ITGA5) agonist in the form of a cyclic peptide ligand having the sequence CRRETAWAC, i.e., RRETAWA comprising terminal cysteines to form a disulfide bridge, which corresponds “ITGaS cys” (Abstract; page 4, lines 10-21; page 10, lines 33-35; page 11, lines 1-2; claim 1). One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Marie in order to advantageously improve the metabolic stability of the peptide with a reasonable expectation of success.
As such, the instant claims are not patentably distinct from the conflicting claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 40 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, and 8-11 of copending Application No. 17/184,400 (reference application) in view of Marie as applied to claims 37-38 above, and further in view of AAPPTEC.
The rejection of claims 37-38 are set forth above. None of the conflicting claims disclose the integrin ligand is ITGA-DAPD. However, AAPPTEC teaches peptide modification that better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application (see pg. 1, para 1). Known modification techniques include cyclization of the peptide, used to impose desired conformation in the protein (see pg. 1, para 2). AAPPTEC further teaches specific cyclization techniques, including sidechain-to-sidechain cyclization via amide formation between an aspartic acid or glutamic acid residue and one of the basic amino acids like lysine (Lys), ornithine (Orn), 2,4-diaminobutyric acid (Dab) and 2,3-diaminopropionic acid (Dap) (i.e., DAP-D) (pg. 2, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘400 using art recognized peptide cyclization techniques for use in the compound with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously impose a desired conformation in the peptide, better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application.
As such, the instant claims are not patentably distinct from the conflicting claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 41 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-4, and 8-11 of copending Application No. 17/184,400 (reference application) as applied to claims 20-23 above, and further in view of Wang2.
The rejection of claims 20-27 and 30 is set forth above. The conflicting claims do not disclose formulating for systemic administration. However, Wang2 teaches that systemically delivered, fracture-targeted systems have the advantages of simple dosing control, non-invasive administration, and fewer side-effects, which may make translation of therapeutics more feasible (pg. 15, para 2). Wang also teaches that as active targeting mechanisms, bisphosphonates have been widely explored as effective strategies to target bone due to their high affinity to hydroxyapatite (HAp), which is the main mineral component of bone (see pg. 15, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘400 by formulating for systemic administration as taught by Wang2 with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously deliver fracture-targeted systems having simple dosing control, non-invasive administration, and fewer side-effects.
As such, the instant claims are not patentably distinct from the conflicting claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 20-27, 37, and 42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43, 48, and 57 of copending Application No. 18/033,658 (reference application).
Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claims are drawn to an overlapping compound having a structure of structure of X-Y-Z, wherein X is, e.g., ITGA, Y is a non-releasable linker, and Z comprises at least 10 repeating D-glutamic acid amino acid residues (D10), at least 15 repeating D-glutamic acid amino acid residues (DE15), or at least 20 repeating D-glutamic acid amino acid residues (DE20) (claims 43, 48, and 57). The conflicting claims do not teach that the ligand retains receptor-binding activity without cleavage of Y from Z.
However, Low (in the same or similar field of endeavor of bone targeting therapeutics) teaches the creation of a bone-targeting drug that contains 8-Amino-3,6-dioxaoctanoic acid (miniPEG) which was placed between 11-aminoundecanoic acid (AUA) moieties and the D-Asp8 bone-targeting moiety for additional flexibility of the backbone (see scheme 1 and 2; pg. 2013); pg. 2014, col 1, paragraph 1).
It would have been prima facie obvious to combine the ligand of ‘658 (i.e., “X” as instantly claimed) to a bone targeting polypeptide such as the D-aspartic acid octapeptide (i.e., “Z” as instantly claimed) via a non-releasable linker as taught by Low (i.e., “Y” as instantly claimed) with a reasonable expectation of successfully creating a compound that retains functional activity when it is fused to Z directly or when linked to Z through Y as claimed. One of ordinary skill would have been motivated to make the modification because Low teaches miniPEG noncleavable spacer/linker useful for exhibiting high drug loading while retaining covalent bonds between the targeting ligand and the drug (see Scheme 1 and 2; pg. 2013, col 1).
Further regarding claim 42 while Low does not explicitly teach use of four miniPEG units, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of oxyethylene units, e.g., four, for use in the compound taught by ‘275 with a reasonable expectation of success. One of ordinary skill would have been motivated to do so to further increase the flexibility of the backbone of the drug, especially since Low teaches that at least one miniPEG unit adds additional flexibility of the backbone.
As such, the instant claims are not patentably distinct from the conflicting claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 30-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43, 48, and 57 of copending Application No. 18/033,658 as applied to claims 20-27 and 37 above, and further in view of Wang and Low.
The rejection of claims 20-27 and 37 is set forth above. The conflicting claims do not disclose the linkers of claims 30-32. However, Wang teaches that drugs can be targeted to bone using aspartic or glutamic acid residues (page 853, second column; page 854, Scheme 1, reproduced, in part, below).
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Wang further teaches, e.g., a D-aspartic acid octapeptide used for bone-targeting can be conjugated to a drug through a polyethylene glycol (PEG) linker (page 855, Scheme 2), using fluorescein isothiocyanate (FITC)) (see pg. 855).
One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Wang in order to advantageously target the ligand to bone using D-aspartic acid octapeptide as taught by Wang with a reasonable expectation of success. As the instant claims require a bone-targeting moiety containing aspartic and glutamic residues, one of ordinary skill would have been motivated to perform a simple substitution of one known element (the bone targeting molecules of the conflicting claims) with another (the D-aspartic octapeptide of Wang) with a reasonable expectation of successful creation of a drug capable of targeting bone.
Moreover, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of aspartic acid or glutamic acid residues, for use in the compound taught by the conflicting claims with Wang with a reasonable expectation of success, especially since the claims contemplates any number of aspartic acid residues and glutamic residues and nothing in the Specification reasonably evidences the criticality or unexpected nature of a particular number of each.
As such, the instant claims are not patentably distinct from the conflicting claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 38 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43, 48, and 57 of copending Application No. 18/033,658 as applied to claims 20-27 and 37 above, and further in view of Marie.
The rejection of claims 20-27 and 37 is set forth above. The conflicting claims do not disclose the integrin ligands of claim 38. However, Marie teaches a composition to promote bone repair or regeneration comprising an integrin alpha 5 (ITGA5) agonist in the form of a cyclic peptide ligand having the sequence CRRETAWAC, i.e., RRETAWA comprising terminal cysteines to form a disulfide bridge, which corresponds “ITGaS cys” (Abstract; page 4, lines 10-21; page 10, lines 33-35; page 11, lines 1-2; claim 1). One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Marie in order to advantageously improve the metabolic stability of the peptide with a reasonable expectation of success.
As such, the instant claims are not patentably distinct from the conflicting claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 40 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43, 48, and 57 of copending Application No. 18/033,658 (reference application) as applied to claims 20-27 and 37 above, and further in view of AAPPTEC.
The rejection of claims 20-27 and 37 are set forth above. None of the conflicting claims disclose the integrin ligand is ITGA-DAPD. However, AAPPTEC teaches peptide modification that better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application (see pg. 1, para 1). Known modification techniques include cyclization of the peptide, used to impose desired conformation in the protein (see pg. 1, para 2). AAPPTEC further teaches specific cyclization techniques, including sidechain-to-sidechain cyclization via amide formation between an aspartic acid or glutamic acid residue and one of the basic amino acids like lysine (Lys), ornithine (Orn), 2,4-diaminobutyric acid (Dab) and 2,3-diaminopropionic acid (Dap) (i.e., DAP-D) (pg. 2, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘658 using art recognized peptide cyclization techniques for use in the compound with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously impose a desired conformation in the peptide, better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application.
As such, the instant claims are not patentably distinct from the conflicting claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 41 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 43, 48, and 57 of copending Application No. 18/033,658 (reference application) as applied to claim 20-27 and 37 above, and further in view of Wang2.
The rejection of claims 20-27 and 37 is set forth above. The conflicting claims do not disclose formulating for systemic administration. However, Wang2 teaches that systemically delivered, fracture-targeted systems have the advantages of simple dosing control, non-invasive administration, and fewer side-effects, which may make translation of therapeutics more feasible (pg. 15, para 2). Wang also teaches that as active targeting mechanisms, bisphosphonates have been widely explored as effective strategies to target bone due to their high affinity to hydroxyapatite (HAp), which is the main mineral component of bone (see pg. 15, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘658 by formulating for systemic administration as taught by Wang2 with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously deliver fracture-targeted systems having simple dosing control, non-invasive administration, and fewer side-effects.
As such, the instant claims are not patentably distinct from the conflicting claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 20-27, 30, and 42 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 15 and 24-25 of copending Application No. 18/033,665.
Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claims are drawn to an overlapping compound having a structure of structure of X-Y-Z, wherein X is a bone anabolic agent selected from the group consisting of a parathyroid hormone (PTH) or a derivative or fragment thereof, a PTH-related protein (PTHrP) or a derivative or fragment thereof, and abaloparatide or a derivative or fragment thereof, i.e., agents that activate an extracellular matrix component; Y is a non-releasable linker; and Z is an osteotropic ligand (claims 1, 5). The conflicting claims disclose that the osteotropic ligand of Z comprises 4 to 20 D-glutamic acid amino acid residues or 4 to 20 D-aspartic acid amino acid residues (claim 15). The conflicting claims disclose that Y is a non-releasable linker comprising at least one carbon-carbon bond and/or at least one amide bond (claims 24-25). The conflicting claims do not teach that the ligand retains receptor-binding activity without cleavage of Y from Z.
However, Low (in the same or similar field of endeavor of bone targeting therapeutics) teaches the creation of a bone-targeting drug that contains 8-Amino-3,6-dioxaoctanoic acid (miniPEG) which was placed between 11-aminoundecanoic acid (AUA) moieties and the D-Asp8 bone-targeting moiety for additional flexibility of the backbone (see scheme 1 and 2; pg. 2013); pg. 2014, col 1, paragraph 1).
It would have been prima facie obvious to combine the ligand of ‘665 (i.e., “X” as instantly claimed) to a bone targeting polypeptide such as the D-aspartic acid octapeptide (i.e., “Z” as instantly claimed) via a non-releasable linker as taught by Low (i.e., “Y” as instantly claimed) with a reasonable expectation of successfully creating a compound that retains functional activity when it is fused to Z directly or when linked to Z through Y as claimed. One of ordinary skill would have been motivated to make the modification because Low teaches miniPEG noncleavable spacer/linker useful for exhibiting high drug loading while retaining covalent bonds between the targeting ligand and the drug (see Scheme 1 and 2; pg. 2013, col 1).
Further regarding claim 42 while Low does not explicitly teach use of four miniPEG units, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of oxyethylene units, e.g., four, for use in the compound taught by ‘275 with a reasonable expectation of success. One of ordinary skill would have been motivated to do so to further increase the flexibility of the backbone of the drug, especially since Low teaches that at least one miniPEG unit adds additional flexibility of the backbone.
As such, the instant claims are not patentably distinct from the conflicting claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 31-32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 15 and 24-25 of copending Application No. 18/033,665 as applied to claims 20-28, 30, and 42 above, and further in view of Wang and Low.
The rejection of claims 20-27 and 30 is set forth above. The conflicting claims do not disclose the linkers of claims 31-32. However, Wang teaches that drugs can be targeted to bone using aspartic or glutamic acid residues (page 853, second column; page 854, Scheme 1, reproduced, in part, below).
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Wang further teaches, e.g., a D-aspartic acid octapeptide used for bone-targeting can be conjugated to a drug through a polyethylene glycol (PEG) linker (page 855, Scheme 2), using fluorescein isothiocyanate (FITC)) (see pg. 855).
One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Wang in order to advantageously target the ligand to bone using D-aspartic acid octapeptide as taught by Wang with a reasonable expectation of success. As the instant claims require a bone-targeting moiety containing aspartic and glutamic residues, one of ordinary skill would have been motivated to perform a simple substitution of one known element (the bone targeting molecules of the conflicting claims) with another (the D-aspartic octapeptide of Wang) with a reasonable expectation of successful creation of a drug capable of targeting bone.
Moreover, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of aspartic acid or glutamic acid residues, for use in the compound taught by the conflicting claims with Wang with a reasonable expectation of success, especially since the claims contemplates any number of aspartic acid residues and glutamic residues and nothing in the Specification reasonably evidences the criticality or unexpected nature of a particular number of each.
As such, the instant claims are not patentably distinct from the conflicting claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 37-38 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 15 and 24-25 of copending Application No. 18/033,665 as applied to claims 20-27, 30, and 42 above, and further in view of Marie.
The rejection of claims 20-27, 30and 42 is set forth above. The conflicting claims do not disclose the integrin ligands of claims 37-38. However, Marie teaches a composition to promote bone repair or regeneration comprising an integrin alpha 5 (ITGA5) agonist in the form of a cyclic peptide ligand having the sequence CRRETAWAC, i.e., RRETAWA comprising terminal cysteines to form a disulfide bridge, which corresponds “ITGaS cys” (Abstract; page 4, lines 10-21; page 10, lines 33-35; page 11, lines 1-2; claim 1). One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Marie in order to advantageously improve the metabolic stability of the peptide with a reasonable expectation of success.
As such, the instant claims are not patentably distinct from the conflicting claims. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 40 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 15 and 24-25 of copending Application No. 18/033,665 and Marie as applied to claims 37-38 above, and further in view of AAPPTEC.
The rejection of claims 37-38 are set forth above. None of the conflicting claims disclose the integrin ligand is ITGA-DAPD. However, AAPPTEC teaches peptide modification that better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application (see pg. 1, para 1). Known modification techniques include cyclization of the peptide, used to impose desired conformation in the protein (see pg. 1, para 2). AAPPTEC further teaches specific cyclization techniques, including sidechain-to-sidechain cyclization via amide formation between an aspartic acid or glutamic acid residue and one of the basic amino acids like lysine (Lys), ornithine (Orn), 2,4-diaminobutyric acid (Dab) and 2,3-diaminopropionic acid (Dap) (i.e., DAP-D) (pg. 2, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘665 using art recognized peptide cyclization techniques for use in the compound with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously impose a desired conformation in the peptide, better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application.
As such, the instant claims are not patentably distinct from the conflicting claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 41 provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 15 and 24-25 of copending Application No. 18/033,665 as applied to claims 20-27 and 30 above, and further in view of Wang2.
The rejection of claims 20-27 and 30 is set forth above. The conflicting claims do not disclose formulating for systemic administration. However, Wang2 teaches that systemically delivered, fracture-targeted systems have the advantages of simple dosing control, non-invasive administration, and fewer side-effects, which may make translation of therapeutics more feasible (pg. 15, para 2). Wang also teaches that as active targeting mechanisms, bisphosphonates have been widely explored as effective strategies to target bone due to their high affinity to hydroxyapatite (HAp), which is the main mineral component of bone (see pg. 15, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘665 by formulating for systemic administration as taught by Wang2 with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously deliver fracture-targeted systems having simple dosing control, non-invasive administration, and fewer side-effects.
As such, the instant claims are not patentably distinct from the conflicting claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 20-27 and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 10,744,203.
Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claims are drawn to a compound for treating bone fractures, comprising: a compound of the formula X-Y-Z, wherein X is a negatively charged oligopeptide; Y is a (hydrolysable) linker; and Z is an active compound selected from prostaglandin E1 or prostaglandin E2, i.e., agents that activate an extracellular matrix component (claims 1, 5). The conflicting claims disclose that the acidic oligopeptide comprises not less than 4 and not more than 10 amino acids, including D-aspartic acid and D-glutamic acid (claims 2-4). It is noted that the order of X and Z in the conflicting claims is reversed compared to the instant claims. However, it would have been prima facie obvious at the time of filing to place X and Z in either order with a reasonable expectation of success since, inter alia, nothing in the Specification evidences the criticality or unexpected nature of any particular order.
The conflicting claims do not teach that the ligand retains receptor-binding activity without cleavage of Y from Z.
However, Low (in the same or similar field of endeavor of bone targeting therapeutics) teaches the creation of a bone-targeting drug that contains 8-Amino-3,6-dioxaoctanoic acid (miniPEG) which was placed between 11-aminoundecanoic acid (AUA) moieties and the D-Asp8 bone-targeting moiety for additional flexibility of the backbone (see scheme 1 and 2; pg. 2013); pg. 2014, col 1, paragraph 1).
It would have been prima facie obvious to combine the ligand of ‘203 (i.e., “X” as instantly claimed) to a bone targeting polypeptide such as the D-aspartic acid octapeptide (i.e., “Z” as instantly claimed) via a non-releasable linker as taught by Low (i.e., “Y” as instantly claimed) with a reasonable expectation of successfully creating a compound that retains functional activity when it is fused to Z directly or when linked to Z through Y as claimed. One of ordinary skill would have been motivated to make the modification because Low teaches miniPEG noncleavable spacer/linker useful for exhibiting high drug loading while retaining covalent bonds between the targeting ligand and the drug (see Scheme 1 and 2; pg. 2013, col 1).
Further regarding claim 42 while Low does not explicitly teach use of four miniPEG units, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of oxyethylene units, e.g., four, for use in the compound taught by ‘275 with a reasonable expectation of success. One of ordinary skill would have been motivated to do so to further increase the flexibility of the backbone of the drug, especially since Low teaches that at least one miniPEG unit adds additional flexibility of the backbone.
As such, the instant claims are not patentably distinct from the conflicting claims.
Claims 30-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 10,744,203 as applied to claims 20-27 above, and further in view of Wang and Low.
The rejection of claims 20-27 and 42 is set forth above. The conflicting claims do not disclose the linkers of claims 30-32. However, Wang teaches that drugs can be targeted to bone using aspartic or glutamic acid residues (page 853, second column; page 854, Scheme 1, reproduced, in part, below).
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Wang further teaches, e.g., a D-aspartic acid octapeptide used for bone-targeting can be conjugated to a drug through a polyethylene glycol (PEG) linker (page 855, Scheme 2), using fluorescein isothiocyanate (FITC)) (see pg. 855).
One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Wang in order to advantageously target the ligand to bone using D-aspartic acid octapeptide as taught by Wang with a reasonable expectation of success. As the instant claims require a bone-targeting moiety containing aspartic and glutamic residues, one of ordinary skill would have been motivated to perform a simple substitution of one known element (the bone targeting molecules of the conflicting claims) with another (the D-aspartic octapeptide of Wang) with a reasonable expectation of successful creation of a drug capable of targeting bone.
Moreover, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of aspartic acid or glutamic acid residues, for use in the compound taught by the conflicting claims with Wang with a reasonable expectation of success, especially since the claims contemplates any number of aspartic acid residues and glutamic residues and nothing in the Specification reasonably evidences the criticality or unexpected nature of a particular number of each.
As such, the instant claims are not patentably distinct from the conflicting claims.
Claim 40 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 10,744,203 as applied to claims 20-27 and 42 above, and further in view of AAPPTEC.
The rejection of claims 20-27 and 42 are set forth above. None of the conflicting claims disclose the integrin ligand is ITGA-DAPD. However, AAPPTEC teaches peptide modification that better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application (see pg. 1, para 1). Known modification techniques include cyclization of the peptide, used to impose desired conformation in the protein (see pg. 1, para 2). AAPPTEC further teaches specific cyclization techniques, including sidechain-to-sidechain cyclization via amide formation between an aspartic acid or glutamic acid residue and one of the basic amino acids like lysine (Lys), ornithine (Orn), 2,4-diaminobutyric acid (Dab) and 2,3-diaminopropionic acid (Dap) (i.e., DAP-D) (pg. 2, para 2). One of ordinary skill in the art would have been motivated to modify the integrin ligand compound of ‘203 using art recognized peptide cyclization techniques for use in the compound with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously impose a desired conformation in the peptide, better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application.
As such, the instant claims are not patentably distinct from the conflicting claims.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of U.S. Patent No. 10,744,203 as applied to claims 20-27 above, and further in view of Wang2.
The rejection of claims 20-27 is set forth above. The conflicting claims do not disclose formulating for systemic administration. However, Wang2 teaches that systemically delivered, fracture-targeted systems have the advantages of simple dosing control, non-invasive administration, and fewer side-effects, which may make translation of therapeutics more feasible (pg. 15, para 2). Wang also teaches that as active targeting mechanisms, bisphosphonates have been widely explored as effective strategies to target bone due to their high affinity to hydroxyapatite (HAp), which is the main mineral component of bone (see pg. 15, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘203 by formulating for systemic administration as taught by Wang2 with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously deliver fracture-targeted systems having simple dosing control, non-invasive administration, and fewer side-effects.
As such, the instant claims are not patentably distinct from the conflicting claims.
Claims 20-23 and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 11-12 of U.S. Patent No. 10,960,054.
Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claims are drawn to a compound having a structure of X-Y-Z wherein X is a polypeptide having an amino acid sequence of SEQ ID NO: 3; Y is a linker; and Z is a bone-targeting molecule; or a pharmaceutically acceptable salt thereof (claim 1). The conflicting claims disclose that Y is a non-releasable linker (claim 2). The conflicting claims disclose that Z comprises not less than 6 and not more than 35 glutamic acid residues or not less than 6 and not more than 35 aspartic acid residues (claims 11-12). The conflicting claims do not explicitly teach that the ligand retains receptor-binding activity without cleavage of Y from Z.
However, Low (in the same or similar field of endeavor of bone targeting therapeutics) teaches the creation of a bone-targeting drug that contains 8-Amino-3,6-dioxaoctanoic acid (miniPEG) which was placed between 11-aminoundecanoic acid (AUA) moieties and the D-Asp8 bone-targeting moiety for additional flexibility of the backbone (see scheme 1 and 2; pg. 2013); pg. 2014, col 1, paragraph 1).
It would have been prima facie obvious to combine the ligand of ‘054 (i.e., “X” as instantly claimed) to a bone targeting polypeptide such as the D-aspartic acid octapeptide (i.e., “Z” as instantly claimed) via a non-releasable linker as taught by Low (i.e., “Y” as instantly claimed) with a reasonable expectation of successfully creating a compound that retains functional activity when it is fused to Z directly or when linked to Z through Y as claimed. One of ordinary skill would have been motivated to make the modification because Low teaches miniPEG noncleavable spacer/linker useful for exhibiting high drug loading while retaining covalent bonds between the targeting ligand and the drug (see Scheme 1 and 2; pg. 2013, col 1).
Further regarding claim 42 while Low does not explicitly teach use of four miniPEG units, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of oxyethylene units, e.g., four, for use in the compound taught by ‘275 with a reasonable expectation of success. One of ordinary skill would have been motivated to do so to further increase the flexibility of the backbone of the drug, especially since Low teaches that at least one miniPEG unit adds additional flexibility of the backbone.
As such, the instant claims are not patentably distinct from the conflicting claims.
Claims 24-27 and 30-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 11-12 of U.S. Patent No. 10,960,054 as applied to claims 20-23 and 28 above, and further in view of Wang and Low.
The rejection of claims 20-23 and 42 is set forth above. The conflicting claims do not disclose the D-amino acids of claims 24-27 or the linkers of claims 30-32. However, Wang teaches that drugs can be targeted to bone using aspartic or glutamic acid residues (page 853, second column; page 854, Scheme 1, reproduced, in part, below).
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Wang further teaches, e.g., a D-aspartic acid octapeptide used for bone-targeting can be conjugated to a drug through a polyethylene glycol (PEG) linker (page 855, Scheme 2), using fluorescein isothiocyanate (FITC)) (see pg. 855).
One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Wang in order to advantageously target the ligand to bone using D-aspartic acid octapeptide as taught by Wang with a reasonable expectation of success. As the instant claims require a bone-targeting moiety containing aspartic and glutamic residues, one of ordinary skill would have been motivated to perform a simple substitution of one known element (the bone targeting molecules of the conflicting claims) with another (the D-aspartic octapeptide of Wang) with a reasonable expectation of successful creation of a drug capable of targeting bone.
Moreover, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of aspartic acid or glutamic acid residues, for use in the compound taught by the conflicting claims with Wang with a reasonable expectation of success, especially since the claims contemplates any number of aspartic acid residues and glutamic residues and nothing in the Specification reasonably evidences the criticality or unexpected nature of a particular number of each.
As such, the instant claims are not patentably distinct from the conflicting claims.
Claim 40 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 11-12 of U.S. Patent No. 10,960,054 as applied to claims 20-23 and 42 above, and further in view of AAPPTEC.
The rejection of claims 20-23 and 42are set forth above. None of the conflicting claims disclose the integrin ligand is ITGA-DAPD. However, AAPPTEC teaches peptide modification that better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application (see pg. 1, para 1). Known modification techniques include cyclization of the peptide, used to impose desired conformation in the protein (see pg. 1, para 2). AAPPTEC further teaches specific cyclization techniques, including sidechain-to-sidechain cyclization via amide formation between an aspartic acid or glutamic acid residue and one of the basic amino acids like lysine (Lys), ornithine (Orn), 2,4-diaminobutyric acid (Dab) and 2,3-diaminopropionic acid (Dap) (i.e., DAP-D) (pg. 2, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘054 using art recognized peptide cyclization techniques for use in the compound with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously impose a desired conformation in the peptide, better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application.
As such, the instant claims are not patentably distinct from the conflicting claims.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-2 and 11-12 of U.S. Patent No. 10,960,054 as applied to claims 20-23 above, and further in view of Wang2.
The rejection of claims 20-23 is set forth above. The conflicting claims do not disclose formulating for systemic administration. However, Wang2 teaches that systemically delivered, fracture-targeted systems have the advantages of simple dosing control, non-invasive administration, and fewer side-effects, which may make translation of therapeutics more feasible (pg. 15, para 2). Wang2 also teaches that as active targeting mechanisms, bisphosphonates have been widely explored as effective strategies to target bone due to their high affinity to hydroxyapatite (HAp), which is the main mineral component of bone (see pg. 15, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘004 by formulating for systemic administration as taught by Wang2 with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously deliver fracture-targeted systems having simple dosing control, non-invasive administration, and fewer side-effects.
As such, the instant claims are not patentably distinct from the conflicting claims.
Claims 20-27 and 42 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, and 11-12 of U.S. Patent No. 10,279,044.
Although the claims at issue are not identical, they are not patentably distinct from each other because the conflicting claims are drawn to a compound for treating bone fractures, comprising: a compound of the formula X-Y-Z, wherein: X is at least one negatively charged oligopeptide; Y is at least one linker; and Z is at least one active compound comprising at least one anabolic compound, wherein the anabolic compound is 6′-bromoindirubin-3′-oxime, i.e., an agent that activates an extracellular matrix component (claim 1). The conflicting claims disclose that the negatively charged oligopeptides comprise mot less than 4 and not more than 20 amino acids D-aspartic acid or D-glutamic acid (claims 2-4, 8). The conflicting claims disclose that Y is a hydrolysable linker (claim 5). It is noted that the order of X and Z in the conflicting claims is reversed compared to the instant claims. However, it would have been prima facie obvious at the time of filing to place X and Z in either order with a reasonable expectation of success since, inter alia, nothing in the Specification evidences the criticality or unexpected nature of any particular order. The conflicting claims do not teach that the ligand retains receptor-binding activity without cleavage of Y from Z, where Y is a nonreleasable linker.
However, Low (in the same or similar field of endeavor of bone targeting therapeutics) teaches the creation of a bone-targeting drug that contains 8-Amino-3,6-dioxaoctanoic acid (miniPEG) which was placed between 11-aminoundecanoic acid (AUA) moieties and the D-Asp8 bone-targeting moiety for additional flexibility of the backbone (see scheme 1 and 2; pg. 2013); pg. 2014, col 1, paragraph 1).
It would have been prima facie obvious to combine the ligand of ‘044 (i.e., “X” as instantly claimed) to a bone targeting polypeptide such as the D-aspartic acid octapeptide (i.e., “Z” as instantly claimed) via a non-releasable linker as taught by Low (i.e., “Y” as instantly claimed) with a reasonable expectation of successfully creating a compound that retains functional activity when it is fused to Z directly or when linked to Z through Y as claimed. One of ordinary skill would have been motivated to make the modification because Low teaches miniPEG noncleavable spacer/linker useful for exhibiting high drug loading while retaining covalent bonds between the targeting ligand and the drug (see Scheme 1 and 2; pg. 2013, col 1).
Further regarding claim 42 while Low does not explicitly teach use of four miniPEG units, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of oxyethylene units, e.g., four, for use in the compound taught by ‘275 with a reasonable expectation of success. One of ordinary skill would have been motivated to do so to further increase the flexibility of the backbone of the drug, especially since Low teaches that at least one miniPEG unit adds additional flexibility of the backbone.
As such, the instant claims are not patentably distinct from the conflicting claims.
Claims 30-32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, and 11-12 of U.S. Patent No. 10,279,044 as applied to claims 20-27 and 42, and further in view of Wang and Low.
The rejection of claims 20-27 and 42 is set forth above. The conflicting claims do not disclose the linkers of claims 30-32. However, Wang teaches that drugs can be targeted to bone using aspartic or glutamic acid residues (page 853, second column; page 854, Scheme 1, reproduced, in part, below).
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Wang further teaches, e.g., a D-aspartic acid octapeptide used for bone-targeting can be conjugated to a drug through a polyethylene glycol (PEG) linker (page 855, Scheme 2), using fluorescein isothiocyanate (FITC)) (see pg. 855).
One of ordinary skill in the art would have been motivated to modify the conflicting claims in view of Wang in order to advantageously target the ligand to bone using D-aspartic acid octapeptide as taught by Wang with a reasonable expectation of success. As the instant claims require a bone-targeting moiety containing aspartic and glutamic residues, one of ordinary skill would have been motivated to perform a simple substitution of one known element (the bone targeting molecules of the conflicting claims) with another (the D-aspartic octapeptide of Wang) with a reasonable expectation of successful creation of a drug capable of targeting bone.
Moreover, it would have been matter of routine experimentation using standard laboratory techniques available at the time of filing to determine the optimal number of aspartic acid or glutamic acid residues, for use in the compound taught by the conflicting claims with Wang with a reasonable expectation of success, especially since the claims contemplates any number of aspartic acid residues and glutamic residues and nothing in the Specification reasonably evidences the criticality or unexpected nature of a particular number of each.
Furthermore, Low (in the same or similar field of endeavor of bone targeting therapeutics) teaches the creation of a bone-targeting drug that contains a d-aspartic acid octapeptide (d-Asp8), that was selected for its optimized targeting potential, its stability toward protease degradation associated with d-peptides, as well as its hydrophilic nature (pg. 2014; col 1, paragraph 1). Low further teaches that 8-Amino-3,6-dioxaoctanoic acid (miniPEG) (8-amino-3,6-dioxaoctanoic acid units as in claim 42) was placed between AUA and the d-Asp8 for additional flexibility of the backbone (see scheme 1 and 2; pg. 2013); pg. 2014, col 1, paragraph 1).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time of filing to modify the compound of the conflicting claims and include 8-Amino-3,6-dioxaoctanoic acid (miniPEG) with a reasonable expectation of success. One of ordinary skill would have been motivated to make the modification because Low explicitly teaches that 8-amino-3,6-dioxaoctanoic acid can advantageously used in bone-targeting therapeutics to increase the flexibility of the drug conjugate backbone.
As such, the instant claims are not patentably distinct from the conflicting claims.
Claim 40 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, and 11-12 of U.S. Patent No. 10,279,044 as applied to claims 20-27 and 42, and further in view of AAPPTEC.
The rejection of claims 20-27 are set forth above. None of the conflicting claims disclose the integrin ligand is ITGA-DAPD. However, AAPPTEC teaches peptide modification that better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application (see pg. 1, para 1). Known modification techniques include cyclization of the peptide, used to impose desired conformation in the protein (see pg. 1, para 2). AAPPTEC further teaches specific cyclization techniques, including sidechain-to-sidechain cyclization via amide formation between an aspartic acid or glutamic acid residue and one of the basic amino acids like lysine (Lys), ornithine (Orn), 2,4-diaminobutyric acid (Dab) and 2,3-diaminopropionic acid (Dap) (i.e., DAP-D) (pg. 2, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘044 using art recognized peptide cyclization techniques for use in the compound with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously impose a desired conformation in the peptide, better mimic the native peptides or protein fragments, or to introduce elements that enhance the peptide’s later application.
As such, the instant claims are not patentably distinct from the conflicting claims.
Claim 41 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, and 11-12 of U.S. Patent No. 10,279,044 as applied to claims 20-27 and 42, and further in view of Wang2.
The rejection of claims 20-27 and 42 is set forth above. The conflicting claims do not disclose formulating for systemic administration. However, Wang2 teaches that systemically delivered, fracture-targeted systems have the advantages of simple dosing control, non-invasive administration, and fewer side-effects, which may make translation of therapeutics more feasible (pg. 15, para 2). Wang also teaches that as active targeting mechanisms, bisphosphonates have been widely explored as effective strategies to target bone due to their high affinity to hydroxyapatite (HAp), which is the main mineral component of bone (see pg. 15, para 2). One of ordinary skill in the art would have been motivated to modify the compound of ‘004 by formulating for systemic administration as taught by Wang2 with a reasonable expectation of success. One of ordinary skill would have been motivated to make such a modification in order to advantageously deliver fracture-targeted systems having simple dosing control, non-invasive administration, and fewer side-effects.
As such, the instant claims are not patentably distinct from the conflicting claims.
Response to Arguments
Applicant's arguments filed 02/20/2026 have been fully considered but they are not persuasive.
On pg. 12-15 of the remarks, Applicant argues that the prior art assumes therapeutic activity requires payload release. First, Applicant argues that Marie only discloses free ITGA5 without conjugation, linker chemistry, or retained biological activity of a tethered ligand, Kopacek emphasizes linker selection to control drug release, AAPPTEC and Wang2 are cited for general cyclization techniques and systemic delivery concepts and do not allude to non-releasable linkers in context of biologically active therapeutics, and Wang explicitly teaches bone therapeutic “should be covalently attached” via acid or enzyme cleavable linkers and reinforces release-dependent paradigm. Applicant also argues that Low does not disclose non-releasable linkers or suggest the therapeutic activity can be retained while covalently tethered. Applicant cites to Low teaches correlating cytotoxicity and therapeutic performance with release of free DOX not with the activity of the tethered drug such that Low requires linker cleavage for efficacy.
In response, the examiner disagrees. First, while Marie discloses ITGA5, Marie explicitly teaches that ITGA5 “can be chemically associated with a bone seeking agent such as calcium, strontium or a bisphosphonate to target the bone tissue” (pg. 4, lines 13-15), which runs contrary to Applicant’s argument that Marie is silent to, at least, conjugation of ITGA5 with another substance. Second, while Wang discusses using enzyme cleavable linkers, Wang is utilized for its specific teachings regarding a D-aspartic acid octapeptide used for bone-targeting can be conjugated to a drug through a polyethylene glycol (PEG) linker (page 855, Scheme 2). Third, Low teaches the creation of a bone-targeting drug that contains 8-Amino-3,6-dioxaoctanoic acid (miniPEG) which was placed between 11-aminoundecanoic acid (AUA) moieties and the D-Asp8 bone-targeting moiety for additional flexibility of the backbone (see scheme 1 and 2; pg. 2013); pg. 2014, col 1, paragraph 1) and that by inserting aliphatic hydrocarbon chains and a flexible miniPEG spacer between DOX and the aspartic acid octapeptide, the design advantageously exhibits high drug loading while retaining covalent bonds between the targeting ligand and the drug. (see Scheme 1 and 2; pg. 2013, col 1). This disclosure of Low runs contrary to Applicant’s assertion that does not disclose non-releasable linkers or suggest the therapeutic activity can be retained while covalently tethered.
On pg. 15-17, Applicant argues Low’s system is built around amphiphilic unimers into micelles with therapeutic efficacy depending on precise control of polymer composition, hydrophilic-hydrophobic balance, micelle stability, circulation lifetime, and acid triggered linker cleavage to operate together as an integrated delivery strategy while the other references do not use this strategy. Applicant argues that a PHOSITA would recognize that incorporating integrin ligands or ECM components into the micellar platform would require substantial redesign of polymer architecture, linker chemistry, etc. which are not routine and would undermine the design principles of Low. Applicant further urges there is no reasonable expectation of success. Applicant argues much of the same regarding the double patenting rejections.
In response, the examiner disagrees for much of the same reasons as set forth above. First, claim 1 requires, inter alia, a compound having a structure of X-Y-Z, wherein X is an extracellular matrix component, Y is a non-releasable linker, and Z is a bone -targeting molecule polypeptide or a pharmaceutically acceptable salt thereof that binds to hydroxyapatite. The claim has been amended to recite “X is an extracellular matrix component or a fragment of an extracellular matrix component comprising an integrin ligand that retains integrin ligand receptor-binding activity without cleavage of Y or from Z”. This claim has been interpreted under broadest reasonable interpretation to mean that X (the ligand) retains functional activity when it is fused to Z directly or when linked to Z through Y. Low is specifically cited for providing the teaching that including miniPEG (i.e., a non-releasable linker, which is the same as the one used by Applicant) in a bone-targeting drug conjugate advantageously exhibits high drug loading while retaining covalent bonds between the targeting ligand and the drug. (see Scheme 1 and 2; pg. 2013, col 1). Thus, the rejections are maintained as set forth above.
Conclusion
NO CLAIMS ALLOWED.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/G.C.R./Examiner, Art Unit 1651
/THOMAS J. VISONE/Supervisory Patent Examiner, Art Unit 1672
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