DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Priority
Priority to US 62/678,016, filed 5/30/2018, is acknowledged.
Claim Status
Claims 19, 20, 23-27, 29-32, and 39-41 are under examination and claims 33-38 are currently withdrawn. Claims 1-18, 21-22, and 28 are canceled.
Claim Rejections - 35 USC § 112
Response to Arguments
Claims 19, 20, 23, 25, 27, 29-32, and 39-41 were previously rejected under 35 U.S.C. 112(a), first paragraph, as failing to comply with the written description requirement.
Applicant wrote on page 3, section IV: “Claims 19, 20, 23, 25 27, 29-32, and 39-41 are rejected under 35 § U.S.C. §112(a) as allegedly failing to comply with the written description requirement. Office Action at page 3-11. Applicant respectfully traverses, but in an effort to expedite prosecution, amends claim 19 to explicitly recite Z comprises "not less than 4 and not more than 20 amino acid residues" which the Office indicates is enabled in the Office Action at page 8. As each of the remaining claims depend (directly or indirectly) from claim 19, the rejection thereagainst under 35 § U.S.C. §112(a) are also obviated.”
Regarding claims 19, 20, 27, 29-32, and 39-40, Applicant's arguments filed 9/25/2025 have been fully considered but they are not persuasive. Applicant’s amendments have reduced the claimed genus size from 20^98 members to 20^18 members for claim 19. However, the specification fails to disclose a representative number of species for amended claim 19. This rejection is maintained as fully described below.
Regarding claims 23, 25, and 41, Applicant’s arguments, see page 3, section IV, filed 9/25/2025, with respect to claims 23, 25, and 41 have been fully considered and are persuasive. In the case of these claims, claims 23 and 25 have a minimum threshold of six aspartic acid or glutamic acid residues, which are known in the art to possess the required structure-function relationship ((Low et al., pg. 1192, Table 1). In the case of claim 41, this claim requires 20 acidic residues, which is known to possess the required structure-function relationship (Goldberg et al., page 32, col. 2, para. 1). The rejection of claims 23, 25, and 41 has been withdrawn.
Claims 19, 20, 23, 25, 27, 29-32, and 39-41 were previously rejected under 35 U.S.C. 112(a), first paragraph, because specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
Applicant wrote on page 3, section IV: “Claims 19, 20, 23, 25 27, 29-32, and 39-41 are rejected under 35 § U.S.C. §112(a) as allegedly failing to comply with the written description requirement. Office Action at page 3-11. Applicant respectfully traverses, but in an effort to expedite prosecution, amends claim 19 to explicitly recite Z comprises "not less than 4 and not more than 20 amino acid residues" which the Office indicates is enabled in the Office Action at page 8. As each of the remaining claims depend (directly or indirectly) from claim 19, the rejection thereagainst under 35 § U.S.C. §112(a) are also obviated.”
Regarding claims 19, 20, 23, 25, 27, 29-32, and 41, Applicant’s arguments, see page 3, section IV, filed 9/25/2025, with respect to claims 19, 20, 23, 25, 27, 29-32, and 41 have been fully considered and are persuasive.
As shown by Goldberg et al. (Goldberg et al. Connective Tissue Research, 42(1), 25–37 (2001)), 20 amino acid acidic oligopeptides were known in the art before the effective filing date of the claimed invention. (Goldberg et al., page 32, col. 2, para. 1). Applicant has amended the maximum length of the claimed peptides to 20 amino acids, which brings the length in line with what was known in the art. (Goldberg et al., page 32, col. 2, para. 1). For this reason, this length was previously indicated as allowable. Consequently, the enablement rejection of claims 19, 20, 23, 25, 27, 29-32, and 41 has been withdrawn.
Maintained Rejections:
Claims 19, 20, 27, 29-32, and 39-40 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.
Claim 19 is drawn to a large genus of possible bone-targeting molecules, with a potential of 20^18 members. In this case, 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 Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. (MPEP § 2163 (II.A.3.a.ii.))
According to MPEP § 2163 (II.A.3.a.ii.), 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 following bone-targeting molecules are disclosed by the Applicant:
D10, representing ten aspartic acid residues;
E10, representing ten glutamic acid residues;
(D)E10, representing ten D-glutamic acid residues.
MPEP § 2163 (II.A.3.a.ii.) states that “for inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are ‘representative of the full variety or scope of the genus,’ or by the establishment of ‘a reasonable structure-function correlation.’”
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus.
In the instant case, three species members have been disclosed with limited variation as described above. Importantly, claim 19 also allows for a bone-targeting molecule that has only two aspartic acid or glutamic acid residues. Low et al. (Advanced Drug Delivery Reviews, Vol 64, pages 1189-1204) shows in Table 1 that a targeting molecule with two acidic amino acids possesses very poor or no activity. (Low et al., pg. 1192, Table 1)
At the time the invention was made, the level of skill for preparing bone-targeting molecules and then selecting those bone-targeting molecules with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify bone-targeting molecules with the recited properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by the three provided species, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what peptide with a particular set of properties would look like structurally.
The bulk of the data provided by Applicant focuses on a bone-targeting molecule having ten aspartic acid residues. Assuming the other disclosed species have similar activity, the total number of provided peptides is still only three and possess limited structural diversity. Since only a few species of peptides are taught within the claimed genus above, the instant claims above fail the written description requirement. A representative number of species has not been taught to describe this genus. A single point mutation can change the biophysical properties of a peptide: “In summary, we have shown that the structural changes in the fibrillar state of the Aβ42 peptide that are observed to occur upon introduction of single point mutations can be accompanied by changes in the dominance of the microscopic processes by which these aggregates are themselves formed.” (Bolognesi et al. ACS Chem Bio 9:2 (2013) page 381 col. 2 para. 3) and “In summary, while ovispirin-1 and novispirin G-10 both had solution structures that were helical and amphipathic in the presence of TFE, a relatively simple change in their primary structure (a single glycine–isoleucine exchange) had profound effects on their respective toxicities for human erythrocytes and epithelial cells.” (Sawai et al. Protein Eng. 15:3 (2002) page 232 col. 1 para. 3). Given this unpredictability of protein design, the skilled artisan would not have been in possession of the vast repertoire of peptide-based bone-targeting molecules and the large number of possible peptide-based bone-targeting molecules encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every bone-targeting molecule recited by claim 19. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genus. Therefore, claim 19 is rejected.
Regarding claim 20, the limitation of requiring the bone-targeting molecule to possess an overall negative charge does not sufficiently limit the size of the genus. The genus would still include a substantial fraction of 20^18 members (any combination where negatively charged residues outnumbered positively charged residues), which is not represented by the disclosed species as described above for claim 19. Therefore, claim 20 is rejected.
Regarding claim 23, claim 23 introduces some additional constraints in the form of glutamic acid residue minimums. However, in the case where Z is Therefore, claim 23 is rejected.
Regarding claim 27, a limitation upon the linker of the compound does not change the genus-species analysis of claim 19 discussed above. Therefore, claim 27 is rejected.
Regarding claim 29, a limitation upon the linker of the compound does not change the genus-species analysis of claim 19 discussed above. Therefore, claim 29 is rejected.
Regarding claim 30, a limitation upon the linker of the compound does not change the genus-species analysis of claim 19 discussed above. Therefore, claim 30 is rejected.
Regarding claim 31, a limitation upon the linker of the compound does not change the genus-species analysis of claim 19 discussed above. Therefore, claim 31 is rejected.
Regarding claim 32, a limitation upon the Src kinase inhibitor does not change the genus-species analysis of claim 19 discussed above. Therefore, claim 32 is rejected.
Regarding claim 39, the formulation of the compound does not change the genus-species analysis of claim 19 discussed above. Requiring the bone-targeting molecule to bind to hydroxyapatite does not sufficiently reduce the size of the genus in question because a required binding target in such a large genus does not sufficiently describe functional characteristics coupled with a known or disclosed correlation between function and structure. Genus members that possess a known or disclosed correlation between function and structure make up such a small fraction of the 20^18 possible members that one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genus of every bone-targeting molecule recited by claim 39. Consequently, claim 39 is rejected.
Regarding claim 40, introducing a limitation wherein the bone-targeting molecule must possess more than ten amino acid residues inhibitor does not change the genus-species analysis of claim 19 discussed above. This yields a genus size of 20^10 members as currently claimed. Therefore, claim 40 is rejected.
Claim Rejections - 35 USC § 103
Response to Arguments
Claims 19, 20, 23-27, and 29-32 were previously rejected as being unpatentable over Pierce, Jr. et al. (U.S. Patent Application Publication 2013/0029901) in view of Low et al. (Advanced Drug Delivery Reviews, Vol 64, pages 1189-1204).
Claim 39 was previously rejected under 35 U.S.C. 103 as being unpatentable over Pierce, Jr. et al. (U.S. Patent Application Publication 2013/0029901) in view of Low et al. (Advanced Drug Delivery Reviews, Vol 64, pages 1189-1204) and in further view of Pang et al. (Pang et al. Expert Opinion on Drug Delivery, 11(7), 1075–1086 (2014)).
Claims 40 and 41 were previously rejected under 35 U.S.C. 103 as being unpatentable over Pierce, Jr. et al. (U.S. Patent Application Publication 2013/0029901) in view of Low et al. (Advanced Drug Delivery Reviews, Vol 64, pages 1189-1204) and in further view of Goldberg et al. (Goldberg et al. Connective Tissue Research, 42(1), 25–37 (2001)).
Applicant argues that Low does not describe a linker being absent or nonreleasable: “Low, taken as a whole, does not describe or otherwise allude to its linker being absent or nonreleasable. Nonreleasable linkers are not described or otherwise contemplated in Low at all, nor are there any examples provided of a conjugate having anything other than a hydrolyzable linker. Instead, Low repeatedly states that "drug release mechanisms . . . play a critical role" in its delivery systems. As such, it is erroneous to conclude that one of ordinary skill in the art would be motivated to combine the AO of Low with a nonreleasable linker with an expectation of success as alleged by the Office.” (Applicant reply, filed 9/25/2025 page 5, para 2.)
Applicant's arguments filed 9/25/2025 have been fully considered but they are not persuasive. Pierce discloses a non-releasable linker: RL can be a non-releasable linker, as to minimize susceptibility to hydrolysis such as an ether linkage. (Pierce, para. [0140], formula 76). The fact that Low does not disclose such a linker does not alter the combination of Pierce and Low: In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Applicant further argues that the nonreleasable linker of Pierce is incompatible with the targeting moiety of Low:
“This is especially true given that Low underscores the importance of drug-linker selection and the resulting release profile on the resulting conjugate's targeting and uptake efficacy. For example, Low describes that the specific linker should be selected depending on the specific payload in the conjugate and targeted delivery site to ensure timely cleavage of the linkers. For example:
Due to expression of Cat K outside the cell, Cat K specific linkers are an excellent choice for signaling compounds such as prostaglandins and bone morphogenic protein-2 (BMP-2), whereas hydrazone bonds, disulfide bonds and cathepsin B (Cat B)-sensitive linkers are better options for drugs such as chemotherapeutics, which rely on internalization by cells prior to release. Low at page 1194.
Accordingly, the Low linker cannot just be "any linker" as alleged by the Office; instead, Low describes specific considerations for linker design to effectuate release (and resulting cellular uptake) of the therapeutic payload such that the conjugate can effectively target the desired site.” ((Applicant reply, filed 9/25/2025 page 5, para 3.)
Applicant's arguments have been fully considered but they are not persuasive. The cited combination of Pierce and Low does not utilize the linker disclosed by Low. The cited combination utilizes the linker described by Pierce. Furthermore, in response to applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., a specific release and cellular uptake profile) are not recited in the rejected claims. Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Furthermore, MPEP 2143.02(I) states: “Conclusive proof of efficacy is not required to show a reasonable expectation of success. OSI Pharm., LLC v. Apotex Inc., 939 F.3d 1375, 1385, 2019 USPQ2d 379681 (Fed. Cir. 2019) .” Pierce discloses many embodiments of the formula of RT-RL-RA wherein RT is a bone targeting portion analogous to “Z” in the instant claim 1, RL is a linking portion analogous to “Y” in the instant claim 1, and RA is a bone action portion analogous to “X” in the instant claim 1. (Pierce, claims 27,28, and 29). Substitution of the targeting motif of Low into the formula of Pierce has a reasonable expectation of success because the following properties of the Low targeting moieties were measured in absence of any linker at all:
PNG
media_image1.png
284
440
media_image1.png
Greyscale
(Low, pg. 1192, Table 1).
Low remarks that Cat K linkers are a good choice in some conditions: “Due to expression of Cat K outside the cell, Cat K specific linkers are an excellent choice for signaling compounds such as prostaglandins and bone morphogenic protein-2 (BMP-2), whereas hydrazone bonds, disulfide bonds and cathepsin B (Cat B)-sensitive linkers are better options for drugs such as chemotherapeutics, which rely on internalization by the cells prior to release.” (Low, page 1194, col. 2, para. 1), but the properties of the acidic oligopeptides were measured independently of this linker type. (Low, pg. 1192, Table 1). Furthermore, this does not serve as evidence that the acidic oligopeptides will fail to function as targeting moieties in the context of the Pierce constructs. This is especially true because the properties of the acidic oligopeptides were measured independently of the effects of linkers.
Maintained Rejections:
Claims 19, 20, 23-27, and 29-32 are rejected under 35 U.S.C. 103 as being unpatentable over Pierce, Jr. et al. (U.S. Patent Application Publication 2013/0029901) in view of Low et al. (Advanced Drug Delivery Reviews, Vol 64, pages 1189-1204).
Pierce discloses a bone targeted compound with a formula of RT-RL-RA wherein RT is a bone targeting portion analogous to “Z” in the instant claim 1, RL is a linking portion analogous to “Y” in the instant claim 1, and RA is a bone action portion analogous to “X” in the instant claim 1.
RA can be Dasatinib, which is an Src kinase inhibitor: “In some embodiments, RA is a bone active portion derived from an anti-cancer agent. In some embodiments, the anti-cancer agent is doxorubicin. In some embodiments, the anti-cancer agent is dasatinib.” (Pierce, para. [0022]).
RL can be a non-releasable linker, as to minimize susceptibility to hydrolysis such as an ether linkage. (Pierce, para. [0140], formula 76).
Pierce does not teach RT wherein RT is a bone-targeting molecule comprising not less than 4 and not more than 100 amino acid residues, wherein at least two amino acids are aspartic acid or at least two amino acids are glutamic acid.
However, Low discloses that acidic oligopeptides can target bone tissue: “Similar to BPs, the HAp binding capabilities of these oligopeptides are retained after conjugation to a nanomedicine carrier via the peptide's alpha amino group.” (Low, pg. 1192, col. 2, para. 4). Low discloses acidic oligopeptides with 2, 4, 6, 8, and 10 aspartic acids and 2, 4, 6, 8, and 10 glutamic acids. (Low, pg. 1192, Table 1).
PNG
media_image1.png
284
440
media_image1.png
Greyscale
It would have been obvious to a person of ordinary skill in the art before the effective filing date of the claimed invention to combine the linker and bone active agent of Pierce with the targeting molecule Low to arrive at the invention of Applicant claim 19. A person of ordinary skill in the art would use the rationale of simple substitution for one known elemental for another to obtain predictable results to replace the reduced tetracycline motif of Pierce with the acidic oligopeptide of Low with a reasonable expectation of success. Low discloses in Figure 3 a variety of bone-targeting motifs that would all yield a reasonable expectation of success. (Low, pg. 1191, Figure 3). A person of ordinary skill in the art would also be motivated by the fact that the biocompatibility of acidic oligopeptides can be altered: “Biocompatibility can be further increased as D peptides, which are not easily recognized by the body's immune system, can replace L peptides.” (Low, pg. 1192, col. 2, para. 4). Consequently, claim 19 is rejected.
Regarding claim 20, the bone-targeted compound of claim 19 is obvious as described above. The oligopeptides disclosed by Low are negatively charged because they comprise only negatively charged amino acids (Low, pg. 1192, Table 1). Consequently, the combination of Pierce and Low read on this limitation and claim 20 is rejected.
Regarding claim 23, the bone-targeted compound of claim 19 is obvious as described above. The oligopeptides disclosed by Low can be 6, 8, or 10 glutamic acid residues (Low, pg. 1192, Table 1). Consequently, the combination of Pierce and Low read on this limitation and claim 23 is rejected.
Regarding claim 24, the bone-targeted compound of claim 23 is obvious as described above. Low discloses an oligopeptide that has 10 glutamic acids and that these glutamic acids may be D-amino acids (Low, pg. 1192, Table 1 and pg. 1192, col. 2, para. 4). Consequently, the combination of Pierce and Low read on this limitation and claim 24 is rejected.
Regarding claim 25, the bone-targeted compound of claim 19 is obvious as described above. The oligopeptides disclosed by Low can be 6, 8, or 10 aspartic acid residues (Low, pg. 1192, Table 1). Consequently, the combination of Pierce and Low read on this limitation and claim 25 is rejected.
Regarding claim 26, the bone-targeted compound of claim 25 is obvious as described above. Low discloses an oligopeptide that has 10 aspartic acids and that these glutamic acids may be D-amino acids (Low, pg. 1192, Table 1 and pg. 1192, col. 2, para. 4). Consequently, the combination of Pierce and Low read on this limitation and claim 26 is rejected.
Regarding claim 27, the bone-targeted compound of claim 19 is obvious as described above. Pierce discloses a non-releasable linker, as to minimize susceptibility to hydrolysis such as an ether linkage. (Pierce, para. [0140], formula 76). Consequently, the combination of Pierce and Low read on this limitation and claim 27 is rejected.
Regarding claim 29, the bone-targeted compound of claim 27 is obvious as described above. Pierce discloses a non-releasable linker, as to minimize susceptibility to hydrolysis such as an ether linkage. (Pierce, para. [0140], formula 76). Consequently, the combination of Pierce and Low read on this limitation and claim 29 is rejected.
Regarding claim 30, the bone-targeted compound of claim 19 is obvious as described above. Pierce discloses a non-releasable linker that can comprise two or more ethylene glycol units (Pierce, para. [0198], [0199], [0200] and formula 74). In formula 74, shown below, n’ is 1 to about 4 and RS may independently be a hydroxy group.
PNG
media_image2.png
108
424
media_image2.png
Greyscale
Consequently, the combination of Pierce and Low read on this limitation and claim 30 is rejected.
Regarding claim 31, the bone-targeted compound of claim 30 is obvious as described above. Pierce discloses a non-releasable linker that can comprise two or more ethylene glycol units (Pierce, para. [0198], [0199], [0200] and formula 74). In formula 74, shown above, n’ is 1 to about 4 and RS may independently be a hydroxy group. Consequently, the combination of Pierce and Low read on this limitation and claim 31 is rejected.
Regarding claim 32, the bone-targeted compound of claim 19 is obvious as described above. Pierce discloses that the bone active portion can be Dasatinib: “In some embodiments, RA is a bone active portion derived from an anti-cancer agent. In some embodiments, the anti-cancer agent is doxorubicin. In some embodiments, the anti-cancer agent is dasatinib.” (Pierce, para. [0022]). Consequently, the combination of Pierce and Low read on this limitation and claim 32 is rejected.
Claim 39 is rejected under 35 U.S.C. 103 as being unpatentable over Pierce, Jr. et al. (U.S. Patent Application Publication 2013/0029901) in view of Low et al. (Advanced Drug Delivery Reviews, Vol 64, pages 1189-1204) and in further view of Pang et al. (Pang et al. Expert Opinion on Drug Delivery, 11(7), 1075–1086 (2014)).
The bone-targeted compound of claim 19 is obvious as described above. Low discloses in Table 1 that acidic oligonucleotides oligopeptides with 2, 4, 6, 8, and 10 aspartic acids and 2, 4, 6, 8, and 10 glutamic acids bind to hydroxyapatite (Low, pg. 1192, Table 1). Pierce and Low do not explicitly disclose systemic or intravenous administration.
However, Pang discloses that: “In general, polymer-protein conjugates are typically administered subcutaneously or intramuscularly, whereas polymer-drug conjugates are given intravenously.” (Pang, page 1078, col. 1, para. 1). It would have been obvious to a person of ordinary skill in the art at the time of filing to combine the bone-targeted compound with the intravenous administration of Pang. A person of ordinary skill in the art would be motivated to use intravenous administration because of the advantages disclosed by Pang: “The i.v. route is the most straightforward one, and its advantages are obvious. As it shows the ability to be directed to the blood circulation and distributed throughout the body within seconds, i.v. administration is able to address the variable absorption patterns of the GI tract, resulting in immediate and complete bioavailability and thereby, accurate dosage.” (Pang, page 1078, col. 1, para. 2). Consequently, the combination of Pierce, Low, and Pang read on this limitation and claim 39 is rejected.
Claims 40 and 41 are rejected under 35 U.S.C. 103 as being unpatentable over Pierce, Jr. et al. (U.S. Patent Application Publication 2013/0029901) in view of Low et al. (Advanced Drug Delivery Reviews, Vol 64, pages 1189-1204) and in further view of Goldberg et al. (Goldberg et al. Connective Tissue Research, 42(1), 25–37 (2001)).
Regarding claim 40, the bone-targeted compound of claim 19 is obvious as described above. The combination of Pierce and Low does not explicitly disclose a bone-targeting molecule of more than 10 amino acid residues. However, Table 1 of Low shows an increasing trend in Kd. A person of ordinary skill in the art seeking to increase the Kd of binding would be motivated to make and test acidic oligopeptides of lengths greater than 10 based off the data provided by Low. A person of ordinary skill in the art would have a reasonable expectation of success because such a person has ordinary creativity according to MPEP 2141.03(I): "A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton." KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 421, 82 USPQ2d 1385, 1397 (2007)" and such a person would be able to project out the simple pattern provided by Low.
Additionally, Goldberg discloses that: “The dissociation constant for Poly(Asp) found in
this study, 1.83 μM, is intermediate between those previously reported for 20-residue (KD = 0.25 μM) and 6-residue (KD= 3.9 μM) Poly(Asp) preparations.” (Goldberg, page 32, col. 2, para. 1)
Therefore, it would have been obvious to a person of ordinary skill in the art at the time of filing to apply the known technique of making a longer acidic oligonucleotide to increase the Kd property for the purpose of creating a more tightly binding molecule with a reasonable expectation of success based on the data of Low and Goldberg. A person of ordinary skill in the art would be particularly motivated by the data of Goldberg continuing the trend established by Low. Therefore, claim 40 is rejected.
Regarding claim 41, the bone-targeted compound of claim 40 is obvious as described above. The data of Goldberg provides a KD value for the case of 20 aspartic acid residues, which is a tighter binder than the acidic oligopeptides disclosed by Low. The amino acid length disclosed by Goldberg also specifically reads on the range recited in claim 41. Consequently, it would have been obvious to a person of ordinary skill in the art at the time of filing to use the amino acid length disclosed by Goldberg as a starting point to achieve even tighter KD values. Therefore, claim 41 is rejected.
Double Patenting
Response to Arguments
Claims 19, 20, 23-27, 29 and 32 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7, 10,12, 14, 15, 19,25, 26, 28-30, 32, 33, 43-45, 48, 50, 57, 62, 64, 65, 67-70, 74, 75, and 79 of copending Application No. 18/033,658 (reference application) as evidenced by Garcia-Gomez et al. (Garcia-Gomez et al. PLoS One. 2012;7(4) (2012)).
Claims 40 and 41 were provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7, 10,12, 14, 15, 19, 25, 26, 28-30, 32, 33, 43-45, 48, 50, 57, 62, 64, 65, 67-70, 74, 75, and 79 of copending Application No. 18/033,658 (reference application) as evidenced by Garcia-Gomez et al. (Garcia-Gomez et al. PLoS One. 2012;7(4) (2012)).
Applicant's arguments filed 9/26/2025 have been fully considered but they are not persuasive. Applicant argues that: “The pending claims are patentably distinct from the cited claims of the Low '658 patent, which is not remedied by its combination Garcia- Gomez or Goldberg. In particular, the presently pending claims recite different subject matter and require structural and functional limitations not present in the cited claims of the Low '658 patent, even when considered in view of Goldberg or Garcia-Gomez. The cited combinations fail to teach or suggest the presently claimed subject matter.” (Applicant Reply, filed 9/26/2025, page 7, para. 3).
Applicant's arguments fail to comply with 37 CFR 1.111(b) because they amount to a general allegation that the claims define a patentable invention without specifically pointing out how the language of the claims patentably distinguishes them from the references.
Specifically, the ‘658 copending application discloses the following key features. Claim 1 of ‘658 discloses:
“A method of treating a spinal fusion of a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound having a structure of Formula (I):X-Y-Z Formula (I), or a pharmaceutically acceptable salt thereof, wherein: X is a bone anabolic agent; Y is absent or a linker; and Z is an osteotropic ligand, thereby treating the spinal fusion of the patient.” (emphasis added)
Claim 7 of ‘658 discloses:
“The method of claim 1, wherein Z is an AOP comprising 4 to 20 amino acid residues.”
Claim 19 of ‘658 discloses:
“The method of claim 1, wherein Z is DE10 or DE20.”
Claim 43 of ‘658 discloses:
“A pharmaceutical composition comprising a compound having a structure of Formula (I):X-Y-Z Formula (I), or a pharmaceutically acceptable salt thereof,wherein: X is a therapeutic agent for treating a spinal fusion or a diagnostic agent for identifying a spinal fusion, wherein the therapeutic agent comprises a bone anabolic agent selected from the group consisting of abaloparatide, preptin, integrin 5 beta 1 (ITGA), dasatinib, or a derivative or fragment of any of the foregoing having bone anabolic activity, and the diagnostic agent is an imaging agent,Y is absent or a linker, and Z is an osteotropic ligand.”
Claim 57 of ‘658 discloses:
“The pharmaceutical composition of claim 43 any one of claims 43, 44 and 46, wherein 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).”
Maintained Rejections:
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 19, 20, 23-27, 29 and 32 were provisionally rejected as being unpatentable overclaims 1-5, 7, 10,12, 14, 15, 19,25, 26, 28-30, 32, 33, 43-45, 48, 50, 57, 62, 64, 65, 67-70, 74, 75, and 79 of copending Application No. 18/033,658 (reference application). This rejection is maintained and further described below.
Claims 19, 20, 23-27, 29 and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7, 10,12, 14, 15, 19,25, 26, 28-30, 32, 33, 43-45, 48, 50, 57, 62, 64, 65, 67-70, 74, 75, and 79 of copending Application No. 18/033,658 (reference application) as evidenced by Garcia-Gomez et al. (Garcia-Gomez et al. PLoS One. 2012;7(4) (2012)). Although the claims at issue are not identical, they are not patentably distinct from each other because.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 19, claim 43 of the ‘658 application discloses a pharmaceutical composition of X-Y-Z, wherein X can be a therapeutic agent for treating a spinal fusion which in turn may be dasatinib, Y can be absent or a linker, and Z is an osteotropic ligand, which is equivalent to a bone-targeting moiety. Furthermore, claim 48 of the ‘658 application discloses that the linker may be a non-releasable linker. Garcia-Gomez describes how dasatinib can be used a therapeutic agent for bone disease states: “In concordance with these expectations and also in line with previous data from other groups [19–21], we were able to observe that dasatinib treatment effectively promoted the osteogenic differentiation of mesenchymal progenitors (both primary bone marrow MSCs and the hMSC-TERT cell line) as observed by increased ALP and Runx2 activities, augmented matrix mineralization and elevated expression levels of genes associated with OB differentiation (Runx2/Cbfa1, Osterix, ALP and COLIA1). (Garcia-Gomez, page 12, col. 1, para. 2). Furthermore, dasatinib is an Src inhibitor: “This in vivo efficacy is shown by the acceleration of fracture healing observed using the Src inhibitors Dasatinib and E738” (Specification, para [0011]).
Regarding the functional language “for treating a spinal fusion”, it has been shown above that all structural elements of claim Applicant claim 19 are present in ‘658 claim 43. MPEP 2112.01(II) states: “"Products of identical chemical composition can not have mutually exclusive properties." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present.”
Consequently, ‘658 discloses every element of the instant claim 19 and claim 19 is provisionally rejected.
Regarding claim 20, claim 57 of ‘658 discloses that the osteotropic ligand may be a poly D-glutamic acid chain which is necessarily negatively charged. Consequently, claim 20 is provisionally rejected.
Regarding claim 23, claim 57 of ‘658 discloses that the osteotropic ligand may be a poly D-glutamic acid chain of at least 10 repeating D-glutamic acid residues. Claim 23 recites at least 6 and no more than 20 glutamic acid residues. MPEP 2144.05 (I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.”. These ranges of residues overlap, and therefore the claim is prima facie obvious and claim 23 is provisionally rejected.
Regarding claim 24, claim 57 of ‘658 discloses that the osteotropic ligand may be a poly D-glutamic acid chain of at least 10 repeating D-glutamic acid residues. Claim 24 recites 10 glutamic acid residues. MPEP 2144.05 (I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.”. These ranges of residues overlap, and therefore the claim is prima facie obvious and claim 24 is provisionally rejected.
Regarding claim 25, claim 75 of ‘658 discloses that the osteotropic ligand may be 4 to 20
D-aspartic acid residues. Claim 25 recites a range of not less than 6 and no more than 20 aspartic acid residues. MPEP 2144.05 (I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.”. These ranges of residues overlap, and therefore the claim is prima facie obvious and claim 25 is provisionally rejected.
Regarding claim 26, claim 75 of ‘658 discloses that the osteotropic ligand may be 4 to 20
D-aspartic acid residues. Claim 26 recites 10 D-aspartic acid residues. MPEP 2144.05 (I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.”. These ranges of residues overlap, and therefore the claim is prima facie obvious and claim 25 is provisionally rejected.
Regarding claim 27, claim 48 of the ‘658 application discloses that the linker may be a non-releasable linker. Claims 27 is provisionally rejected.
Regarding claim 29, claim 25 of the ‘658 application discloses that the linker may possess at least one carbon-carbon bond, at least one amide bond, or at least one carbon-carbon bond and at least one amide bond. Claim 25 of the instant application recites a carbon-carbon bond or an amide bond, and so consequently, claim 29 is provisionally rejected.
Regarding claim 32, claim 43 of the ‘658 application discloses that the therapeutic agent may be dasatinib. Consequently claim 32 is provisionally rejected.
Claims 40 and 41 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7, 10,12, 14, 15, 19, 25, 26, 28-30, 32, 33, 43-45, 48, 50, 57, 62, 64, 65, 67-70, 74, 75, and 79 of copending Application No. 18/033,658 (reference application) as evidenced by Garcia-Gomez et al. (Garcia-Gomez et al. PLoS One. 2012;7(4) (2012)). Although the claims at issue are not identical, they are not patentably distinct from each other because.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 40, claim 57 of the ‘658 application recites an osteotropic ligand which can be at least 10 repeating D-glutamic acid residues. Claim 40 recites a bone-targeting molecule having more than 10 amino acids. MPEP 2144.05 (I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.”. These ranges of residues overlap, and therefore the claim is prima facie obvious and claim 40 is provisionally rejected.
Regarding claim 41, claim 57 of the ‘658 application recites an osteotropic ligand which can be at least 20 repeating D-glutamic acid residues. Claim 41 recites a bone-targeting molecule having at least 20 aspartic acid or glutamic amino acids. MPEP 2144.05 (I) states: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists.”. These ranges of residues overlap, and therefore the claim is prima facie obvious and claim 41 is provisionally rejected.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to David Paul Bowles whose telephone number is (571)272-0919. The examiner can normally be reached Monday-Friday 8:30-5:00.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Lianko Garyu can be reached on (571) 270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/DAVID PAUL BOWLES/ Examiner, Art Unit 1654
/LIANKO G GARYU/ Supervisory Patent Examiner, Art Unit 1654