A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 4/21/2026 has been entered.
DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Amendment after Final office action filed on 4/21/2026 is acknowledged.
3. Claims 5-10, 14, 15 and 21 have been cancelled.
4. Claims 1-4, 11-13, 16-20 and 22 are pending in this application.
5. Claims 13 and 16-20 remain withdrawn from consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim. Claim 12 remains withdrawn from consideration as being not read on either the elected species or the non-elected species found in the prior art.
6. Applicant elected without traverse of Group 1 (claims 1-12) and elected without traverse of compound of X-Y-Z wherein Z comprises not less than 6 and not more than 35 glutamic acid residues (Claim 3), Y is a non-releasable linker (Claim 5), and X is at least one polypeptide having at least 80% sequence identity to a full length parathyroid hormone (SEQ ID NO: 13) (Claim 12) as species of compound in the reply filed on 3/13/2023.
Please note: As stated in the previous office actions, first, compound of X-Y-Z wherein Z comprises not less than 6 and not more than 35 glutamic acid residues (Claim 3), Y is a non-releasable linker (Claim 5), and X is at least one polypeptide having at least 80% sequence identity to a full length parathyroid hormone (SEQ ID NO: 13) (Claim 12) as the elected species of compound in the reply filed on 3/13/2023 is improper, since the elected compound is a subgenus, not a species. A proper species of compound of X-Y-Z should be a single disclosed species of compound of X-Y-Z wherein ALL the variables are elected to arrive at a compound of X-Y-Z with a specific/defined structure and/or consisting of a specific/defined amino acid sequence (if Y is a peptide). Second, the elected species of compound in the reply filed on 3/13/2023 does not read on the pending claims, because X being at least one polypeptide having at least 80% sequence identity to a full length parathyroid hormone (SEQ ID NO: 13) in the elected species of compound of X-Y-Z does not read on X being a bone anabolic agent comprising a parathyroid hormone receptor 1 (PTHR1) polypeptide agonist having at least 80% sequence identity to SEQ ID NO: 3 recited in instant claimed compound having a structure of X-Y-Z. Therefore, compound of X-Y-Z wherein Z comprises not less than 6 and not more than 35 glutamic acid residues (Claim 3), Y is a non-releasable linker (Claim 5), and X is at least one polypeptide having at least 80% sequence identity to a full length parathyroid hormone (SEQ ID NO: 13) (Claim 12) as the elected species of compound would not be searched and examined in the current office action.
Restriction requirement was deemed proper and made FINAL in the previous office actions. Group 1 is drawn to a compound having a structure of: X-Y-Z, wherein: Z is a peptide that comprises glutamic acid residues, aspartic acid residues, or a combination thereof, wherein the peptide is 6 to 35 acidic amino acid residues selected from glutamic acid residues, aspartic acid residues, or a combination thereof; Y is a peptide linker consisting of amino acid residues joined exclusively by peptide bonds, wherein Y is non-releasable and does not comprise a hydrolytically cleavable linkage; and X is a bone anabolic agent comprising a parathyroid hormone receptor 1 (PTHR1) polypeptide agonist having at least 80% sequence identity to SEQ ID NO: 3, or a pharmaceutically acceptable salt thereof. A search was conducted on the genus in claim 1; and prior art was found. Claim 12 remains withdrawn from consideration as being not read on either the elected species or the non-elected species found in the prior art. Claims 1-4, 11 and 22 are examined on the merits in this office action.
Response to Applicant's Arguments About the Elected Species
7. With regards to Applicant’s arguments about the elected species of compound of X-Y-Z, as stated in the Non-final office action dated 3/27/2025, this application has been transferred to the current Examiner. And in the Non-final office action dated 3/27/2025 (the first office action issued by the current Examiner), the Examiner explicilty states that the elected species of compound in the reply filed on 3/13/2023 is improper, since the elected compound is a subgenus, not a species. Furthermore, X being at least one polypeptide having at least 80% sequence identity to a full length parathyroid hormone (SEQ ID NO: 13) in the elected species of compound of X-Y-Z does not read on X being a bone anabolic agent comprising a parathyroid hormone receptor 1 (PTHR1) polypeptide agonist having at least 80% sequence identity to SEQ ID NO: 3 recited in the instant claimed compound having a structure of X-Y-Z, as shown below with Query being instant SEQ ID NO: 3, and Sbjct being instant SEQ ID NO: 13:
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156
688
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. Based on the sequence alignment above, one of ordinary skilled in the art would understand and reasonably expect that X being at least one polypeptide having at least 80% sequence identity to a full length parathyroid hormone (SEQ ID NO: 13) cannot read on X being a bone anabolic agent comprising a parathyroid hormone receptor 1 (PTHR1) polypeptide agonist having at least 80% sequence identity to SEQ ID NO: 3. Therefore, it is proper for the current Examiner to state that the elected species of compound in the reply filed on 3/13/2023 does not read on the pending claims; and the elected species of compound would not be searched and examined in the current office action.
Withdrawn Rejections
8. Rejection to claim 21 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph is hereby withdrawn in view of Applicant’s amendment to the claim.
Maintained/Revised Rejections
Claim Rejections - 35 U.S.C. § 112 paragraph (b)
9. The following is a quotation of 35 U.S.C. 112(b):
(B) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
10. Claims 1-4, 11 and 22 remain rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
11. (Revised due to Applicant’s amendment to the claim) Claim 1 recites the limitation “Y is a peptide linker consisting of amino acid residues joined exclusively by peptide bonds, wherein Y is non-releasable and does not comprise a hydrolytically cleavable linkage”. With regards to the recited “Y is a peptide linker consisting of amino acid residues joined exclusively by peptide bonds, wherein Y is non-releasable and does not comprise a hydrolytically cleavable linkage”, the instant specification fails to define it. The instant specification provides some examples of a non-releasable peptide linker, such as “In some aspect of the disclosure, the linker may be any portion of the extension of PTH or PTHrP's active fragment, namely from residues 35-84 of PTH or 35-173 of PTHrP. Such extension of the active fragment is usually non-releasable and the linker sequence can be any portion of the extension or the combinations of different portions of the extension” (see for example, page 32, paragraph [00239] of instant specification). However, based on the PTH35-84 peptide cut document (2025, pages 1-5, from https://web.expasy.org/peptide_cutter/, cited and enclosed in the previous office action), residues 35-84 of PTH comprise various hydrolytically cleavable linkages (see for example, page 4). Therefore, it is unclear what is encompassed within the recited “Y is a peptide linker consisting of amino acid residues joined exclusively by peptide bonds, wherein Y is non-releasable and does not comprise a hydrolytically cleavable linkage”; and the metes and bounds of instant claim 1 is vague and indefinite. Because claims 2-4, 11 and 22 depend from indefinite claim 1, and none of the dependent claims clarifies the point of confusion, they must also be rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph.
Response to Applicant's Arguments
12. Applicant argues that “The specification clearly and repeatedly distinguishes between "non-releasable" and "releasable" linkers…A person of ordinary skill in the art would understand that a "non-releasable" linker is one that is not designed to cleave in response to a defined biological trigger and remains intact under physiological conditions.” Applicant further argues “the Office's own reliance on McCombs and Chen in the § 103 rejection, which describe "non-cleavable" or "non-releasable" linkers as linkers that are not designed to undergo cleavage to release a payload under physiological conditions. The Office cannot reasonably rely on these references to establish what constitutes a non-releasable linker while simultaneously asserting that Applicant's use of the same term is indefinite.” Applicant also argues that “the Office's reliance on Peptide Linker Document output for PTH 35-84 is misplaced. Such tools identify theoretical cleavage sites, not actual in vivo release behavior in the context of the claimed conjugates. The cited sequence is merely an example, not a definitional boundary.” Furthermore, Applicant argues that “Under the Office's interpretation, no peptide linker could qualify as "non-releasable," because all peptides are theoretically susceptible to proteolysis. Such an interpretation is not reasonable and is inconsistent with how the term is used in the art.”; and “The rejection is based on an unreasonably strict and technically incorrect interpretation of "non-releasable," not on any genuine ambiguity in the claims. In view of the clarifying amendment, the consistent disclosure, and the established understanding in the art (including in the Office's own cited references), the rejection under 35 U.S.C. § 112(b) should be withdrawn.”
13. Applicant's arguments have been fully considered but have not been found persuasive.
In response to Applicant's arguments about instant rejection:
First, as stated in Section 11 above, in the instant case, with regards to the recited “Y is a peptide linker consisting of amino acid residues joined exclusively by peptide bonds, wherein Y is non-releasable and does not comprise a hydrolytically cleavable linkage”, the instant specification fails to define it. The Examiner would like to point out that preferred embodiments and/or examples are not the same as definition.
Second, as stated in Section 11 above, the instant specification discloses PTH35-84 peptide as an example of the instant claimed linker Y. The Examiner has provided evidence that PTH35-84 peptide comprises various hydrolytically cleavable linkages. And since the USPTO lacks the experimental facilities to make a further determination, the burden is on the Applicant to prove the otherwise. However, in the instant case, other than statements/arguments, Applicant fails to provide any data and/or evidence to prove these various hydrolytically cleavable linkages in PTH35-84 peptide are only theoretical cleavage sites, not actually hydrolytically cleavable linkages.
Third, the Examiner would like to point out that the Examiner’s interpretation of non-releasable peptide linker is both reasonable and consistent with how the term is used in the peptide/protein art, including McCombs et al and Chen et al cited in the § 103 rejection. As an example, the peptide linker (GGGGS)3 is known in the peptide/protein art as a non-releasable peptide linker (as explicilty taught in Chen et al cited in the § 103 rejection). And based on the GGGGS linker peptide cut document (from https://web.expasy.org/peptide_cutter/, 2025, pages 1-2, cited and enclosed in the previous office action), the peptide linker (GGGGS)3 is indeed non-releasable and does not comprise any hydrolytically cleavable linkage (see page 2).
Taken all these together, the rejection is deemed proper and is hereby maintained.
The GGGGS linker peptide cut document is cited only for the purpose of rebutting the Applicant’s arguments, therefore, it is not cited as a prior art reference.
Claim Rejections - 35 U.S.C. § 112 paragraph (a)
Written Description
14. The following is a quotation 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 35 U.S.C. 112 (pre-AIA ), first paragraph:
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.
15. (Revised due to Applicant’s amendment to the claim) Applicant is required to cancel the new matter in the reply to this Office Action.
Claim 22 remains 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 claims contain 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, at the time the application was filed, had possession of the claimed invention.
The MPEP states that “The introduction of claim changes which involve narrowing the claims by introducing elements or limitations which are not supported by the as-filed disclosure is a violation of the written description requirement of 35 U.S.C. 112, first paragraph. See, e.g., Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) (a “laundry list” disclosure of every possible moiety does not constitute a written description of every species in a genus because it would not “reasonably lead” those skilled in the art to any particular species); In re Ruschig, 379 F.2d 990, 995, 154 USPQ 118, 123 (CCPA 1967) (“If n-propylamine had been used in making the compound instead of n-butylamine, the compound of claim 13 would have resulted. Appellants submit to us, as they did to the board, an imaginary specific example patterned on specific example 6 by which the above butyl compound is made so that we can see what a simple change would have resulted in a specific supporting disclosure being present in the present specification. The trouble is that there is no such disclosure, easy though it is to imagine it.”) (emphasis in original). In Ex parte Ohshiro, 14 USPQ2d 1750 (Bd. Pat. App. & Inter. 1989), the Board affirmed the rejection under 35 U.S.C. 112, first paragraph, of claims to an internal combustion engine which recited “at least one of said piston and said cylinder (head) having a recessed channel.” The Board held that the application which disclosed a cylinder head with a recessed channel and a piston without a recessed channel did not specifically disclose the “species” of a channeled piston.” (see MPEP § 2163).
In the instant case, claim 22 recites “The compound of claim 1, wherein the PTHR1 polypeptide agonist has a valine at residue 2, a serine at residue 3, a glutamic acid at residue 4, a glutamine at residue 6, a leucine at residue 7, a histidine at residue 9, a glycine at residue 12, and a lysine at residue 13”.
With regards to the recited “wherein the PTHR1 polypeptide agonist has a valine at residue 2, a serine at residue 3, a glutamic acid at residue 4, a glutamine at residue 6, a leucine at residue 7, a histidine at residue 9, a glycine at residue 12, and a lysine at residue 13”, the recitation has never been explicitly disclosed and/or discussed in the instant specification. The detailed explanations are as followings:
Lack of Ipsis Verbis Support
The specification is void of any literal support for the limitation “wherein the PTHR1 polypeptide agonist has a valine at residue 2, a serine at residue 3, a glutamic acid at residue 4, a glutamine at residue 6, a leucine at residue 7, a histidine at residue 9, a glycine at residue 12, and a lysine at residue 13” recited in instant claim 22. Therefore, the instant specification fails to provide literal support to the limitation “wherein the PTHR1 polypeptide agonist has a valine at residue 2, a serine at residue 3, a glutamic acid at residue 4, a glutamine at residue 6, a leucine at residue 7, a histidine at residue 9, a glycine at residue 12, and a lysine at residue 13” recited in instant claim 22.
Lack of Implicit or Inherent Support
“While there is not in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure.” See MPEP § 2163. Thus support can be furnished implicitly or inherently for a specifically claimed limitation. In the instant case, the instant specification discloses PTHR1 polypeptide agonist is homologous to SEQ ID NO: 3 at least at residues 2, 3, 4, 6, 7, 9, 12, and 13 of SEQ ID NO: 3, for example, page 6, paragraph [0023] of instant specification. However, as stated in the previous office actions, it is well known in the art that “In its precise biological meaning, “homology” is a concept of quality. The word asserts a type of relationship between two or more things. Thus, amino acid or nucleotide sequences are either homologous or they are not. They cannot exhibit a particular “level of homology” or “percent homology”. Instead, two sequences possess a certain level of similarity. Similarity is thus a quantitative property. Homologous proteins or nucleic acid segments can range from highly similar to not recognizably similar (where similarity has disappeared through divergent evolution).” (see page 667, left column, the 2nd paragraph in Reeck et al, Cell, 1987, 50, page 667, cited and enclosed in the previous office action). Furthermore, Pearson (Current Protocols in Bioinformatics, 2013, pages 3.1.1-3.1.8, cited and enclosed in the previous office action) explicitly states that homologous sequences do not always share significant sequence similarity; there are thousands of homologous protein alignments that are not significant, but are clearly homologous based on statistically significant structural similarity or strong sequence similarity to an intermediate sequence (see page 3.1.2, the 2nd paragraph). Therefore, it is determined that the instant specification fails to provide any implicit or inherent support to the limitation “wherein the PTHR1 polypeptide agonist has a valine at residue 2, a serine at residue 3, a glutamic acid at residue 4, a glutamine at residue 6, a leucine at residue 7, a histidine at residue 9, a glycine at residue 12, and a lysine at residue 13” recited in instant claim 22.
Taken all these together, the instant specification fails to provide support to the limitation “wherein the PTHR1 polypeptide agonist has a valine at residue 2, a serine at residue 3, a glutamic acid at residue 4, a glutamine at residue 6, a leucine at residue 7, a histidine at residue 9, a glycine at residue 12, and a lysine at residue 13” recited in instant claim 22.
Response to Applicant's Arguments
16. Applicant argues that “Without conceding the merits of this rejection, in this response, Applicant cancels claim 22, thereby obviating this rejection. Accordingly, Applicant respectfully submits that this rejection should be withdrawn.”
17. Applicant's arguments have been fully considered but have not been found persuasive.
In response to Applicant’s arguments about instant rejection, the Examiner would like to point out that instant claim 22 is not cancelled in the claim filed on 4/21/2026. Therefore, the rejection is deemed proper and is hereby maintained.
Claim Rejections - 35 U.S.C. § 103
18. 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 of this title, 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.
19. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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.
20. (Revised due to Applicant’s amendment to the claim) Claims 1-4, 11 and 22 remain rejected under 35 U.S.C. 103 as being unpatentable over Bentz et al (WO 92/20371 A1, filed with IDS) in view of Takahashi-Nishioka et al (Current Drug Discovery Technologies, 2008, 5, pages 39-48, cited and enclosed in the previous office action) and Leder et al (J Clin Endocrinol Metab, 2015, 100, pages 697-706, cited and enclosed in the previous office action), and as evidenced by the Abaloparatide document (from https://pubchem.ncbi.nlm.nih.gov/compound/Abaloparatide, 2026, enclosed pages 1-40) and the Aminoisobutyric acid document (2026, enclosed pages 1-56, from https://pubchem.ncbi.nlm.nih.gov/compound/Aminoisobutyric-acid), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351, cited and enclosed in the previous office action) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369, cited and enclosed in the previous office action), and as evidenced by the GGGGS linker peptide cut document (2025, pages 1-2, from https://web.expasy.org/peptide_cutter/, cited and enclosed in the previous office action).
The instant claims 1-4, 11 and 22 are drawn a compound having a structure of: X-Y-Z, wherein: Z is a peptide that comprises glutamic acid residues, aspartic acid residues, or a combination thereof, wherein the peptide is 6 to 35 acidic amino acid residues selected from glutamic acid residues, aspartic acid residues, or a combination thereof; Y is a peptide linker consisting of amino acid residues joined exclusively by peptide bonds, wherein Y is non-releasable and does not comprise a hydrolytically cleavable linkage; and X is a bone anabolic agent comprising a parathyroid hormone receptor 1 (PTHR1) polypeptide agonist having at least 80% sequence identity to SEQ ID NO: 3, or a pharmaceutically acceptable salt thereof.
Bentz et al, throughout the patent, teach a conjugate comprising bone growth factor and targeting molecule, wherein the bone growth factor and the targeting molecule are chemically conjugated via a crosslinker; wherein the crosslinker preferably is a synthetic hydrophilic polymer such as polyethylene glycol (PEG); wherein the targeting molecules preferably have an affinity for bone, such as polyaspartic acid, polyglutamic acid and many others; and wherein such conjugate can be used to repair, prevention, or alleviation of bone defects, especially defects due to loss of bone, such as bone loss due to osteoporosis, for example, Abstract; page 6, line 31 to page 7, line 6; page 9, line 30 to page 10, line 33; and page 12, lines 10-19. It meets the limitation of Z comprising glutamic acid residues or aspartic acid residues recited in instant claim 1; and the limitation of instant claim 2.
The difference between the reference and instant claims 1-4, 11 and 22 is that the reference does not explicitly teach X, Y and the length of Z in the compound recited in instant claim 1; and the limitations of instant claims 3, 4, 11 and 22.
However, similar to the bone targeting molecules taught in Bentz et al, Takahashi-Nishioka et al, throughout the literature, teach acidic oligopeptides consisting of 6, 8 or 10 L-Glu or L-Asp bind strongly to hydroxyapatite (HAP), and function as a bone targeting molecule for targeting drug delivery to bone, for example, Abstract; and page 40, Table 1. Therefore, in view of the combined teachings of Bentz et al and Takahashi-Nishioka et al, it would have been obvious to one of ordinary skilled in the art to apply the bone targeting molecule taught in Takahashi-Nishioka et al in the conjugate taught in Bentz et al.
Furthermore, Leder et al, throughout the literature, teach osteoporotic fractures are expected to have an increasing effect on the health of our population; abaloparatide as a potential anabolic agent in the treatment of postmenopausal osteoporosis; and compared with placebo, 24 weeks of daily sc abaloparatide increases BMD of the lumbar spine, femoral neck, and total hip in a dose-dependent fashion, for example, page 697, Sections “Context” and “Conclusions”; and page 698, left column, the 1st paragraph. And as evidenced by the Abaloparatide document, the abaloparatide in Leder et al consists of the amino acid sequence AVSEHQLLHDKGKSIQDLRRRELLEK LLAibKLHTA-NH2 (see the amino acid sequence on page 4). And further as evidenced by the Aminoisobutyric acid document, Aib is the same as 2-methyl-alanine (see page 1, Section “Synonyms”). Therefore, the abaloparatide in Leder et al is 100% identical to the peptide of instant SEQ ID NO: 3.
In addition, McCombs et al teach that the greatest advantage of having non-cleavable linkers in active targeting drug conjugate is their increased plasma stability when compared to many cleavable linkers; and despite the limited “bystander” effect, the resistance to cleavage outside of target cells may actually increase the specificity of drug release, for example, page 344, right column, the 2nd paragraph in Section “Non-cleavable Linkers”.
And, Chen et al teach flexible linkers such as (GGGGS)3 are usually applied when the joined domains require a certain degree of movement or interaction, and such linkers increase stability and/or folding of the fusion product, for example, pages 1359-1361, Section “3.1. Flexible linkers”; and Table 3. And as evidenced by the GGGGS linker peptide cut document, (GGGGS)3 is a peptide linker that is non-releasable and does not comprise a hydrolytically cleavable linkage.
Therefore, it would have been obvious to one of ordinary skilled in the art to combine the teachings of Bentz et al, Takahashi-Nishioka et al, Leder et al, McCombs et al and Chen et al to develop a conjugate/compound of X-Y-Z, wherein X is abaloparatide as a bone anabolic agent (100% identical to the peptide of instant SEQ ID NO: 3), Y is a peptide linker consisting of amino acid residues joined exclusively by peptide bonds and is non-releasable and does not comprise a hydrolytically cleavable linkage, such as (GGGGS)3, and Z consists of 6, 8 or 10 L-Glu or L-Asp and binds to hydroxyapatite (HAP), and wherein such conjugate/compound can be used to repair, prevention, or alleviation of bone defects, especially defects due to loss of bone, such as bone loss due to osteoporosis and osteoporotic fractures.
One of ordinary skilled in the art would have been motivated to combine the teachings of Bentz et al, Takahashi-Nishioka et al, Leder et al, McCombs et al and Chen et al to develop a conjugate/compound of X-Y-Z, wherein X is abaloparatide as a bone anabolic agent (100% identical to the peptide of instant SEQ ID NO: 3), Y is a peptide linker consisting of amino acid residues joined exclusively by peptide bonds and is non-releasable and does not comprise a hydrolytically cleavable linkage, such as (GGGGS)3, and Z consists of 6, 8 or 10 L-Glu or L-Asp and binds to hydroxyapatite (HAP), and wherein such conjugate/compound can be used to repair, prevention, or alleviation of bone defects, especially defects due to loss of bone, such as bone loss due to osteoporosis and osteoporotic fractures, because similar to the bone targeting molecules taught in Bentz et al, Takahashi-Nishioka et al teach acidic oligopeptides consisting of 6, 8 or 10 L-Glu or L-Asp bind strongly to hydroxyapatite (HAP), and function as a bone targeting molecule for targeting drug delivery to bone. Therefore, in view of the combined teachings of Bentz et al and Takahashi-Nishioka et al, it would have been obvious to one of ordinary skilled in the art to apply the bone targeting molecule taught in Takahashi-Nishioka et al in the conjugate taught in Bentz et al. Leder et al, throughout the literature, teach osteoporotic fractures are expected to have an increasing effect on the health of our population; abaloparatide (100% identical to the peptide of instant SEQ ID NO: 3) as a potential anabolic agent in the treatment of postmenopausal osteoporosis; and compared with placebo, 24 weeks of daily sc abaloparatide increases BMD of the lumbar spine, femoral neck, and total hip in a dose-dependent fashion. McCombs et al teach that the greatest advantage of having non-cleavable linkers in active targeting drug conjugate is their increased plasma stability when compared to many cleavable linkers; and despite the limited “bystander” effect, the resistance to cleavage outside of target cells may actually increase the specificity of drug release. And, Chen et al teach flexible linkers such as (GGGGS)3 are usually applied when the joined domains require a certain degree of movement or interaction, and such linkers increase stability and /or folding of the fusion product. In the instant case, the conjugate/compound developed from the combined teachings of Bentz et al, Takahashi-Nishioka et al, Leder et al, McCombs et al and Chen et al is a simple substitution of one known element for another to obtain predictable results (see MPEP § 2143 I).
A person of ordinary skilled in the art would have reasonable expectation of success in combining the teachings of Bentz et al, Takahashi-Nishioka et al, Leder et al, McCombs et al and Chen et al to develop a conjugate/compound of X-Y-Z, wherein X is abaloparatide as a bone anabolic agent (100% identical to the peptide of instant SEQ ID NO: 3), Y is a peptide linker consisting of amino acid residues joined exclusively by peptide bonds and is non-releasable and does not comprise a hydrolytically cleavable linkage, such as (GGGGS)3, and Z consists of 6, 8 or 10 L-Glu or L-Asp and binds to hydroxyapatite (HAP), and wherein such conjugate/compound can be used to repair, prevention, or alleviation of bone defects, especially defects due to loss of bone, such as bone loss due to osteoporosis and osteoporotic fractures.
Response to Applicant's Arguments
21. Applicant argues that there is no motivation to combine the cited prior art references and there is no reasonable expectation of success by arguing about each of the cited prior art references individually; and the claimed invention is not a "simple substitution". Applicant further argues that the rejection is based on impermissible hindsight reconstruction; and the rejection is inconsistent with Federal Circuit precedent on obviousness.
22. Applicant's arguments have been fully considered but have not been found persuasive.
Please note: For the better understanding of the amino acid sequence of the abaloparatide in Leder et al, the Abaloparatide document (2026, enclosed pages 1-40, from https://pubchem.ncbi.nlm.nih.gov/compound/Abaloparatide) and the Aminoisobutyric acid document (2026, enclosed pages 1-56, from https://pubchem.ncbi.nlm.nih.gov/compound/Aminoisobutyric-acid) are cited as evidentiary references in instant rejection.
In response to Applicant's arguments about instant rejection, the Examiner agrees that none of the cited references individually teaches or suggests the compound recited in instant claims 1-4, 11 and 22; and none of the cited references anticipates the compound recited in instant claims 1-4, 11 and 22. However, the Examiner would like to point out that instant claims 1-4, 11 and 22 are rejected under 35 U.S.C. 103 (obviousness type), and the rejection is based on the combined teachings of Bentz et al, Takahashi-Nishioka et al, Leder et al, McCombs et al and Chen et al; therefore, it is not necessary for each of the cited references to teach all the limitations of instant claims. Furthermore, the Examiner would like to point out that the MPEP states "One cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references…" (see MPEP § 2145 IV). In addition, with regards to Applicant’s arguments of the numbers (5) of reference cited in instant rejection, the Examiner would like to point out that the MPEP states “Reliance on a large number of references in a rejection does not, without more, weigh against the obviousness of the claimed invention…” (see MPEP § 2145 V).
In response to Applicant's arguments that there is no motivation to combine the cited prior art references and there is no reasonable expectation of success:
First, the Examiner would like to point out that Bentz et al, Takahashi-Nishioka et al, Leder et al, McCombs et al and Chen et al are all in the same field of active targeting drug delivery via a conjugate and/or fusion protein comprising a targeting moiety coupled to a drug via a linker.
Second, as stated in Section 20 above, in the instant case, Bentz et al, throughout the patent, teach a conjugate comprising bone growth factor and targeting molecule, wherein the bone growth factor and the targeting molecule are chemically conjugated via a crosslinker, and wherein the targeting molecules preferably have an affinity for bone, such as polyaspartic acid, polyglutamic acid and many others. Similar to the bone targeting molecules taught in Bentz et al, Takahashi-Nishioka et al teach acidic oligopeptides consisting of 6, 8 or 10 L-Glu or L-Asp bind strongly to hydroxyapatite (HAP), and function as a bone targeting molecule for targeting drug delivery to bone. Therefore, in view of the combined teachings of Bentz et al and Takahashi-Nishioka et al, it would have been obvious to one of ordinary skilled in the art to apply the bone targeting molecule taught in Takahashi-Nishioka et al in the conjugate taught in Bentz et al. And Leder et al, throughout the literature, teach osteoporotic fractures are expected to have an increasing effect on the health of our population; abaloparatide (100% identical to the peptide of instant SEQ ID NO: 3) as a potential anabolic agent in the treatment of postmenopausal osteoporosis. The Examiner understands that in the cited Takahashi-Nishioka et al reference, the linker used in the active targeting conjugates comprising three different small molecular drugs is releasable linker; and for these particular small molecular drugs, in comparison to the free/released drug, the activity of drug in the conjugate is decreased. However, in the instant case, Takahashi-Nishioka et al explicilty teach that for these particular small molecular drugs, such effect is likely due to the increased hydrophilicity arising from the acidic oligopeptide tag. Therefore, in the instant case, considering the state of art regarding active targeting drug delivery via a conjugate and/or fusion protein comprising a targeting moiety coupled to a drug via a linker, and in view of the teachings of Takahashi-Nishioka et al as a whole, one of ordinary skilled in the art would understand and reasonably expect that the observation regarding these three small molecular drugs in Takahashi-Nishioka et al is less likely to apply to all type of conjugate and/or fusion protein/polypeptide comprising a targeting moiety coupled to a drug via a linker, such as a conjugate comprising the 34-amino acid peptide abaloparatide (100% identical to the peptide of instant SEQ ID NO: 3). And one of ordinary skilled in the art would not reach the conclusion that Takahashi-Nishioka et al teach away from a non-releasable linker in all type of conjugate and/or fusion protein/polypeptide comprising a targeting moiety coupled to a drug via a linker. Furthermore, McCombs et al explicilty teach that the greatest advantage of having non-cleavable linkers in conjugate is their increased plasma stability when compared to many cleavable linkers; and despite the limited “bystander” effect, the resistance to cleavage outside of target cells may actually increase the specificity of drug release. And, Chen et al teach flexible linkers such as (GGGGS)3 are usually applied when the joined domains require a certain degree of movement or interaction, and such linkers increase stability and /or folding of the fusion product. In addition, other than statements/arguments, Applicant fails to provide any evidence and/or reasoning that abaloparatide taught in Leder et al cannot be conjugated to a bone targeting molecule via a peptide linker such as (GGGGS)3 for targeting delivery to bone. And, the Examiner would like to point out that in the instant case, since X in the claimed compound is one comprising the amino acid sequence that is at least 80% identical to instant SEQ ID NO: 3, X in the claimed compound can have extra amino acids added to instant SEQ ID NO: 3. Considering both Z and Y in the claimed compound are peptides, one of ordinary skilled in the art would understand and reasonably expect the fusion protein/conjugate/compound developed from the combined teachings of Bentz et al, Takahashi-Nishioka et al, Leder et al, McCombs et al and Chen et al in Section 20 above would have similar property/functionality as that of abaloparatide (100% identical to the peptide of instant SEQ ID NO: 3). Therefore, in the instant case, in view of the combined teachings of the cited prior art references as set forth in Section 20 above, it would have been obvious to one of ordinary skilled in the art, and/or one of ordinary skilled in the art would have been motivated to develop a conjugate/compound of X-Y-Z recited in instant claims 1-4, 11 and 22.
Third, with regards to Applicant’s arguments regarding instant SEQ ID NO: 3, the Examiner understands that Leder et al do not explicilty disclose the amino acid sequence of abaloparatide. However, in the instant case, as evidenced by both the Abaloparatide document and the Aminoisobutyric acid document, one of ordinary skilled in the art would understand that the abaloparatide in Leder et al is 100% identical to the peptide of instant SEQ ID NO: 3. It is unclear to the Examiner how and/or why Applicant reaches the conclusion that instant SEQ ID NO: 3 is not disclosed in the cited prior art references. Further clarification is required. And since the abaloparatide in Leder et al is 100% identical to the peptide of instant SEQ ID NO: 3, it is unclear to the Examiner what kind of sequence alignment, residue-by-residue comparison and analysis of sequence identity is required by Applicant. In the instant case, since the instant application is in the field of peptide/protein science, it is the Examiner’s position that Applicant is capable of determining whether a prior art peptide sequence is the same as the instant claimed peptide sequence or not; and Applicant is capable of understanding what the statement “the abaloparatide in Leder et al is 100% identical to the peptide of instant SEQ ID NO: 3” means. In the event that Applicant is incapable of doing any of these above, below is a sequence alignment between instant SEQ ID NO: 3 (being Query) and the abaloparatide in Leder et al (being Sbjct), wherein A at position 29 is Aib (the same as 2-methyl-alanine) and C-terminus is amidated:
PNG
media_image2.png
120
680
media_image2.png
Greyscale
.
Fourth, as stated above, considering the state of art regarding active targeting drug delivery via a conjugate and/or fusion protein comprising a targeting moiety coupled to a drug via a linker, and in view of the teachings of McCombs et al, one or ordinary skilled in the art would understand that Takahashi-Nishioka et al do not teach away a non-releasable linker in every type of active targeting drug delivery via a conjugate and/or fusion protein comprising a targeting moiety coupled to a drug via a linker.
Fifth, the Examiner understands that not all linkers are the same, and McCombs et al discuss potential issues with a conjugate and/or fusion protein wherein the drug is MMAE. However, in the instant case, considering the state of art regarding active targeting drug delivery via a conjugate and/or fusion protein comprising a targeting moiety coupled to a drug via a linker, and in view of the teachings of McCombs et al as a whole, one of ordinary skilled in the art would understand and reasonably expect that the potential issue with a ADC comprising the drug MMAE in McCombs et al is less likely to apply to every type of active targeting drug delivery via a conjugate and/or fusion protein comprising a targeting moiety coupled to a drug via a linker.
Sixth, with regards to Applicant’s arguments about Chen et al and the instant claimed compound is a polypeptide, not a protein, the Examiner would like to point out that the compound recited in instant claims can be a protein, since there is no limitation on the number of amino acids of X recited in instant claims 1-4 and 22; and the length of Y in the instant claimed compound is not limited. Therefore, it is unclear to the Examiner how and/or why the teachings of Chen et al would not be apply to instant claimed compound. Further clarification is required.
Seventh, with regards to Applicant’s arguments that the conjugate/compound developed from the combined teachings of Bentz et al, Takahashi-Nishioka et al, Leder et al, McCombs et al and Chen et al is not a simple substitution of one known element for another to obtain predictable results, as stated above, Bentz et al, Takahashi-Nishioka et al, Leder et al, McCombs et al and Chen et al are all in the same field of active targeting drug delivery via a conjugate and/or fusion protein comprising a targeting moiety coupled to a drug via a linker. And in the instant case, other than statements/arguments, Applicant fails to provide any data and/or evidence to indicate modify the conjugate comprising bone growth factor and targeting molecule in Bentz et al with the teachings of Takahashi-Nishioka et al, Leder et al, McCombs et al and Chen et al would result in a conjugate that cannot be used to repair, prevention, or alleviation of bone defects, especially defects due to loss of bone, such as bone loss due to osteoporosis. Furthermore, it appears to the Examiner that Applicant firmly believes that any issue observed with any specific conjugate and/or fusion protein comprising a targeting moiety coupled to a drug via a linker would/should apply to each and every type of such conjugate, but any advantages and common knowledge in these field is only limited to the specific conjugate. It is unclear on what Applicant’s belief is based. Further clarification is required.
Taken all these together, considering the state of art regarding active targeting drug delivery via a conjugate and/or fusion protein comprising a targeting moiety coupled to a drug via a linker and in view of the combined teachings of the cited prior art reference as set forth in Section 20 above, a person of ordinary skilled in the art would have reasonable expectation of success in developing the compound recited in instant claims 1-4, 11 and 22. Furthermore, with regards to the expectation of success, the MPEP states: “Absolute predictability is not a necessary prerequisite to a case of obviousness. Rather, a degree of predictability that one of ordinary skill would have found to be reasonable is sufficient. The Federal Circuit concluded that “[g]ood science and useful contributions do not necessarily result in patentability.” Id. at 1364, 83 USPQ2d at 1304.” (see MPEP § 2145).
In response to Applicant’s arguments about impermissible hindsight reconstruction, in the instant case, Applicant fails to point to any facet of instant rejection that is not found in the cited prior art references. It is unclear to the Examiner which part of the instant rejection is not based on the combined teachings of the cited references. Merely pointing out the differences between each of the cited references and instant claimed invention is not proof of hindsight reasoning. Furthermore, the MPEP states “"[a]ny judgment on obviousness is in a sense necessarily a reconstruction based on hindsight reasoning, but so long as it takes into account only knowledge which was within the level of ordinary skill in the art at the time the claimed invention was made and does not include knowledge gleaned only from applicant’s disclosure, such a reconstruction is proper." In re McLaughlin, 443 F.2d 1392, 1395, 170 USPQ 209, 212 (CCPA 1971).” (See MPEP § 2145).
Taken all these together, the rejection is consistent with Federal Circuit precedent on obviousness. Therefore, the rejection is deemed proper and is hereby maintained.
Obviousness Double Patenting
23. 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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
24. (Revised due to Applicant’s amendment to the claim) Claims 1-4, 11 and 22 remain rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-12 of US patent 10279044 B2, and in view of Bentz et al (WO 92/20371 A1, filed with IDS), Takahashi-Nishioka et al (Current Drug Discovery Technologies, 2008, 5, pages 39-48, cited and enclosed in the previous office action) and Leder et al (J Clin Endocrinol Metab, 2015, 100, pages 697-706, cited and enclosed in the previous office action), and as evidenced by the Abaloparatide document (2026, enclosed pages 1-40, from https://pubchem.ncbi.nlm.nih.gov/compound/Abaloparatide) and the Aminoisobutyric acid document (2026, enclosed pages 1-56, from https://pubchem.ncbi.nlm.nih.gov/compound/Aminoisobutyric-acid), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351, cited and enclosed in the previous office action) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369, cited and enclosed in the previous office action), and as evidenced by the GGGGS linker peptide cut document (2025, pages 1-2, cited and enclosed in the previous office action, from https://web.expasy.org/peptide_cutter/).
25. Instant claims 1-4, 11 and 22 are drawn a compound having a structure of: X-Y-Z, wherein: Z is a peptide that comprises glutamic acid residues, aspartic acid residues, or a combination thereof, wherein the peptide is 6 to 35 acidic amino acid residues selected from glutamic acid residues, aspartic acid residues, or a combination thereof; Y is a peptide linker consisting of amino acid residues joined exclusively by peptide bonds, wherein Y is non-releasable and does not comprise a hydrolytically cleavable linkage; and X is a bone anabolic agent comprising a parathyroid hormone receptor 1 (PTHR1) polypeptide agonist having at least 80% sequence identity to SEQ ID NO: 3, or a pharmaceutically acceptable salt thereof.
26. Claims 1-12 of US patent 10279044 B2 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'-bromoindimbin-3'-oxime; a method of treating a bone fracture, comprising the steps of: administering a therapeutic amount of the compound of claim 1 to a patient suffering from the bone fracture; and a kit for treating a bone fracture comprising: at least one therapeutically effective dose of any of the compound according to claim 1, or a pharmaceutically acceptable salt thereof.
27. The difference between the compound recited in claims 1-12 of US patent 10279044 B2 and the compound recited in instant claims 1-4, 11 and 22 is that the compound recited in claims 1-12 of US patent 10279044 B2 does not explicilty teach the length of Z, Y and X in instant claimed compound.
However, in the instant case, in view of the combined teachings of Bentz et al, Takahashi-Nishioka et al, Leder et al, McCombs et al and Chen et al as set forth in Section 20 above, it would have been obvious to one of ordinary skilled in the art to modify the compound recited in claims 1-12 of US patent 10279044 B2 and develop the compound recited in instant claims 1-4, 11 and 22.
28. (Revised due to Applicant’s amendment to the claim) For the same/similar reasoning/rational as the rejection set forth in Sections 24-27 above, instant claims 1-4, 11 and 22 remain rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-10 of US patent 10744203 B2, claims 1-13 of US patent 11623009 B2, and claim 1-16 of US patent 12319721 B2 and in view of the combined teachings of Bentz et al (WO 92/20371 A1, filed with IDS), Takahashi-Nishioka et al (Current Drug Discovery Technologies, 2008, 5, pages 39-48, cited and enclosed in the previous office action) and Leder et al (J Clin Endocrinol Metab, 2015, 100, pages 697-706, cited and enclosed in the previous office action), and as evidenced by the Abaloparatide document (2026, enclosed pages 1-40, from https://pubchem.ncbi.nlm.nih.gov/compound/Abaloparatide) and the Aminoisobutyric acid document (from https://pubchem.ncbi.nlm.nih.gov/compound/Aminoisobutyric-acid, 2026, enclosed pages 1-56), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351, cited and enclosed in the previous office action) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369, cited and enclosed in the previous office action), and as evidenced by the GGGGS linker peptide cut document (2025, pages 1-2, from https://web.expasy.org/peptide_cutter/, cited and enclosed in the previous office action) as set forth in Section 20 above.
29. (Revised due to Applicant’s amendment to the claim) For the same/similar reasoning/rational as the rejection set forth in Sections 24-27 above, instant claims 1-4, 11 and 22 remain provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 19, 20, 23-27 and 29-41 of co-pending Application No. 17/058887; and claims 1 and 11-33 of co-pending Application No. 18/547837; and in view of the combined teachings of Bentz et al (WO 92/20371 A1, filed with IDS), Takahashi-Nishioka et al (Current Drug Discovery Technologies, 2008, 5, pages 39-48, cited and enclosed in the previous office action) and Leder et al (J Clin Endocrinol Metab, 2015, 100, pages 697-706, cited and enclosed in the previous office action), and as evidenced by the Abaloparatide document (2026, enclosed pages 1-40, from https://pubchem.ncbi.nlm.nih.gov/compound/Abaloparatide) and the Aminoisobutyric acid document (2026, enclosed pages 1-56, from https://pubchem.ncbi.nlm.nih.gov/compound/Aminoisobutyric-acid), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351, cited and enclosed in the previous office action) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369, cited and enclosed in the previous office action), and as evidenced by the GGGGS linker peptide cut document (2025, pages 1-2, cited and enclosed in the previous office action, from https://web.expasy.org/peptide_cutter/) as set forth in Section 20 above.
These are all provisional obviousness-type double patenting rejections because the conflicting claims have not in fact been patented.
30. (Revised due to Applicant’s amendment to the claim) For the same/similar reasoning/rational as the rejection set forth in Sections 24-27 above, instant claims 1-4, 11 and 22 remain provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 20-27 and 30-41 of co-pending Application No. 17/058891; and in view of the combined teachings of Bentz et al (WO 92/20371 A1, filed with IDS), Leder et al (J Clin Endocrinol Metab, 2015, 100, pages 697-706, cited and enclosed in the previous office action), and as evidenced by the Abaloparatide document (2026, enclosed pages 1-40, from https://pubchem.ncbi.nlm.nih.gov/compound/Abaloparatide) and the Aminoisobutyric acid document (from https://pubchem.ncbi.nlm.nih.gov/compound/Aminoisobutyric-acid, 2026, enclosed pages 1-56), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351, cited and enclosed in the previous office action) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369, cited and enclosed in the previous office action), and as evidenced by the GGGGS linker peptide cut document (2025, pages 1-2, from https://web.expasy.org/peptide_cutter/, cited and enclosed in the previous office action) as set forth in Section 20 above.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
31. (Revised due to Applicant’s amendment to the claim) Claims 1-4, 11 and 22 remain provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 2, 4, 5, 7, 11, 14, 15, 18, 19, 23-25, 28, 30, 33-37, 39, 41, 42, 44, 45 and 49 of co-pending Application No. 18/033665, and as evidenced by the Abaloparatide document (2026, enclosed pages 1-40, from https://pubchem.ncbi.nlm.nih.gov/compound/Abaloparatide) and the Aminoisobutyric acid document (from https://pubchem.ncbi.nlm.nih.gov/compound/Aminoisobutyric-acid, 2026, enclosed pages 1-56), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351, cited and enclosed in the previous office action) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369, cited and enclosed in the previous office action), and as evidenced by the GGGGS linker peptide cut document (2025, pages 1-2, cited and enclosed in the previous office action, from https://web.expasy.org/peptide_cutter/).
32. Instant claims Instant claims 1-4, 11 and 22 are drawn a compound having a structure of: X-Y-Z, wherein: Z is a peptide that comprises glutamic acid residues, aspartic acid residues, or a combination thereof, wherein the peptide is 6 to 35 acidic amino acid residues selected from glutamic acid residues, aspartic acid residues, or a combination thereof; Y is a peptide linker consisting of amino acid residues joined exclusively by peptide bonds, wherein Y is non-releasable and does not comprise a hydrolytically cleavable linkage; and X is a bone anabolic agent comprising a parathyroid hormone receptor 1 (PTHR1) polypeptide agonist having at least 80% sequence identity to SEQ ID NO: 3, or a pharmaceutically acceptable salt thereof.
33. Claims 1, 2, 4, 5, 7, 11, 14, 15, 18, 19, 23-25, 28, 30, 33-37, 39, 41, 42, 44, 45 and 49 of co-pending Application No. 18/033665 are drawn to 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 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; Y is absent, a releasable linker or a non-releasable linker; and Z is an osteotropic ligand; 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 bone anabolic agent selected from the group consisting of a parathyroid hormone (PTH) or a derivative or fragment thereof, aPTH-related protein (PTHrP) or a derivative or fragment thereof, and abaloparatide or a derivative or fragment thereof; Y is absent, a releasable linker or anon-releasable linker; and Z is an osteotropic ligand; and a method of treating a bone fracture or promoting bone growth in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutical composition, thereby treating the bone fracture in the patient, wherein the compound has a structure of Formula (I) X-Y-Z Formula (I), or is a pharmaceutically acceptable salt thereof, 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; Y is absent, a releasable linker or anon-releasable linker, and the pharmaceutical composition comprises the compound, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
And as evidenced by the Abaloparatide document, abaloparatide recited in claims of co-pending Application No. 18/033665 consists of the amino acid sequence AVSEHQLLHDKGKSIQDLRRRELLEKLLAibKLHTA-NH2. And further as evidenced by the Aminoisobutyric acid document, Aib is the same as 2-methyl-alanine (see page 1, Section “Synonyms”). Therefore, abaloparatide recited in claims of co-pending Application No. 18/033665 is 100% identical to the peptide of instant SEQ ID NO: 3.
Furthermore, in view of the combined teachings of claims of co-pending Application No. 18/033665, it would have been obvious to one of ordinary skilled in the art to develop the compound recited in instant claims 1-4, 11 and 22, except the linker Y.
In addition, the compound of SEQ ID NO: 4 or 14 recited in claims of co-pending Application No. 18/033665 is instant claimed compound of X-Y-Z with Z being 20 Glu (SEQ ID NO: 14) or 10 Glu (SEQ ID NO: 4) and X being instant SEQ ID NO: 3, except the linker Y.
Furthermore, in view of the combined teachings of McCombs et al and Chen et al as set forth in Section 20 above, it would have been obvious to one of ordinary skilled in the art to modify the compound developed from the combined teachings of claims of co-pending Application No. 18/033665 and develop the compound recited in instant claims 1-4, 11 and 22.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
34. (Revised due to Applicant’s amendment to the claim) For the same/similar reasoning/rational as the rejection set forth in Sections 31-33 above, instant claims 1-4, 11 and 22 remain provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-5, 7, 10, 12, 14, 15, 19, 25, 28-30, 32, 33, 43-45, 48, 50, 57, 62, 64. 65, 68-70, 74, 75 and 79 of co-pending Application No. 18/033658; and claims 1, 3-8, 12, 13, 16, 18-21, 24-27, 29, 33-38, 40, 41, 44, 45 and 48 of co-pending Application No. 18/728874; and as evidenced by the Abaloparatide document (2026, enclosed pages 1-40, from https://pubchem.ncbi.nlm.nih.gov/compound/Abaloparatide) and the Aminoisobutyric acid document (from https://pubchem.ncbi.nlm.nih.gov/compound/Aminoisobutyric-acid, 2026, enclosed pages 1-56), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351, cited and enclosed in the previous office action) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369, cited and enclosed in the previous office action), and as evidenced by the GGGGS linker peptide cut document (2025, pages 1-2, from https://web.expasy.org/peptide_cutter/, cited and enclosed in the previous office action) as set forth in Section 20 above.
These are all provisional obviousness-type double patenting rejections because the conflicting claims have not in fact been patented.
Response to Applicant's Arguments
35. Applicant argues that for the same reason as the arguments presented in Section 21 above, all ODP rejections with the references cited in the rejection under 35 U.S.C. 103 should be withdrawn. Applicant further argues that for ODP rejections over co-pending U.S. Patent Application Nos. 18/033665 and 18/033658, these application have later effective filing dates.
36. Applicant's arguments have been fully considered but have not been found persuasive.
In response to Applicant’s arguments about the ODP rejections with the references cited in the rejection under 35 U.S.C. 103, Applicant’s arguments presented in Section 21 above have been addressed in Section 22 above.
In response to Applicant’s arguments about the ODP rejections over co-pending U.S. Patent Application Nos. 18/033665 and 18/033658, in the instant case, provisional ODP rejection is not the only rejection remained in the current office action.
Taken all these together, these double patenting rejections are deemed proper. And until a proper terminal disclaimer is filed and approved by the Office, these double patenting rejections are hereby maintained.
New Objections
37. Claim 1 is objected to for the following minor informality: Applicant is suggested to amend claim 1 as “…wherein: Z is a peptide consisting of 6 to 35 acidic amino acid residues selected from glutamic acid residues, aspartic acid residues, or a combination thereof; Y is…”.
38. Claim 3 is objected to for the following minor informality: Applicant is suggested to amend claim 3 as “…wherein Z consists of 6 to 20 glutamic acid residues”.
39. Claim 4 is objected to for the following minor informality: Applicant is suggested to amend claim 4 as “…wherein Z consists of 6 to 35 aspartic acid residues”.
40. Claim 11 is objected to for the following minor informality: Applicant is suggested to amend claim 11 as “…wherein X is 10 to 35 amino acids in length”.
New Rejections
Claim Rejections - 35 U.S.C. § 112 paragraph (d)
41. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), fourth paragraph:
Subject to the [fifth paragraph of 35 U.S.C. 112 (pre-AIA )], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
42. Claims 2 and 11 are rejected under 35 U.S.C. 112(d) or 35 U.S.C. 112 (pre-AIA ), 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
43. Claim 2 depends on claim 1; and claim 2 recites “The compound of claim 1, wherein Z is charged”. However, instant claim 1 recites “Z is a peptide that comprises glutamic acid residues, aspartic acid residues, or a combination thereof, wherein the peptide is 6 to 35 acidic amino acid residues selected from glutamic acid residues, aspartic acid residues, or a combination thereof“. Therefore, Z recited in instant claim 1 is charged. Thus, the scope of the compound in claim 2 is identical to that of the compound of claim 1. Claim 2 does not further limit the structure of the compound in instant claim 1; therefore, claim 2 is improper dependent form for failing to further limit the subject matter of claim 1.
44. Claim 11 depends on claim 1; and claim 11 recites “The compound of claim 1, wherein X is 10 to 35 amino acid residues”. Since the peptide of instant SEQ ID NO: 3 is 34 amino acids in length, X being a bone anabolic agent comprising a parathyroid hormone receptor 1 (PTHR1) polypeptide agonist having at least 80% sequence identity to SEQ ID NO: 3 cannot be less than 28 amino acids in length. Therefore, the scope of the compound in claim 11 is broader than that of the compound in claim 1. Claim 11 does not further limit the structure of the compound in claim 1; therefore, claim 11 is improper dependent form for failing to further limit the subject matter of claim 1.
Obviousness Double Patenting
45. 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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
46. For the same/similar reasoning/rational as the rejection set forth in Sections 24-27 above, instant claims 1-4, 11 and 22 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-12, 17 and 19 of co-pending Application No. 19/213926; and in view of the combined teachings of Bentz et al (WO 92/20371 A1, filed with IDS), Leder et al (J Clin Endocrinol Metab, 2015, 100, pages 697-706, cited and enclosed in the previous office action), and as evidenced by the Abaloparatide document (2026, enclosed pages 1-40, from https://pubchem.ncbi.nlm.nih.gov/compound/Abaloparatide) and the Aminoisobutyric acid document (from https://pubchem.ncbi.nlm.nih.gov/compound/Aminoisobutyric-acid, 2026, enclosed pages 1-56), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351, cited and enclosed in the previous office action) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369, cited and enclosed in the previous office action), and as evidenced by the GGGGS linker peptide cut document (2025, pages 1-2, from https://web.expasy.org/peptide_cutter/, cited and enclosed in the previous office action) as set forth in Section 20 above.
This is a provisional obviousness-type double patenting rejection because the conflicting claims have not in fact been patented.
Conclusion
No claim is allowed.
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/LI N KOMATSU/Primary Examiner, Art Unit 1658
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