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 Non-final office action filed on 9/26/2025 is acknowledged.
3. Claims 5-10, 14 and 15 have been cancelled.
4. Claims 1-4, 11-13 and 16-22 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 Claims 13 and 16-20 remain withdrawn from consideration pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim. Claim 12 remains withdrawn from consideration as being not read on either the elected species or the non-elected species found in the prior art.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 action, 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 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 is 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 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 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 40 amino acid residues in length; Y is a peptide linker that is non-releasable in vivo; 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, 21 and 22 are examined on the merits in this office action.
Withdrawn Objections and Rejections
7. Objection to the specification is hereby withdrawn in view of Applicant’s amendment to the specification.
8. Objection to claims 1, 10 and 21 is hereby withdrawn in view of Applicant’s amendment to the claim.
9. Rejection to claims 9 and 10 under 35 U.S.C. 112(d) or 35 U.S.C. 112 (pre-AIA ), 4th paragraph is hereby withdrawn in view of Applicant’s amendment to the claim.
10. Rejection to claims 1, 2, 9-11, 21 and 22 under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph (written description) is hereby withdrawn in view of Applicant’s amendment to the claim.
Maintained/Revised Rejections
Claim Rejections - 35 U.S.C. § 112 paragraph (b)
11. 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.
12. Claims 1-4, 11, 21 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.
13. (Revised due to Applicant’s amendment to the claim) Claim 1 recites “Y is a peptide linker that is non-releasable in vivo”. With regards to the recited “a peptide linker that is non-releasable in vivo”, 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 can be cut by various enzymes in vivo (see for example, page 4). Therefore, it appears that the term “a peptide linker that is non-releasable in vivo” recited in instant claims is not the same as what is known as a non-releasable peptide linker in the peptide/protein art. Thus, it is unclear what is encompassed within the recited “Y is a peptide linker that is non-releasable in vivo”; and the metes and bounds of instant claim 1 is vague and indefinite. Because claims 2-4, 11, 21 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
14. Applicant argues that “Application as originally filed consistently distinguishes between "non-releasable" and "releasable" linkers…A person of ordinary skill in the art at the time the Application was filed would therefore readily understand that a "non-releasable" linker is one that remains intact under in vivo conditions, as opposed to a "releasable" linker, which is designed to cleave in response to a defined biological trigger.” Applicant further argues that “the state of the art at the time the Application was filed confirms the definiteness of this terminology. The cited references themselves repeatedly employ the terms "releasable", "non-degradable," and "non-releasable" when describing moiety behavior in the context of conjugates. This demonstrates that the terminology was already well-established and commonly understood in the relevant art.”
15. 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 13 above, in the instant case, with regards to the term “a peptide linker that is non-releasable in vivo”, 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 13 above, PTH35-84 peptide as an example of a non-releasable peptide linker disclosed in instant specification can be cut by various enzymes in vivo. Therefore, it appears to the Examiner that the term “a peptide linker that is non-releasable in vivo” recited in instant claims is not the same as what is known as a non-releasable peptide linker in the peptide/protein art. As an example, the peptide linker (GGGGS)3 is known in the peptide/protein art as a peptide linker that is non-releasable in vivo. And based on the GGGGS linker peptide cut document (2025, enclosed pages 1-2, from https://web.expasy.org/peptide_cutter/), in contrast to the PTH35-84 peptide as an example of a non-releasable peptide linker disclosed in instant specification, the peptide linker (GGGGS)3 is indeed non-releasable in vivo (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.
16. (Revised due to Applicant’s amendment to the claim) Claim 3 recites the limitation “wherein Z has not less than 6 and not more than 35 glutamic acid residues”; claim 4 recites the limitation “wherein Z has not less than 6 and not more than 35 aspartic acid residues”; and claim 11 recites the limitation “wherein X has 10 to 70 amino acid residues”. In the instant case, based on instant specification, it is unclear whether the transitional phrase “has” is open-ended or not. If the transitional phrase “has” is open-ended (as comprises), since the recited range of the number of amino acids residues is close-ended, it is unclear what is encompassed within the recited “wherein Z has not less than 6 and not more than 35 glutamic acid residues”, “wherein Z has not less than 6 and not more than 35 aspartic acid residues” and “wherein X has 10 to 70 amino acid residues”. If the transitional phrase “has” is close-ended (as consists of), for claim 11, 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. Taken all these together, the metes and bounds of instant claims 3, 4 and 11 are vague and indefinite.
Response to Applicant's Arguments
17. Applicant argues that “Without conceding the merits of this rejection, Applicant respectfully submits that the claim amendments submitted herewith obviate this rejection.”
18. Applicant's arguments have been fully considered but have not been found persuasive.
In response to Applicant's arguments about instant rejection, as stated in Section 16 above, in the instant case, it remains unclear what is encompassed within the recited “wherein Z has not less than 6 and not more than 35 glutamic acid residues”, “wherein Z has not less than 6 and not more than 35 aspartic acid residues” and “wherein X has 10 to 70 amino acid residues”. Therefore, the rejection is deemed proper and is hereby maintained.
19. (Revised due to Applicant’s amendment to the claim) Claim 21 recites the term “IC50 0.46 nM and IC50 135 nM”. However, it is well known in the art that there are many factors affected the IC50 value, such as IC50 depends on Kd of the displaced ligand and its concentration, as discussed in Hulme et al (British Journal of Pharmacology, 2010, 161, pages 1219-1237, cited and enclosed in the previous office action, see for example, page 1220, left column, the paragraph starting with “Competition/modulation experiments…”). Therefore, it is unclear what is encompassed within the recited “IC50 0.46 nM and IC50 135 nM”. Thus, the metes and bounds of instant claim 21 is vague and indefinite.
Response to Applicant's Arguments
20. Applicant argues that “The Examiner's observation that IC50 values may vary depending on assay conditions does not render the claims indefinite, as many accepted claim parameters (e.g., molecular weight, melting point, viscosity) similarly depend on methodology yet are definite when, as here, the specification provides sufficient guidance. IC50 is a universally recognized pharmacological parameter and is routinely employed in both the patent literature and scientific community to define ligand potency against specific targets. Accordingly, when read in light of the specification, claim 21 informs the skilled artisan with reasonable certainty as to its scope, satisfying the applicable standard. In view of the foregoing, Applicant respectfully requests the withdrawal of the §112(b) rejection against claim 21.”
21. Applicant's arguments have been fully considered but have not been found persuasive.
In response to Applicant's arguments about instant rejection, the Examiner understands that IC50 is a universally recognized pharmacological parameter and is routinely employed in both the patent literature and scientific community to define ligand potency against specific targets. The Examiner also understand the instant specification discusses IC50 on page 27, paragraph [00218] of instant specification. However, in the instant case, as stated in Section 19 above, it is well known in the art that there are many factors affected the IC50 value, such as IC50 depends on Kd of the displaced ligand and its concentration. Therefore, it is unclear what is encompassed within the recited “IC50 0.46 nM and IC50 135 nM”. Thus, the metes and bounds of instant claim 21 is vague and indefinite.
Taken all these together, the rejection is deemed proper and is hereby maintained.
Claim Rejections - 35 U.S.C. § 103
22. 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.
23. 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.
24. (Revised due to Applicant’s amendment to the claim) Claims 1-4, 11, 21 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 (page 1, cited and enclosed in the previous office action, 2025, from https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=8299), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369), and as evidenced by the GGGGS linker peptide cut document (2025, enclosed pages 1-2, from https://web.expasy.org/peptide_cutter/).
The instant claims 1-4, 11, 21 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 40 amino acid residues in length; Y is a peptide linker that is non-releasable in vivo; 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, 21 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, 21 and 22.
However, 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.
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, abaloparatide in Leder et al consists of the amino acid sequence AVSEHQLLHDKGKSIQDLRRRELLEKLLAK LHTA-NH2 with A at position 29 being methyl-Ala (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 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 in vivo.
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 (identical to the peptide of instant SEQ ID NO: 3), Y is a peptide linker that is non-releasable in vivo 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.
With regards to the limitation recited in instant claim 21, since 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 above meets all the structural limitations of the compound recited in instant claim 1 with X being identical to the peptide of instant SEQ ID NO: 3, 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 above would necessarily have the same properties and functionalities of the compound in instant claim 1. Therefore, for 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 above, an therapeutic affinity index to PTHR1 of X is between IC50 0.46 nM and IC50 135 nM. Furthermore, the MPEP states “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Claims were directed to a titanium alloy containing 0.2-0.4% Mo and 0.6-0.9% Ni having corrosion resistance. A Russian article disclosed a titanium alloy containing 0.25% Mo and 0.75% Ni but was silent as to corrosion resistance. The Federal Circuit held that the claim was anticipated because the percentages of Mo and Ni were squarely within the claimed ranges. The court went on to say that it was immaterial what properties the alloys had or who discovered the properties because the composition is the same and thus must necessarily exhibit the properties.).” (see MPEP § 2112.01 I). In addition, since the USPTO lacks the experimental facilities to make a further determination, the burden is on the Applicant to prove the otherwise.
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 (identical to the peptide of instant SEQ ID NO: 3), Y is a peptide linker that is non-releasable in vivo 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 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. Leder et al, throughout the literature, teach osteoporotic fractures are expected to have an increasing effect on the health of our population; abaloparatide (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 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 (identical to the peptide of instant SEQ ID NO: 3), Y is a peptide linker that is non-releasable in vivo 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
25. Applicant argues about each of the cited Bentz et al, Takahashi-Nishioka et al and Leder et al references individually. Applicant further argues that the rejection is based on impermissible hindsight reconstruction.
26. Applicant's arguments have been fully considered but have not been found persuasive.
Please note: In view of Applicant’s amendment to the claim, McCombs et al (The AAPS Journal, 2015, 17, pages 339-351) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369) are further cited as prior art 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, 21 and 22; and none of the cited references anticipates the compound recited in instant claims 1-4, 11, 21 and 22. However, the Examiner would like to point out that instant claims 1-4, 11, 21 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 response to Applicant's arguments about instant rejection, as stated in Section 24 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. 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. And Leder et al, throughout the literature, teach osteoporotic fractures are expected to have an increasing effect on the health of our population; abaloparatide (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 the linker used in Takahashi-Nishioka et al is releasable linker. However, in the instant case, 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. Furthermore, 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. Therefore, 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 24 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, 21 and 22. And 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).
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 deemed proper and is hereby maintained.
Obviousness Double Patenting
27. 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.
28. (Revised due to Applicant’s amendment to the claim) Claims 1-4, 11, 21 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 (from https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=8299, page 1, accessed 2025, cited and enclosed in the previous office action), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369), and as evidenced by the GGGGS linker peptide cut document (2025, enclosed pages 1-2, from https://web.expasy.org/peptide_cutter/).
29. Instant claims 1-4, 11, 21 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 40 amino acid residues in length; Y is a peptide linker that is non-releasable in vivo; 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.
30. 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.
31. 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, 21 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 24 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, 21 and 22.
32. (Revised due to Applicant’s amendment to the claim) For the same/similar reasoning/rational as the rejection set forth in Sections 28-31 above, instant claims 1-4, 11, 21 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 (issued patent of Application No. 18/074275), 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 (from https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=8299, page 1, accessed 2025, cited and enclosed in the previous office action), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369), and as evidenced by the GGGGS linker peptide cut document (2025, enclosed pages 1-2, from https://web.expasy.org/peptide_cutter/) as set forth in Section 24 above.
33. (Revised due to Applicant’s amendment to the claim) For the same/similar reasoning/rational as the rejection set forth in Sections 28-31 above, instant claims 1-4, 11, 21 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 (accessed 2025, from https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=8299, page 1, cited and enclosed in the previous office action), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369), and as evidenced by the GGGGS linker peptide cut document (2025, enclosed pages 1-2, from https://web.expasy.org/peptide_cutter/) as set forth in Section 24 above.
These are all provisional obviousness-type double patenting rejections 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 28-31 above, instant claims 1-4, 11, 21 and 22 are 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 (cited and enclosed in the previous office action, from https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=8299, accessed 2025, page 1,), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369), and as evidenced by the GGGGS linker peptide cut document (2025, enclosed pages 1-2, from https://web.expasy.org/peptide_cutter/) as set forth in Section 24 above.
This is a provisional obviousness-type double patenting rejections because the conflicting claims have not in fact been patented.
35. (Revised due to Applicant’s amendment to the claim) Claims 1-4, 11, 21 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 (page 1, accessed 2025, from https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=8299, cited and enclosed in the previous office action), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369), and as evidenced by the GGGGS linker peptide cut document (2025, enclosed pages 1-2, from https://web.expasy.org/peptide_cutter/).
36. Instant claims Instant claims 1-4, 11, 21 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 40 amino acid residues in length; Y is a peptide linker that is non-releasable in vivo; 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.
37. 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 AVSEHQLLHDKGKSIQDLRRRELLEKLLAKLHTA-NH2 with A at position 29 being methyl-Ala (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 24 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.
And, with regards to the limitation recited in instant claim 21, since the modified compound developed above meets all the structural limitations of the compound recited in instant claim 1 with X being identical to the peptide of instant SEQ ID NO: 3, the modified compound developed above would necessarily have the same properties and functionalities of the compound in instant claim 1. Therefore, for the modified compound developed above, an therapeutic affinity index to PTHR1 of X is between IC50 0.46 nM and IC50 135 nM. In addition, the MPEP states “Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). Therefore, the prima facie case can be rebutted by evidence showing that the prior art products do not necessarily possess the characteristics of the claimed product. In re Best, 562 F.2d at 1255, 195 USPQ at 433. See also Titanium Metals Corp. v. Banner, 778 F.2d 775, 227 USPQ 773 (Fed. Cir. 1985) (Claims were directed to a titanium alloy containing 0.2-0.4% Mo and 0.6-0.9% Ni having corrosion resistance. A Russian article disclosed a titanium alloy containing 0.25% Mo and 0.75% Ni but was silent as to corrosion resistance. The Federal Circuit held that the claim was anticipated because the percentages of Mo and Ni were squarely within the claimed ranges. The court went on to say that it was immaterial what properties the alloys had or who discovered the properties because the composition is the same and thus must necessarily exhibit the properties.).” (see MPEP § 2112.01 I). In addition, since the USPTO lacks the experimental facilities to make a further determination, the burden is on the Applicant to prove the otherwise.
This is a provisional obviousness-type double patenting rejections because the conflicting claims have not in fact been patented.
38. (Revised due to Applicant’s amendment to the claim) For the same/similar reasoning/rational as the rejection set forth in Sections 35-37 above, instant claims 1-4, 11, 21 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 (cited and enclosed in the previous office action, from https://www.guidetopharmacology.org/GRAC/LigandDisplayForward?tab=structure&ligandId=8299, page 1, accessed 2025), and further in view of McCombs et al (The AAPS Journal, 2015, 17, pages 339-351) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369), and as evidenced by the GGGGS linker peptide cut document (2025, enclosed pages 1-2, from https://web.expasy.org/peptide_cutter/) as set forth in Section 24 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
39. Applicant argues that for the same reason as the arguments presented in Section 25 above, all ODP rejections with the references cited in the rejection under 35 U.S.C. 103 should be withdrawn. Applicant further argues for ODP rejections over co-pending U.S. Patent Application Nos. 18/033665 and 18/033658, Applicant respectfully requests that these rejections be tabled to be addressed (if needed) when all other rejections and objections to the present Application are overcome.
40. Applicant's arguments have been fully considered but have not been found persuasive.
Please note: In view of Applicant’s amendment to the claim, McCombs et al (The AAPS Journal, 2015, 17, pages 339-351) and Chen et al (Advanced Drug Delivery Reviews, 2013, 65, pages 1357-1369) are further cited as prior art references in instant rejections.
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 25 above have been addressed in Section 26 above.
In response to Applicant’s arguments about 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.
Furthermore, the Examiner would like to point out that Applicant fails to address certain ODP rejections.
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 Rejections
Claim Rejections - 35 U.S.C. § 112 paragraph (a)
Written Description
41. 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 manne