Office Action 1: Non-Final Rejection (2024-09-10)
Rejection types: Double Patenting

CLAIMS:
AMENDMENTS TO THE CLAIMS

Amendments to the claims are reflected in the following listing of claims, which replaces

all prior version of listings of the claims.

Listing of Claims:

1\. - 23. (Canceled)222

24\. (Currently Amended) A method of controlling serum calcium levels in a subject in need thereof comprising administering to the subject an effective amount of a parathyroid hormone (PTH)-Fc fusion protein, wherein the PTH-Fc fusion protein comprises a C-terminally mutated and/or truncated PTH or a variant thereof, the variant comprising a F34A substitution, a F34D substitution, a V35S substitution, or a V35T substitution, or a combination thereof, chemically linked to an Fc region of a human IgG antibody, or a derivative thereof, the derivative comprising L234A and L235A substitutions, and wherein the C- terminally mutated and/or truncated PTH or a variant thereof is not PTH(1-34).

25\. (Original) The method of claim 24, wherein the subject has hypoparathyroidism.

26\. (Currently Amended) The method of claim 24,wherein the PTH-Fc fusion protei is administered subcutaneously.

27\. (Currently Amended) The method of claim 24,wherein the PTH-Fc fusion protei is administered once daily.

28\. (Currently Amended) The method of claim 24,wherein the PTH-Fc fusion protei is administered once weekly.

29\. (Currently Amended) The method of claim 24,wherein the PTH-Fc fusion protein is provided to the

subject in an amount from about 20 pg per day to about 100 pg per day of the PTH-Fc fusion protein.

30\. - 45. (Canceled)3144

46\. (New) The method of claim 24, wherein the PTH-Fc fusion protein comprises a C-terminally mutated and/or truncated PTH variant comprising a F34A substitution and a V35S substitution.

47\. (New) The method of claim 24, wherein the PTH-Fc fusion protein is selected from the group consisting of PTH-66 having the amino acid sequence of SEQ ID NO: 8, PTH-67 having the amino acid sequence of SEQ ID NO: 9, PTH-68 having the amino acid sequence of SEQ ID NO: 10, and PTH-69 having the amino acid sequence of SEQ ID NO: 11.

48\. (New) The method of claim 24, wherein the PTH-Fc fusion protein is PTH-66 having the amino acid sequence of SEQ ID NO: 8.

49\. (New) The method of claim 24, wherein the PTH-Fc fusion protein is glycosylated.

50\. (New) A method of controlling serum calcium levels in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical composition comprising a PTH-Fc fusion protein, wherein the PTH-Fc fusion protein comprises a C-terminally mutated and/or truncated PTH or a variant thereof, the variant comprising a F34A substitution, a F34D substitution, a V35S substitution, or a V35T substitution, or a combination thereof, chemically linked to an Fc region of a human IgG antibody, or a derivative thereof, the derivative comprising L234A and L235A substitutions, and wherein the C-terminally mutated and/or truncated PTH or a variant thereof is not PTH(1-34).

51\. (New) The method of claim 50, wherein the pharmaceutical composition is administered subcutaneously.

52\. (New) The method of claim 50, wherein the pharmaceutical composition is administered once daily.

53\. (New) The method of claim 50, wherein the pharmaceutical composition is administered once weekly.

54\. (New) The method of claim 50, wherein the PTH-Fc fusion protein comprises a C-terminally mutated and/or truncated PTH variant comprising a F34A substitution and a V35S substitution.

55\. (New) The method of claim 50, wherein the PTH-Fc fusion protein is selected from the group consisting of PTH-66 having the amino acid sequence of SEQ ID NO: 8, PTH-67 having the amino acid sequence of SEQ ID NO: 9, PTH-68 having the amino acid sequence of SEQ ID NO: 10, and PTH-69 having the amino acid sequence of SEQ ID NO: 11.

56\. (New) The method of claim 50, wherein the PTH-Fc fusion protein is PTH-66 having the amino acid sequence of SEQ ID NO: 8.

57\. (New) The method of claim 50, wherein the PTH-Fc fusion protein is glycosylated.

58\. (New) A method of controlling serum calcium levels in a subject in need thereof comprising administering to the subject an effective amount of a pharmaceutical dosage form comprising a PTH-Fc fusion protein, wherein the PTH-Fc fusion protein comprises a C-terminally mutated and/or truncated PTH or a variant thereof, the variant comprising a F34A substitution, a F34D substitution, a V35S substitution, or a V35T substitution, or a combination thereof, chemically linked to an Fc region of a human IgG antibody, or a derivative thereof, the derivative comprising L234A and L235A substitutions, and wherein the C-terminally mutated and/or truncated PTH or a variant thereof is not PTH(1-34).

59\. (New) The method of claim 58, wherein the pharmaceutical dosage form is administered subcutaneously.

60\. (New) The method of claim 58, wherein the pharmaceutical dosage form is administered once daily.

61\. (New) The method of claim 58, wherein the pharmaceutical dosage form is administered once weekly.

62\. (New) The method of claim 50, wherein the PTH-Fc fusion protein comprises a C-terminally mutated and/or truncated PTH variant comprising a F34A substitution and a V35S substitution.

63\. (New) The method of claim 50, wherein the PTH-Fc fusion protein is selected from the group consisting of PTH-66 having the amino acid sequence of SEQ ID NO: 8, PTH-67 having the amino acid sequence of SEQ ID NO: 9, PTH-68 having the amino acid sequence of SEQ ID NO: 10, and PTH-69 having the amino acid sequence of SEQ ID NO: 11.

64\. (New) The method of claim 58, wherein the PTH-Fc fusion protein is PTH-66 having the amino acid sequence of SEQ ID NO: 8.

65\. (New) The method of claim 58, wherein the pharmaceutical dosage form is a liquid dosage form suitable for administration by injection or infusion.

OFFICE ACTION:
Notice of Pre-AIA  or AIA  Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 24-29 and 46-65 are pending and examined on the merits.  Note:  The only difference between independent method claims 24 and 50 and 58 is the latter two are directed to methods employing the pharmaceutical composition and dosage form respectively comprising the fusion peptide alone (claim 24) comprising e.g. peptide SEQ ID NO: 8.
Allowable Subject Matter – Methods of Using Issued Peptide SEQ ID NO: 8
Peptide species SEQ ID NO: 8 was not found to be reasonably taught or suggested by the prior art of record – as issued in the parent, now U.S. Patent No. 11,634,468.  Were the instant claims amended to the same issued product scope (peptide SEQ ID NO: 8) as in ‘468; the scope of the method claims 24 and 50 preambles amended “A method of [controlling] --increasing—serum calcium levels . . . “,  thereto; and a Terminal Disclaimer filed and approved over parent ‘468 (since there is no 35 USC 121 bar as the claims here were not restricted out of the parent and would have been open to rejoinder upon finding of the allowable product thereof) - the claims would be in condition for allowance.
Prior Art Made of Record, But Not Relied Upon
Culbertson et al. (U.S. Patent No. 9,579,392, applicant’s earlier work) is representative in the art of teachings on fusion protein consisting of the extracellular ligand-binding portions linked to the Fc portion of IgG.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA  as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 24-29 and 46-65 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11,634,468.  Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are drawn to the same issued product scope (peptide SEQ ID NO: 8) as in ‘468 and as the claims here were not restricted out of the parent and the product utility as read in light of the specification includes such, had these claims been presented in the parent as they were fully open to be (no 35 USC 121 bar), such would have been open to rejoinder upon finding of the allowable product peptide SEQ ID NO: 8.  As such, the methods of using the allowed product of ‘468 are prima facie obvious thereover.
The filing and approval of a Terminal Disclaimer would overcome the rejection.
Claim Rejections-35 USC § 112(a)(i)/(pre-AIA )–Written Description, Maintained as in Parent
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.
Claims 24-29 and 46-65 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement.  The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA  the inventor(s), at the time the application was filed, had possession of the claimed invention.
To provide evidence of possession of a claimed genus, the specification must provide sufficient distinguishing/identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof.
In this case:
1.  Claims 24, 50, and 58 are directed to fusion peptides (far beyond e.g. fully defined peptide SEQ ID NO: 8) comprising PTH variants without guidance as to what positions may be modified and with what amino acid substitution are not found within the specification as filed.  In the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
With the exception of e.g. peptide SEQ ID NO: 8, the polypeptide(s) ‘derivatives’ fully defined are found to have been in applicant’s possession as the substitution options cannot be guided to as claimed. The skilled artisan cannot envision the detailed chemical structure of the encompassed variants, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it.  The compound itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
Amendment to peptide SEQ ID NO: 8 per the parent would overcome the rejection.
2.  “Controlling” Serum Calcium.  The only support found in possession for this term is “increasing” as the “controlling” mechanism relevant to serum calcium.
Amendment to “increasing” serum calcium would overcome the rejection.
Therefore, the full breadth of the claims are not presently deemed to have been in Applicant’s ‘possession’ and found to meet the written description provision of 35 U.S.C. §112.
Response to Amendments/Arguments
Applicant’s amendments and arguments have been fully considered such are not found persuasive.  Namely, the new amendments still have not identified and claimed as elements of the claim scope, what may be substituted at F34 or V35 and still carry out the intended function.   Thus, the rejection is maintained for the reasons of record and per the amendments.
Conclusion

APPLICANT REBUTTAL: REMARKS
Applicant has carefully studied the Non-Final Office Action dated September 10, 2024, which issued in connection with the above-identified application. The present response is intended to be fully responsive to all points raised by the Examiner and is believed to place the claims in condition for allowance. Favorable reconsideration and allowance of the present claims are respectfully requested.
I.    Status of the Claims
Claims 24-29 and 46-65 are pending and stand rejected.
Applicant acknowledges, with thanks, the Examiner's statement at p. 2 of the Office Action that the peptide species SEQ ID NO: 8 is free of art, and claims amended to the product scope of the peptide of SEQ ID NO:8 would be allowable.
Independent claims 24, 50, and 58 are amended herein to incorporate the allowable subject matter, i.e., to specify that the PTH-Fc fusion protein is the peptide species SEQ ID NO: 8. Claims 46-48, 54-56 and 62-64 are canceled herein without disclaimer or prejudice. Applicant reserves the right to pursue canceled subject-matter in a subsequent application.
No new matter is added by way of this amendment. Upon entry of this amendment, claims 24-29, 49-53, 57-61, and 65 will be pending and under consideration.
II. Claim rejection under 35 U.S.C. §112(a)
Claims 24-29 and 46-65 have been rejected under 35 U.S.C. § 112(a) or 35 U.S.C. 112 (pre- AIA), first paragraph, as allegedly failing to comply with the written description requirement. According to the Examiner, Applicant is not in 'possession' with the full breadth of the claims with respect to PTH "variants" and polypeptide "derivatives" because guidance as to the positions to be modified was allegedly not provided.
Without acquiescing in the rejection and solely to expedite prosecution, independent claims 24, 50 and 58 are amended herein to specify that the PTH-Fc fusion protein is the peptide species SEQ ID NO: 8. Applicant submits that, as this subject-matter is considered allowable by the Examiner, all claims dependent therefrom are likewise allowable.
Reconsideration and withdrawal of the § 112 rejection is respectfully requested.
III. Non-Statutory Double-Patenting Rejection
Claims 24-29 and 46-65 have been rejected on the ground of nonstatutory double patenting as allegedly being unpatentable over the claims of U.S. Pat. No. 11,634,468. Without acquiescing in the double patenting rejection and solely to expedite allowance of the application, applicant submits concurrently herewith an electronic Terminal Disclaimer over U.S. Pat. No. 11,634,468.
Applicant respectfully submits that the Terminal Disclaimer obviates the present rejection, and the application is now in condition for allowance.
CONCLUSION

NEXT OFFICE ACTION: DETAILED ACTION
Notice of Pre-AIA  or AIA  Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
EXAMINER’S AMENDMENT
An examiner’s amendment to the record appears below. Should the changes and/or additions be unacceptable to applicant, an amendment may be filed as provided by 37 CFR 1.312. To ensure consideration of such an amendment, it MUST be submitted no later than the payment of the issue fee.
Authorization for this examiner’s amendment was given in an interview with Alina Khankin, applicant’s representative, on 12/6/24.
IN THE CLAIMS
In claims 50, 54, and 58, line 1, the term “controlling” has been deleted and the following term inserted: --increasing--.
REASONS FOR ALLOWANCE
The following is an examiner’s statement of reasons for allowance:
Allowable Subject Matter – Methods of Using Issued Peptide SEQ ID NO: 8
Peptide species SEQ ID NO: 8 was not found to be reasonably taught or suggested by the prior art of record – as issued in the parent, now U.S. Patent No. 11,634,468.  Such is now allowed with the previous indication that were the instant claims amended to the same issued product scope (peptide SEQ ID NO: 8) as in ‘468; the scope of the method claims 24, 50, and 58  preambles amended “A method of [controlling] --increasing—serum calcium levels . . . “,  thereto (approved here); and a Terminal Disclaimer filed and approved over parent ‘468 (filed/approved; since there is no 35 USC 121 bar as the claims here were not restricted out of the parent and would have been open to rejoinder upon finding of the allowable product thereof) – as such the claims are now in condition for allowance.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee.  Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion

CITED REFERENCE SUMMARIES: Ref US9579392B2: Claims:
A method of conjugating a water soluble polymer with a compound BâNH 2 having a reactive amine group, the method comprising contacting the compound BâNH 2 with a water soluble polymeric reagent comprising a water soluble polymer and an Î±-hydroxy aldehyde or Î±-hydroxy ketone end group, respectively, thereby forming a conjugate in which said water soluble polymer is linked to a moiety having the structure âC(âO)âCHR 1 âNHâB, where R 1 is hydrogen or methyl, respectively, and NHâB represents the residue of the amine-containing compound.
contacting the compound BâNH 2 with a water soluble polymeric reagent comprising a water soluble polymer and an Î±-hydroxy aldehyde or Î±-hydroxy ketone end group, respectively,
thereby forming a conjugate in which said water soluble polymer is linked to a moiety having the structure âC(âO)âCHR 1 âNHâB, where R 1 is hydrogen or methyl, respectively, and NHâB represents the residue of the amine-containing compound.
The method of claim 1 , wherein said polymeric reagent further comprises a proton-abstracting functional group containing a proton-abstracting atom selected from oxygen and nitrogen, situated such there is a 3- or 4-bond spacing between the proton-abstracting atom and the Î±-carbon of said Î±-hydroxy aldehyde or Î±-hydroxy ketone.
The method of claim 2 , wherein said spacing in said reagent is a 4-bond spacing.
The method of claim 1 , wherein said polymeric reagent has the structure I:
where R 1 is selected from H, lower alkyl, and alkoxyalkyl; R 4 is a two- or three-carbon chain which may be substituted with one or more groups selected from alkyl, alkenyl, aryl, alkoxy, halo, cyano, and a water soluble polymer; wherein the carbon adjacent to CÎ± is not substituted with hydroxy, and wherein two substituents on R 4 may together form an aliphatic or aromatic ring, and NR 5 is a secondary or tertiary amino group which is linked to a water soluble polymer POLY via an optional spacer group Z, where R 5 is hydrogen or an alkyl group, which may form a ring with spacer group Z.
R 1 is selected from H, lower alkyl, and alkoxyalkyl;
R 4 is a two- or three-carbon chain which may be substituted with one or more groups selected from alkyl, alkenyl, aryl, alkoxy, halo, cyano, and a water soluble polymer; wherein the carbon adjacent to CÎ± is not substituted with hydroxy, and wherein two substituents on R 4 may together form an aliphatic or aromatic ring, and
NR 5 is a secondary or tertiary amino group which is linked to a water soluble polymer POLY via an optional spacer group Z, where R 5 is hydrogen or an alkyl group, which may form a ring with spacer group Z.
The method of claim 4 , wherein POLY is a polyethylene glycol (PEG).
The method of claim 5 , wherein R 4 is a three-carbon chain.
The method of claim 1 , wherein said polymeric reagent has the structure II:
where POLY is a water soluble polymer; R 1 is selected from H, alkyl, hydroxyalkyl, and alkoxyalkyl; m is 0-12; and each R 2 and R 3 is independently selected from H, alkyl, alkylene, hydroxy, amino, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkylene, aminoalkyl, iminoalkyl, carboxylic acid, alkylcarboxylic acid, phosphate, alkylphosphate, and a further water soluble polymer, wherein at most one R 2 or R 3 group is a water soluble polymer, and wherein two substituents R 2 and R 3 in â(CR 2 R 3 ) m â can together form a ring.
POLY is a water soluble polymer;
R 1 is selected from H, alkyl, hydroxyalkyl, and alkoxyalkyl;
each R 2 and R 3 is independently selected from H, alkyl, alkylene, hydroxy, amino, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkylene, aminoalkyl, iminoalkyl, carboxylic acid, alkylcarboxylic acid, phosphate, alkylphosphate, and a further water soluble polymer,
wherein at most one R 2 or R 3 group is a water soluble polymer, and wherein two substituents R 2 and R 3 in â(CR 2 R 3 ) m â can together form a ring.
The method of claim 7 , wherein said group R 2 or R 3 and the value of m are selected such that an oxygen or nitrogen atom on R 2 or R 3 is separated from CÎ± by a four-bond path.
The method of claim 7 , wherein at most one group R 2 or R 3 is selected from aminoalkyl, iminoalkyl, carboxylic acid, alkylcarboxylic acid, phosphate, and alkylphosphate.
The method of claim 7 , wherein POLY is a polyethylene glycol.
The method of claim 7 , wherein one group R 2 or R 3 is selected from hydroxy, amino, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkylene, aminoalkyl, iminoalkyl, carboxylic acid, alkylcarboxylic acid, phosphate, and alkylphosphate.
The method of claim 1 , wherein said polymeric reagent has the structure III:
where (i) R 7 is CH(OH)âC(âO)âR 1 , and R 8 is selected from âC(âO)OH, âCH 2 OH, âC(âO)N(R 1 ) 2 , âCH 2 N(R 1 ) 2 , âOH, and âN(R 1 ) 2 ; or (ii) R 7 is âCHR 1 CH(OH)âC(âO)âR 1 , and R 8 is âOH or âN(R 1 ) 2 ; where each R 1 is independently selected from H, lower alkyl, and alkoxyalkyl; and POLY is a water soluble polymer.
(i) R 7 is CH(OH)âC(âO)âR 1 , and R 8 is selected from âC(âO)OH, âCH 2 OH, âC(âO)N(R 1 ) 2 , âCH 2 N(R 1 ) 2 , âOH, and âN(R 1 ) 2 ; or
(ii) R 7 is âCHR 1 CH(OH)âC(âO)âR 1 , and R 8 is âOH or âN(R 1 ) 2 ;
where each R 1 is independently selected from H, lower alkyl, and alkoxyalkyl; and
POLY is a water soluble polymer.
The method of claim 12 , wherein R 7 is âCH(OH)âC(âO)âR 1 , where R 1 is H or methyl, and R 8 is âC(âO)OH or âCH 2 NH 2 .
The method of claim 12 , wherein R 7 is âCHR 1 CH(OH)âC(âO)âR 1 , where each R 1 is independently H or methyl, and R 8 is âOH or âNH 2 .
The method of claim 1 , wherein the water soluble polymeric reagent has the following structure:
wherein m-PEG is CH 3 OâCH 2 CH 2 Oâ(CH 2 CH 2 O) mâ² âCH 2 CH 2 Ë and mâ² is 2 to 4000.
The method of claim 15 , wherein mâ² is 20 to 1000.
Ref US11634468B2: [content unavailable]
Ref US11634468: Claims:
1. A parathyroid hormone (PTH)-Fc fusion protein, wherein the PTH-Fc fusion protein is PTH-66 having the amino acid sequence of SEQ ID NO: 8.
2. The PTH-Fc fusion protein of claim 1, wherein the PTH-Fc fusion protein is glycosylated.
3. A pharmaceutical composition comprising the PTH-Fc fusion protein of claim 1 and a pharmaceutically acceptable carrier.
4. A pharmaceutical dosage form comprising the PTH-Fc fusion protein of claim 1.
5. The pharmaceutical dosage form of claim 4, wherein the dosage form is a liquid dosage form suitable for administration by injection or infusion.
Ref US9579392: Claims:
1. A method of conjugating a water soluble polymer with a compound B—NH2 having a reactive amine group, the method comprising
contacting the compound B—NH2 with a water soluble polymeric reagent comprising a water soluble polymer and an α-hydroxy aldehyde or α-hydroxy ketone end group, respectively,
thereby forming a conjugate in which said water soluble polymer is linked to a moiety having the structure —C(═O)—CHR1—NH—B, where R1 is hydrogen or methyl, respectively, and NH—B represents the residue of the amine-containing compound.
2. The method of claim 1, wherein said polymeric reagent further comprises a proton-abstracting functional group containing a proton-abstracting atom selected from oxygen and nitrogen, situated such there is a 3- or 4-bond spacing between the proton-abstracting atom and the α-carbon of said α-hydroxy aldehyde or α-hydroxy ketone.
3. The method of claim 2, wherein said spacing in said reagent is a 4-bond spacing.
4. The method of claim 1, wherein said polymeric reagent has the structure I:
where
R1 is selected from H, lower alkyl, and alkoxyalkyl;
R4 is a two- or three-carbon chain which may be substituted with one or more groups selected from alkyl, alkenyl, aryl, alkoxy, halo, cyano, and a water soluble polymer; wherein the carbon adjacent to Cα is not substituted with hydroxy, and wherein two substituents on R4 may together form an aliphatic or aromatic ring, and
NR5 is a secondary or tertiary amino group which is linked to a water soluble polymer POLY via an optional spacer group Z, where R5 is hydrogen or an alkyl group, which may form a ring with spacer group Z.
5. The method of claim 4, wherein POLY is a polyethylene glycol (PEG).
6. The method of claim 5, wherein R4 is a three-carbon chain.
7. The method of claim 1, wherein said polymeric reagent has the structure II:
where
POLY is a water soluble polymer;
R1 is selected from H, alkyl, hydroxyalkyl, and alkoxyalkyl;
m is 0-12; and
each R2 and R3 is independently selected from H, alkyl, alkylene, hydroxy, amino, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkylene, aminoalkyl, iminoalkyl, carboxylic acid, alkylcarboxylic acid, phosphate, alkylphosphate, and a further water soluble polymer,
wherein at most one R2 or R3 group is a water soluble polymer, and wherein two substituents R2 and R3 in —(CR2R3)m— can together form a ring.
8. The method of claim 7, wherein said group R2 or R3 and the value of m are selected such that an oxygen or nitrogen atom on R2 or R3 is separated from Cα by a four-bond path.
9. The method of claim 7, wherein at most one group R2 or R3 is selected from aminoalkyl, iminoalkyl, carboxylic acid, alkylcarboxylic acid, phosphate, and alkylphosphate.
10. The method of claim 7, wherein POLY is a polyethylene glycol.
11. The method of claim 7, wherein one group R2 or R3 is selected from hydroxy, amino, alkoxy, hydroxyalkyl, alkoxyalkyl, alkoxyalkylene, aminoalkyl, iminoalkyl, carboxylic acid, alkylcarboxylic acid, phosphate, and alkylphosphate.
12. The method of claim 1, wherein said polymeric reagent has the structure III:
where
(i) R7 is CH(OH)—C(═O)—R1, and R8 is selected from —C(═O)OH, —CH2OH, —C(═O)N(R1)2, —CH2N(R1)2, —OH, and —N(R1)2; or
(ii) R7 is —CHR1CH(OH)—C(═O)—R1, and R8 is —OH or —N(R1)2;
where each R1 is independently selected from H, lower alkyl, and alkoxyalkyl; and
POLY is a water soluble polymer.
13. The method of claim 12, wherein R7 is —CH(OH)—C(═O)—R1, where R1 is H or methyl, and R8 is —C(═O)OH or —CH2NH2.
14. The method of claim 12, wherein R7 is —CHR1CH(OH)—C(═O)—R1, where each R1 is independently H or methyl, and R8 is —OH or —NH2.
15. The method of claim 1, wherein the water soluble polymeric reagent has the following structure:
wherein m-PEG is CH3O—CH2CH2O—(CH2CH2O)m′—CH2CH2˜ and m′ is 2 to 4000.
16. The method of claim 15, wherein m′ is 20 to 1000.