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 .
The rejections under sections 112(a) and 112(b) are withdrawn in view of Applicant’s amendments and remarks in connection with these rejections. Namely, the amendments clarifying the native GLP-1 and GLP-2 derivatives of the instant conjugates.
The rejection under section 103 is withdrawn in favor of the following new grounds of rejection under this section, which were necessitated by Applicants’ amendments:
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 1, 4, 6-26 are rejected under 35 U.S.C. 103 as being unpatentable over:
WO 2014017845 (WO 845); or WO 2019066586, as evidenced by counterpart U.S. Publication No. 20200262888 based on an application by Choi et al. (Choi); both in view of WO 01/49314 (WO 314).
WO 845 also teaches a liquid formulation of long-acting insulinotropic peptide conjugates, including GLP-2-Fc conjugates, which comprises pharmaceutical amounts of a long-acting insulinotropic peptide conjugate, where an insulinotropic peptide, which is a physiologically active peptide, is linked to an immunoglobulin Fc region; and an albumin-free stabilizer, where the stabilizer comprises a buffer, a sugar alcohol, a non-ionic surfactant, and an isotonic agent:
:
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Choi also discloses a long-acting GLP-2 formulation which comprises, as a GLP-2 derivative, a GLP-2 conjugate including sorbitol, mannitol (corresponding to sugar alcohol), a sugar source, and a stabilizing agent as a pharmaceutically acceptable carrier and has increased persistency and stability.
Namely, Choi teaches a GLP-2 conjugate (corresponding to X-L-F) comprising a GLP-2 derivative and an immunoglobulin Fc region which are linked to each other by a covalent bond through a non-peptidyl polymer (corresponding to a linker including ethylene glycol repeating units) (see abstract; paragraphs [0016+]; and claims 1-23).
Choi discloses that the GLP-2 derivative can be modified through any one method of substitution, addition, deletion, and modification of some amino acids, or a combination of the methods.
Choi discloses that the long-acting GLP-2 conjugate is SEQ ID NO: 9 wherein X1= histidine, histidine, imidazoacetyldeshistidine, desaminohistidine, β-hydroxyimidazopropionyldeshistidine, N-dimethylhistidine, or ß-carboxyimidazopropionyldeshistidine; X2 is alanine, glycine, or 2-aminoisobutyric acid (Aib); X30 is lysine or arginine; and X34 is absent, or lysine, arginine, glutamine, histidine, 6-azidolysine, or cysteine.
Choi discloses that
(1) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is cysteine;
(2) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is lysine;
(3) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is lysine;
(4) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is 6-azidolysine;
(5) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is cysteine;
(6) Xl is imidazoacetyldeshistidine, X2 is Aib, X30 is lysine, and X34 is cysteine; or
(7) Xl is histidine, X2 is Aib, X30 is lysine, and X34 is cysteine (see claim 4).
Choi teaches that:
1) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is cysteine;
(2) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is lysine;
(3) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is lysine;
(4) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is 6-azidolysine;
(5) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is cysteine;
(6) X1 is imidazoacetyldeshistidine, X2 is Aib, X30 is lysine, and X34 is cysteine; or
(7) X1 is histidine, X2 is Aib, X30 is lysine, and X34 is cysteine (see claim 4), and the advantages thus achieved could be sufficiently predicted.
Choi discloses that the GLP-2 derivative includes an amino acid sequence selected from the group consisting of SEQ ID NOS: 2 to 8 (see paragraph [0126, Table 1].
Choi discloses that the immunoglobulin Fc fragment is a no-glycosylated IgG4 Fc region (see claim 10).
Choi teaches that the dimer of each constant domain of the heavy chain and the constant region of the light chain and wherein a conjugate is prepared by reacting a non-peptidyl polymer with one of the GLP-2 derivative and an immunoglobulin Fe region such that the complex has the GLP-2 derivative or the immunoglobulin Fe region attached to one terminal end of the non-peptidyl polymer, and a reactive group at the other terminal end (see paragraph [0244]).
Choi discloses the non-peptidyl polymer polyethylene glycol as the linker (see claim 4).
Choi teaches that the molecular weight of the non-peptidyl polymer is in the range of more than 0 kDa to 200 kDa (see paragraph [0217]).
Choi teaches the Fc fragment, see examples.
The difference between the primary references and the claimed inventions is that the primary may not teach the invention with particularity so as to amount to anticipation (See M.P.E.P. § 2131: "[t]he identical invention must be shown in as complete detail as is contained in the ... claim." Richardson v. Suzuki Motor Co., 868 F.2d 1226, 1236, 9 USPQ2d 1913, 1920 (Fed. Cir. 1989). The elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990).). However, based on the above, the primary references teach the elements of the claimed formulations with regard to the recited GLP-2 conjugate, stabilizer and pH with sufficient guidance, particularity, and with a reasonable expectation of success, that the invention would be prima facie obvious to one of ordinary skill (the prior art reference teaches or suggests all the claim limitations with a reasonable expectation of success. See M.P.E.P. § 2143).
Nonetheless, WO 314 teaches that GLP-2 formulations within the recited ranges:
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See page 2.
One of ordinary skill would expect that these formulations would also apply to GLP-2 conjugates, as instantly claimed. In this manner, the recited formulations are prima facie obvious.
Notwithstanding Applicant’s remarks, the applied references teach formulations of the recited GLP-2-Fc conjugates. The recited stabilizers and pH’s overlap with those disclosed by the applied references with sufficient guidance, particularity, and with a reasonable expectation of success, that the invention would be prima facie obvious to one of ordinary skill, as discussed above.
The following double patenting rejections are maintained since the conflicting claims teach or suggest the instant formulations:
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 1, 4, 6-26 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 9833516 in view of Choi.
Although the claims at issue are not identical, they are not patentably distinct from each other.
The liquid formulations set forth in the conflicting claims anticipate those covered in the rejected claims. Alternatively, the difference between the formulations set forth in the conflicting claims and those covered by the rejected claims is that the conflicting claims do not recite the instant formulations with particularity so as to amount to anticipation (See M.P.E.P. § 2131: "[t]he identical invention must be shown in as complete detail as is contained in the ... claim." Richardson v. Suzuki Motor Co., 868 F.2d 1226, 1236, 9 USPQ2d 1913, 1920 (Fed. Cir. 1989). The elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990).). However, the conflicting claims recite the elements of the claimed formulations with sufficient guidance, particularity, and with a reasonable expectation of success, that the invention would be prima facie obvious to one of ordinary skill (the prior art reference teaches or suggests all the claim limitations with a reasonable expectation of success. See M.P.E.P. § 2143). Specifically, the conflicting claims may fail to explicitly recite the amounts of the recited adjuvants and components. However, the amount of these in the disclosed composition are a result-effective parameters that will affect the pharmacological and pharmacokinetic properties of the final composition. In this manner, the amount of a specific ingredient in a composition is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize.
Specifically, it would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve a desired result. For any component, amounts can be estimated initially either in cell culture assays or in animal models, usually rats, rabbits, dogs, or pigs. The animal model also can be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
Normal dosage amounts can vary from micrograms to 100,000 micrograms, up to a maximum total dose, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
In this way, optimization of these parameters is a routine practice, and consequently, would be prima facie obvious, absent factual evidence demonstrating an unexpected benefit of the claimed amount(s).
The conflicting claims may fail to teach a GLP-2 derivative that is represented by Formula 1. However, Choi discloses a long-acting GLP-2 formulation which comprises, as a GLP-2 derivative, a GLP-2 conjugate including sorbitol, mannitol (corresponding to sugar alcohol), a sugar source, and a stabilizing agent as a pharmaceutically acceptable carrier and has increased persistency and stability.
In addition, a person skilled in the art could apply a liquid formulation of the conflicting claims to the GLP-2 conjugate of Choi for the purposes of effective for stabilization of the conjugate. Namely, Choi teaches a GLP-2 conjugate (corresponding to X-L-F) comprising a GLP-2 derivative and an immunoglobulin Fc region which are linked to each other by a covalent bond through a non-peptidyl polymer (corresponding to a linker including ethylene glycol repeating units) (see abstract; paragraphs [0016+]; and claims 1-23).
Regarding claims 2-5, Choi discloses that the GLP-2 derivative can be modified through any one method of substitution, addition, deletion, and modification of some amino acids, or a combination of the methods.
Choi discloses that the long-acting GLP-2 conjugate is SEQ ID NO: 9 wherein X1= histidine, histidine, imidazoacetyldeshistidine, desaminohistidine, β-hydroxyimidazopropionyldeshistidine, N-dimethylhistidine, or ß-carboxyimidazopropionyldeshistidine; X2 is alanine, glycine, or 2-aminoisobutyric acid (Aib); X30 is lysine or arginine; and X34 is absent, or lysine, arginine, glutamine, histidine, 6-azidolysine, or cysteine.
Choi discloses that
(1) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is cysteine;
(2) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is lysine;
(3) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is lysine;
(4) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is 6-azidolysine;
(5) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is cysteine;
(6) Xl is imidazoacetyldeshistidine, X2 is Aib, X30 is lysine, and X34 is cysteine; or
(7) Xl is histidine, X2 is Aib, X30 is lysine, and X34 is cysteine (see claim 4).
Choi teaches that:
1) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is cysteine;
(2) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is lysine;
(3) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is lysine;
(4) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is 6-azidolysine;
(5) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is cysteine;
(6) X1 is imidazoacetyldeshistidine, X2 is Aib, X30 is lysine, and X34 is cysteine; or
(7) X1 is histidine, X2 is Aib, X30 is lysine, and X34 is cysteine (see claim 4), and the advantages thus achieved could be sufficiently predicted.
Regarding claim 6, Choi discloses that the GLP-2 derivative includes an amino acid sequence selected from the group consisting of SEQ ID NOS: 2 to 8 (see paragraph [0126, Table 1].
Regarding claim 7, Choi discloses that the immunoglobulin Fc fragment is a no-glycosylated IgG4 Fc region (see claim 10).
Regarding claim 8, Choi teaches that the dimer of each constant domain of the heavy chain and the constant region of the light chain and wherein a conjugate is prepared by reacting a non-peptidyl polymer with one of the GLP-2 derivative and an immunoglobulin Fe region such that the complex has the GLP-2 derivative or the immunoglobulin Fe region attached to one terminal end of the non-peptidyl polymer, and a reactive group at the other terminal end (see paragraph [0244]).
Regarding claim 9, Choi discloses the non-peptidyl polymer polyethylene glycol as the linker (see claim 4).
Regarding claim 10, Choi teaches that the molecular weight of the non-peptidyl polymer is in the range of more than 0 kDa to 200 kDa (see paragraph [0217]).
Regarding claim 11, Choi teaches the Fc fragment, see examples.
In this way, those of ordinary skill could have applied the liquid formulation of the conflicting claims to the insulinotropic peptide GLP-2 conjugates of Choi for the purposes of providing a long-acting insulin conjugate formulation. As outlined above, the conflicting claims recite a liquid formulation for insulinotropic peptide GLP-2 conjugates. Choi is added for the proposition that the instant GLP-2 conjugates are applicable to these formulations. Specifically, the conflicting claims demonstrate that the particular known technique of using the instant formulations for GLP-2 conjugates was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to GLP-2 conjugates, such as those described by Choi, would have yielded predictable results. Accordingly, using the recited liquid formulations of the recited GLP-2 conjugates for the purposes of providing a long-acting insulin conjugate formulation would have been prima facie obvious.
Claims 1, 4, 6-26 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-24 of U.S. Patent No. 9801950 in view of Choi.
Although the claims at issue are not identical, they are not patentably distinct from each other.
The liquid formulations set forth in the conflicting claims anticipate those covered in the rejected claims. Alternatively, the difference between the formulations set forth in the conflicting claims and those covered by the rejected claims is that the conflicting claims do not recite the instant formulations with particularity so as to amount to anticipation (See M.P.E.P. § 2131: "[t]he identical invention must be shown in as complete detail as is contained in the ... claim." Richardson v. Suzuki Motor Co., 868 F.2d 1226, 1236, 9 USPQ2d 1913, 1920 (Fed. Cir. 1989). The elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990).). However, the conflicting claims recite the elements of the claimed formulations with sufficient guidance, particularity, and with a reasonable expectation of success, that the invention would be prima facie obvious to one of ordinary skill (the prior art reference teaches or suggests all the claim limitations with a reasonable expectation of success. See M.P.E.P. § 2143). Specifically, the conflicting claims may fail to explicitly recite the amounts of the recited adjuvants and components. However, the amount of these in the disclosed composition are a result-effective parameters that will affect the pharmacological and pharmacokinetic properties of the final composition. In this manner, the amount of a specific ingredient in a composition is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize.
Specifically, it would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve a desired result. For any component, amounts can be estimated initially either in cell culture assays or in animal models, usually rats, rabbits, dogs, or pigs. The animal model also can be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
Normal dosage amounts can vary from micrograms to 100,000 micrograms, up to a maximum total dose, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
In this way, optimization of these parameters is a routine practice, and consequently, would be prima facie obvious, absent factual evidence demonstrating an unexpected benefit of the claimed amount(s).
The conflicting claims may fail to teach a GLP-2 derivative that is represented by Formula 1. However, Choi discloses a long-acting GLP-2 formulation which comprises, as a GLP-2 derivative, a GLP-2 conjugate including sorbitol, mannitol (corresponding to sugar alcohol), a sugar source, and a stabilizing agent as a pharmaceutically acceptable carrier and has increased persistency and stability.
In addition, a person skilled in the art could apply a liquid formulation of the conflicting claims to the GLP-2 conjugate of Choi for the purposes of effective for stabilization of the conjugate. Namely, Choi teaches a GLP-2 conjugate (corresponding to X-L-F) comprising a GLP-2 derivative and an immunoglobulin Fc region which are linked to each other by a covalent bond through a non-peptidyl polymer (corresponding to a linker including ethylene glycol repeating units) (see abstract; paragraphs [0016+]; and claims 1-23).
Regarding claims 2-5, Choi discloses that the GLP-2 derivative can be modified through any one method of substitution, addition, deletion, and modification of some amino acids, or a combination of the methods.
Choi discloses that the long-acting GLP-2 conjugate is SEQ ID NO: 9 wherein X1= histidine, histidine, imidazoacetyldeshistidine, desaminohistidine, β-hydroxyimidazopropionyldeshistidine, N-dimethylhistidine, or ß-carboxyimidazopropionyldeshistidine; X2 is alanine, glycine, or 2-aminoisobutyric acid (Aib); X30 is lysine or arginine; and X34 is absent, or lysine, arginine, glutamine, histidine, 6-azidolysine, or cysteine.
Choi discloses that
(1) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is cysteine;
(2) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is lysine;
(3) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is lysine;
(4) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is 6-azidolysine;
(5) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is cysteine;
(6) Xl is imidazoacetyldeshistidine, X2 is Aib, X30 is lysine, and X34 is cysteine; or
(7) Xl is histidine, X2 is Aib, X30 is lysine, and X34 is cysteine (see claim 4).
Choi teaches that:
1) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is cysteine;
(2) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is lysine;
(3) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is lysine;
(4) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is 6-azidolysine;
(5) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is cysteine;
(6) X1 is imidazoacetyldeshistidine, X2 is Aib, X30 is lysine, and X34 is cysteine; or
(7) X1 is histidine, X2 is Aib, X30 is lysine, and X34 is cysteine (see claim 4), and the advantages thus achieved could be sufficiently predicted.
Regarding claim 6, Choi discloses that the GLP-2 derivative includes an amino acid sequence selected from the group consisting of SEQ ID NOS: 2 to 8 (see paragraph [0126, Table 1].
Regarding claim 7, Choi discloses that the immunoglobulin Fc fragment is a no-glycosylated IgG4 Fc region (see claim 10).
Regarding claim 8, Choi teaches that the dimer of each constant domain of the heavy chain and the constant region of the light chain and wherein a conjugate is prepared by reacting a non-peptidyl polymer with one of the GLP-2 derivative and an immunoglobulin Fe region such that the complex has the GLP-2 derivative or the immunoglobulin Fe region attached to one terminal end of the non-peptidyl polymer, and a reactive group at the other terminal end (see paragraph [0244]).
Regarding claim 9, Choi discloses the non-peptidyl polymer polyethylene glycol as the linker (see claim 4).
Regarding claim 10, Choi teaches that the molecular weight of the non-peptidyl polymer is in the range of more than 0 kDa to 200 kDa (see paragraph [0217]).
Regarding claim 11, Choi teaches the Fc fragment, see examples.
In this way, those of ordinary skill could have applied the liquid formulation of the conflicting claims to the insulinotropic peptide GLP-2 conjugates of Choi for the purposes of providing a long-acting insulin conjugate formulation. As outlined above, the conflicting claims recite a liquid formulation for insulinotropic peptide GLP-2 conjugates. Choi is added for the proposition that the instant GLP-2 conjugates are applicable to these formulations. Specifically, the conflicting claims demonstrate that the particular known technique of using the instant formulations for GLP-2 conjugates was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to GLP-2 conjugates, such as those described by Choi, would have yielded predictable results. Accordingly, using the recited liquid formulations of the recited GLP-2 conjugates for the purposes of providing a long-acting insulin conjugate formulation would have been prima facie obvious.
Claims 1, 4, 6-26 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of U.S. Patent No. 10441665 in view of Choi.
Although the claims at issue are not identical, they are not patentably distinct from each other.
The liquid formulations set forth in the conflicting claims anticipate those covered in the rejected claims. Alternatively, the difference between the formulations set forth in the conflicting claims and those covered by the rejected claims is that the conflicting claims do not recite the instant formulations with particularity so as to amount to anticipation (See M.P.E.P. § 2131: "[t]he identical invention must be shown in as complete detail as is contained in the ... claim." Richardson v. Suzuki Motor Co., 868 F.2d 1226, 1236, 9 USPQ2d 1913, 1920 (Fed. Cir. 1989). The elements must be arranged as required by the claim, but this is not an ipsissimis verbis test, i.e., identity of terminology is not required. In re Bond, 910 F.2d 831, 15 USPQ2d 1566 (Fed. Cir. 1990).). However, the conflicting claims recite the elements of the claimed formulations with sufficient guidance, particularity, and with a reasonable expectation of success, that the invention would be prima facie obvious to one of ordinary skill (the prior art reference teaches or suggests all the claim limitations with a reasonable expectation of success. See M.P.E.P. § 2143). Specifically, the conflicting claims may fail to explicitly recite the amounts of the recited adjuvants and components. However, the amount of these in the disclosed composition are a result-effective parameters that will affect the pharmacological and pharmacokinetic properties of the final composition. In this manner, the amount of a specific ingredient in a composition is clearly a result-effective parameter that a person of ordinary skill in the art would routinely optimize.
Specifically, it would have been customary for an artisan of ordinary skill to determine the optimal amount of each ingredient to add in order to best achieve a desired result. For any component, amounts can be estimated initially either in cell culture assays or in animal models, usually rats, rabbits, dogs, or pigs. The animal model also can be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans.
Normal dosage amounts can vary from micrograms to 100,000 micrograms, up to a maximum total dose, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
In this way, optimization of these parameters is a routine practice, and consequently, would be prima facie obvious, absent factual evidence demonstrating an unexpected benefit of the claimed amount(s).
The conflicting claims may fail to teach a GLP-2 derivative that is represented by Formula 1. However, Choi discloses a long-acting GLP-2 formulation which comprises, as a GLP-2 derivative, a GLP-2 conjugate including sorbitol, mannitol (corresponding to sugar alcohol), a sugar source, and a stabilizing agent as a pharmaceutically acceptable carrier and has increased persistency and stability.
In addition, a person skilled in the art could apply a liquid formulation of the conflicting claims to the GLP-2 conjugate of Choi for the purposes of effective for stabilization of the conjugate. Namely, Choi teaches a GLP-2 conjugate (corresponding to X-L-F) comprising a GLP-2 derivative and an immunoglobulin Fc region which are linked to each other by a covalent bond through a non-peptidyl polymer (corresponding to a linker including ethylene glycol repeating units) (see abstract; paragraphs [0016+]; and claims 1-23).
Regarding claims 2-5, Choi discloses that the GLP-2 derivative can be modified through any one method of substitution, addition, deletion, and modification of some amino acids, or a combination of the methods.
Choi discloses that the long-acting GLP-2 conjugate is SEQ ID NO: 9 wherein X1= histidine, histidine, imidazoacetyldeshistidine, desaminohistidine, β-hydroxyimidazopropionyldeshistidine, N-dimethylhistidine, or ß-carboxyimidazopropionyldeshistidine; X2 is alanine, glycine, or 2-aminoisobutyric acid (Aib); X30 is lysine or arginine; and X34 is absent, or lysine, arginine, glutamine, histidine, 6-azidolysine, or cysteine.
Choi discloses that
(1) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is cysteine;
(2) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is lysine;
(3) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is lysine;
(4) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is 6-azidolysine;
(5) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is cysteine;
(6) Xl is imidazoacetyldeshistidine, X2 is Aib, X30 is lysine, and X34 is cysteine; or
(7) Xl is histidine, X2 is Aib, X30 is lysine, and X34 is cysteine (see claim 4).
Choi teaches that:
1) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is cysteine;
(2) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is lysine;
(3) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is lysine;
(4) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is lysine, and X34 is 6-azidolysine;
(5) X1 is imidazoacetyldeshistidine, X2 is glycine, X30 is arginine, and X34 is cysteine;
(6) X1 is imidazoacetyldeshistidine, X2 is Aib, X30 is lysine, and X34 is cysteine; or
(7) X1 is histidine, X2 is Aib, X30 is lysine, and X34 is cysteine (see claim 4), and the advantages thus achieved could be sufficiently predicted.
Regarding claim 6, Choi discloses that the GLP-2 derivative includes an amino acid sequence selected from the group consisting of SEQ ID NOS: 2 to 8 (see paragraph [0126, Table 1].
Regarding claim 7, Choi discloses that the immunoglobulin Fc fragment is a no-glycosylated IgG4 Fc region (see claim 10).
Regarding claim 8, Choi teaches that the dimer of each constant domain of the heavy chain and the constant region of the light chain and wherein a conjugate is prepared by reacting a non-peptidyl polymer with one of the GLP-2 derivative and an immunoglobulin Fe region such that the complex has the GLP-2 derivative or the immunoglobulin Fe region attached to one terminal end of the non-peptidyl polymer, and a reactive group at the other terminal end (see paragraph [0244]).
Regarding claim 9, Choi discloses the non-peptidyl polymer polyethylene glycol as the linker (see claim 4).
Regarding claim 10, Choi teaches that the molecular weight of the non-peptidyl polymer is in the range of more than 0 kDa to 200 kDa (see paragraph [0217]).
Regarding claim 11, Choi teaches the Fc fragment, see examples.
In this way, those of ordinary skill could have applied the liquid formulation of the conflicting claims to the insulinotropic peptide GLP-2 conjugates of Choi for the purposes of providing a long-acting insulin conjugate formulation. As outlined above, the conflicting claims recite a liquid formulation for insulinotropic peptide GLP-2 conjugates. Choi is added for the proposition that the instant GLP-2 conjugates are applicable to these formulations. Specifically, the conflicting claims demonstrate that the particular known technique of using the instant formulations for GLP-2 conjugates was recognized as part of the ordinary capabilities of one skilled in the art. In this manner, those of ordinary skill would have recognized that applying the known technique to GLP-2 conjugates, such as those described by Choi, would have yielded predictable results. Accordingly, using the recited liquid formulations of the recited GLP-2 conjugates for the purposes of providing a long-acting insulin conjugate formulation would have been prima facie obvious.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KARL J PUTTLITZ whose telephone number is (571)272-0645. The examiner can normally be reached on Monday to Friday from 9 a.m. to 5 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Gregory Emch, can be reached at telephone number 571-272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KARL J PUTTLITZ/ Primary Examiner, Art Unit 1646
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