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 . In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 3 April, 2026 has been entered.
Election/Restrictions
Applicants elected formulation C of table 7 in the disclosure without traverse in the reply filed on 23 July, 2024.
Claims Status
Claims 27-36 and 41-53 are pending.
Claims 27 and 48 have been amended.
Claims 31-33, 42-51, and 53 have been withdrawn from consideration due to an election/restriction requirement.
Withdrawn Rejections
The rejection of claims 27-30, 34-36, 41, and 52 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph due to uncertainty as to the cutoff between clear and not clear solutions is hereby withdrawn due to amendment.
Maintained/Modified Rejections
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.
The factual inquiries 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 27-30, 34-36, 41, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079) in view of Zapadka et al (Interface. Focus (2017) 7:20170030) and Vagenende et al (Biochemistry (2009) 48 p11084-11096).
Applicants are claiming a formulation with dulaglutide, polysorbate 80, a phenolic preservative selected from a Markush group comprising phenol, and a solvent modifier selected from a Markush group including glycerol.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph).
The difference between this reference and the examined claims is that this reference does not discuss the formulation used.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize polypeptides is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of Matfin et al, to minimize aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Matfin et al discuss dulaglutide. Zapadka et al and Vagenende et al render obvious formulating it with Tween 80 (another name for polysorbate 80), phenol, and glycerol. Generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art, as this is a parameter that is routinely optimized (MPEP2144.05.II). Note that Zapadka et al states that the concentration and the ionic strength (which is dependent on buffer concentration) will both affect stability. Turbidity is particles, that is instability. The point of the optimization is to improve stability, thus, the material would reasonably be expected to be clear, i.e. very low NTU readings if tested. Thus, the combination of references renders obvious claims 27-30, 34, and 35
Thus, the combination of references renders obvious claims 28-30, and 35.
Zapadka et al list a small number of buffers that are commonly used, including citrate. Should the optimum pH be appropriate for this buffer, it is thus obvious, rendering obvious claims 36 and 41.
Matfin et al discusses an autoinjector, which reads on a vial (a small closed or closable vessel especially for liquids, Merriam Webster online dictionary), rendering obvious claim 52.
response to applicant’s arguments
Applicants argue that Matfin et al uses a placebo rather than dulaglutide in the autoinjector, that the rejection is based on hindsight reasoning, that the rationale is unsupported, that there is no reasonable expectation of success, that there is an unexpected result and fill a long felt need.
Applicant's arguments filed 3 April, 2026 have been fully considered but they are not persuasive.
It is noted that applicant’s arguments about the rationale, expectation of success, and long felt need have previously been argued and are unpersuasive for reasons of record. Please note that repetition does not make an unpersuasive argument persuasive without additional evidence.
Applicants argue that Matfin et al discloses a placebo in an autoinjector, not dulaglutide, so any dependence of dulaglutide in an autoinjector is hindsight reasoning. This is incorrect. While participants in the study were trained with a placebo device (p1072, 2nd column, 2nd paragraph), for the study itself, they used the commercially available (p1071, 2nd column, 2nd paragraph, continues to p1072, 1st column, 1st paragraph) dulaglutide pen (p1072, 2nd column, 1st paragraph). Note that, even if the placebo pen was used in the study, as applicants argue, the dulaglutide pen is disclosed. So even if applicants were correct, their argument would not have been persuasive.
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.
first rejection
Claims 27-30, 34-36, 41, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-5 of U.S. Patent No. 12,059,452 in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096), and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079).
Competing claim 1 describes a fusion protein composition, while competing claims 3-5 specify an additional pharmaceutical agent, specifically dulaglutide.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
response to applicant’s arguments
Applicants refer to their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
second rejection
Claims 27-30, 34-36, 41, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 17/795,797 (US 20230088005) in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096), and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079)
Competing claim 1 describes a method of treating, preventing, or delaying development of a cognitive disorder in a patient, comprising administering dulaglutide.
The difference between the competing claim and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
response to applicant’s arguments
Applicants refer to their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
third rejection
Claims 27-30, 34-36, 41, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 37 and 38 of copending Application No. 17/720,993 (US 20220251172) in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096), and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079).
Competing claims 37 and 38 describe a pharmaceutical composition with some product by process limitations, containing a therapeutic selected from a Markush group including dulaglutide.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
response to applicant’s arguments
Applicants refer to their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
fourth rejection
Claims 27-30, 34-36, 41, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,890,325 in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096), and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079).
Competing claim 1 describes a therapeutic method using dulaglutide.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
response to applicant’s arguments
Applicants refer to their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
fifth rejection
Claims 27-30, 34-36, 41, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of copending Application No. 18/409,277 (US 20240139287) in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096), and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079).
Competing claim 1 describes a therapeutic method using dulaglutide.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
response to applicant’s arguments
Applicants refer to their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
sixth rejection
Claims 27-30, 34-36, 41, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 11,576,950 in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096). , and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079).
Competing claim 1 describes a therapeutic method using dulaglutide.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
response to applicant’s arguments
Applicants refer to their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
seventh rejection
Claims 27-30, 34-36, 41, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 36 of copending Application No. 18/149,982 (US 20240189394) in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096), and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079).
Competing claim 36 describes a therapeutic method using dulaglutide.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
response to applicant’s arguments
Applicants refer to their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
eighth rejection
Claims 27-30, 34-36, 41, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 42 of copending Application No. 18/523,645 (US 20240197835) in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096), and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079).
Competing claim 42 describes a therapeutic method using dulaglutide.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
response to applicant’s arguments
Applicants refer to their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
ninth rejection
Claims 27-30, 34-36, 41, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-5 of U.S. Patent No. 9,884,093 in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096), and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079).
Competing claim 1 describes a fusion protein composition, while competing claims 3-5 specify a method using an additional pharmaceutical agent, specifically dulaglutide.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
response to applicant’s arguments
Applicants refer to their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
tenth rejection
Claims 27-30, 34-36, 41, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 11,253,574 in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096), and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079).
Competing claims 1-3 specify a method using an additional pharmaceutical agent, specifically dulaglutide.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
response to applicant’s arguments
Applicants refer to their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
eleventh rejection
Claims 27-30, 34-36, 41, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 17-21-5 of US Patent No 12,059,452 in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096), and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079).
Competing claims 1-5 describe a fusion protein composition with an additional active ingredient, namely, dulaglutide.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
response to applicant’s arguments
Applicants refer to their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
twelfth rejection
Claims 27-30, 34-36, 41, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 5 of U.S. Patent No. 9,161,953 in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096), and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079).
Competing claim 1 describes a method of treating diabetes using a GLP-1 agonist. Competing claim 5 gives a Markush group of agonists, including dulaglutide.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
response to applicant’s arguments
Applicants refer to their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
thirteenth rejection
Claims 27-30, 34-36, 41, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 7,452,966 in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096), and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079).
Competing claim 1 describes a GLP-1 analog fused to an antibody Fc portion, i.e. dulaglutide.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
response to applicant’s arguments
Applicants refer to their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
fourteenth rejection
Claims 27-30, 34-36, 41, and 52 are rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1 of U.S. Patent No. 8,273,854 in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096), and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079).
Competing claim 1 describes a method using GLP-1 analog fused to an antibody Fc portion, i.e. dulaglutide.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
response to applicant’s arguments
Applicants refer to their arguments with respect to the rejection under 35 USC 103, above, which were answered there.
New Rejections
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 27-30, 34-36, 41, and 52 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Applicants have amended the claims to require a turbidity measurement of 0-1 NTU. The only mention of NTU as units in the application as filed is the drawings. However, all we can tell from the drawings is that some of the samples have a turbidity greater than 0 NTU, and at the lower end of a 0-5 NTU range. While many samples may fall into the range of 0-1 NTU, this does not provide support for that range, as there is no clear showing that these are the endpoints that applicants can meet. The mere fact that the data points may be in that range is not sufficient; they are also in the range of 0.005-200 NTU, for example. Thus, this amendment constitutes new matter.
Double Patenting
The legal basis for these rejections was given above, and will not be repeated here.
fifteenth rejection
Claims 27-30, 34-36, 41, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 28 and 37 of of copending Application No. 19/063,585 (US 20250262373) in view of Zapadka et al (Interface. Focus (2017) 7:20170030) and Vagenende et al (Biochemistry (2009) 48 p11084-11096).
Competing claim 28 describes drug delivery device with a cartridge containing a volume of medication, while competing claim 37 describes a Markush group of medications, including dulaglutide.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
sixteenth rejection
Claims 27-30, 34-36, 41, and 52 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 12 of copending Application No. 19/107,739 (US 20260035428) in view of Zapadka et al (Interface. Focus (2017) 7:20170030), Vagenende et al (Biochemistry (2009) 48 p11084-11096), and Matfin et al (J. Diabetes Sci. Technol. (2015) 9(5) p1071-1079).
Competing claim 1 describes a treatment for diabetes, while competing claim 12 specifies dulaglutide as part of the treatment.
The difference between the competing claims and the examined claims is that the competing claims do not specify the formulation.
Zapadka et al discuss the factors affecting the stability of peptide therapeutics (title). Electrostatic interactions are known to play a role in aggregation (p7, 1st column, 5th paragraph), which is controlled by pH and ionic strength (p7, 2nd column, 1st paragraph). In addition, other decomposition mechanisms are dependent on pH (p8, 1st column, 3d paragraph). This strongly suggests optimizing pH of polypeptide formulations for stability. The most commonly used buffers are acetate, citrate, histidine, phosphate, tris, and glycine (p10, 1st column, 4th paragraph). While they may have some formulation issues, Tween 80 (another name for polysorbate 80) is often used to prevent aggregation and absorption (p10, 1st column, 6th paragraph, continues to 2nd column). Preservatives are often used; the most common ones are m-cresol, phenol, and benzyl alcohol (p10, 2nd column, 5th paragraph). Concentration of the polypeptide also plays an important role in stability, affecting aggregation kinetics (p4, 1st column, 1st paragraph). This reference discusses various components and considerations in polypeptide formulations.
Vagenende et al discuss the mechanisms of protein stabilization by glycerol (title). One of the most widely used polyols to stabilize proteins is glycerol, including in biopharmaceuticals (p11084, 2nd column, 2nd paragraph). This excipient reduces polypeptide flexibility, stabilizes partially unfolded intermediates, and reduces aggregation (p11084, 2nd column, 2nd paragraph). This reference discusses glycerol as a polypeptide stabilizer.
Matfin et al discuss once weekly dulaglutide single dose pen usage (title). This was a study to see if patients could use the single dose pen (interpreted as a vial) to treat type 2 diabetes (p1072, 1st column, 2nd paragraph). It was determined that patients could be used safely and effectively by these patients (p1078, 1st column, 6th paragraph). Pens are shown to be easier to use than syringes, which is suggested leads to improved adherence and glycemic control (p1078, 1st column, 4th paragraph). This reference discusses using pens to administer the drug.
Therefore, it would be obvious to optimize the pH of the dulaglutide formulations of the competing claims, to reduce aggregation and decomposition pathways, as discussed by Zapadka et al. As pH optimization is standard in polypeptide formulations, an artisan in this field would attempt this process with a reasonable expectation of success.
Furthermore, it would be obvious to formulate the material with Tween 80, phenol, a buffer, and glycerol to further stabilize the formulation, as discussed by both Zapadka et al and Vagenende et al. As these materials are commonly used for this purpose, an artisan in this field would add these ingredients with a reasonable expectation of success.
Finally, it would be obvious to use the pen system of Matfin et al, as an easy way of self-administering the material. As Matfin et al states that such systems work well in other studies, an artisan in this field would attempt this device with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Conclusion
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/FRED H REYNOLDS/Primary Examiner, Art Unit 1658
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