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 .
Priority
The instant application, filed 06/02/2023 is a National Stage entry of PCT/EP2021/086133 , International Filing Date: 12/16/2021
claims foreign priority to 20214559.5, filed 12/16/2020.
Information Disclosure Statement
Except for crossed-through references which were not provided, the Examiner has considered the references that were provided in the 6/26/23, 4/9/24, 7/25/24, 1/13/25, 6/30/25, 7/17/25, and 11/12/25 Information Disclosure Statements, and provides a signed and dated copy of each herewith.
Claim Status
Claims 1-20 are pending and under examination.
Claims 1-20 are rejected.
Claims 1, 8 and 10 are objected to.
Claim Objections
Claims 1, 8, 10 are objected to because of the following informalities: these claims list sequences, but not the associated SEQ ID number. Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 5, 7, 12, 16, 17, 19 and 20 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Applicants have stated regarding the modifier “about” “When using terms such as “about” and “approximately” in relation to numerical values, the skilled person should immediately recognise that any effect or result, which may be associated with the given values can be obtained within a certain tolerance from the particular values. The term “about” as used herein thus means in reasonable vicinity of the stated numerical value, such as plus or minus 10%. When the term “about” is used about the chemical stability in this patent application, the reasonable vicinity will be below 2%, such as 0.5% or 0.75%, 1% or 1.5%,” para 138 of corresponding PGPUB 20240299552. While the modifier clearly allows some wiggle room, given the different definitions – one pertaining to chemical stability, the other not, given the use of “such as” before “plus or minus 10%”, it is not clear how much variance is allowed when “about” is used other than pertaining to chemical stability.
Claim Rejections - 35 USC § 103
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.
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) 1, 3-11 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over Larson et al (WO 2018104561, cited by applicants in 6/26/23 IDS, “Larson”) in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”).
Claim 1 is directed to a composition comprising one or more dual agonist comprising general formula A, one or more preservative that comprises m-cresol and/or phenol, and phosphate buffer.
Larson et al discuss acylated dual GLP-1/GLP-2 agonists (abstract) for treating a number of disorders. Among the compounds specifically synthesized is H[Aib]EGSFTSELATILD[K{17 carboxy-heptadecanoyl}isoGlu)]QAARDFIAWLIQHKITD (compound 18, table 1, p69). This compound is a species encompassed by instant claims 1 and 8, and has the identical amino acid sequence as the species of instant claims 9 and 10. This sequence was tested for solubility (table 3, p78, top of page) and chemical stability (table 4, p79, top of page) and was explicitly claimed (claim 42), indicating that the inventors were interested in this particular sequence. Preliminary stability study was conducted, varying the pH in water, without buffers or other salts (example 4, p78, 1st paragraph).
The difference between this reference and claim 1 is that this reference does not describe the claimed formulation components including one or more preservative of m-cresol and/or phenol, and a phosphate buffer.
The level of ordinary skill in the pertinent art is high, and there is great interest in developing more effective and improved formulations of the receptor agonists in this art.
Boss teaches trigonal GLP-1/glucagon/GIP receptor agonists and their medical use, Abstract, and is in the same art field and includes developing suitable compositions of its peptides.
Boss para 43 teaches, “In one embodiment the compounds of the invention have a high solubility at acidic and/or physiological pH values in the presence of an antimicrobial preservative like phenol or m-cresol, e.g., at an acidity range from pH 4 to 5, especially pH 4.5 and/or a more physiological range from pH 6 to 8, especially at pH 7.4 at 25° C. or 40° C., in another embodiment at least 1 mg/ml and in a particular embodiment at least 5 mg/ml.”
Boss paras 191 and 192 teach:
[0191] A “pharmaceutically acceptable carrier” is a carrier which is physiologically acceptable (e.g. physiologically acceptable pH) while retaining the therapeutic properties of the substance with which it is administered. Standard acceptable pharmaceutical carriers and their formulations are known to one skilled in the art and described, for example, in Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro A. R., 2000, Lippencott Williams & Wilkins and in R. C. Rowe et al (Ed), Handbook of Pharmaceutical excipients, PhP, May 2013 update. One exemplary pharmaceutically acceptable carrier is physiological saline solution.
[0192] In one embodiment carriers are selected from the group of buffers (e.g. citrate/citric acid, acetate/acetic acid), acidifying agents (e.g. hydrochloric acid), alkalizing agents (e.g. sodium hydroxide), preservatives (e.g. phenol, m-cresol), co-solvents (e.g. polyethylene glycol 400), tonicity adjusters (e.g. mannitol, glycerol), stabilizers (e.g. surfactant, antioxidants, amino acids).
For solubility testing, Boss teaches evaluating “Solubility buffer system B) Phosphate Buffer pH 7.4, 100 mM sodium hydrogen phosphate, 2.7 mg/ml m-Cresol,” para 359, and also evaluating ” Chemical stability buffer system B) 25 mM phosphate buffer pH 6.0, 3 mg/mL L-Methionine, 2.7 mg/mL m-cresol, 18 mg/mL Glycerol 85%,” para 365. Boss thus teaches combining phosphate buffer and the antimicrobial preservative m-cresol in its peptide compositions. As set forth above regarding antimicrobials, Boss also teaches use of phenol.
As to claim 1, the prior art Larson and Boss included each element claimed, and although not in a single prior art reference, the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference. However, at least given the level of ordinary skill in the art and motivations to improve formulations therein, one of ordinary skill in the art could have combined the elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately. Further, given the known and predictable effects of the antimicrobial preservatives including m-cresol as taught by Boss, and phosphate buffer, one of ordinary skill in the art would have recognized that the results of the combination were predictable. There would have been a reasonable expectation of success based on the references teachings and examples, to combine the respective limitations to obtain the claimed composition of instant claim 1.
Accordingly, claim 1 would have been obvious and is so rejected under this section.
Claims 3 and 4 are rejected because Boss clearly teaches m-cresol and phenol as two specifically recited antimicrobial preservatives.
Boss teaches a chemical stability buffer comprising 25 mM phosphate buffer, at pH 6.0, rendering obvious claim 5 based on teaching a value within the claim 5 claimed range, see MPEP 2144.05.
Boss also teaches a sodium phosphate buffer system, “Solubility buffer system B) Phosphate Buffer pH 7.4, 100 mM sodium hydrogen phosphate, 2.7 mg/ml m-Cresol”, para 359, this with m-cresol, rendering obvious claim 6 and also claim 7, the pH of 7.4 teaching a value within the claim 7 claimed range, see MPEP 2144.05.
Claims 8-10 are rejected as obvious on the same bases as claim 1. Please note that Larson teaches the C-terminus of its peptides having either NH2 or OH, see page 2 line 26, and page 22, lines 28-35.
Claim 11 is rejected based on the teachings and examples of Larson, see Example 3, pages 77-78, where in Table 3 are shown multiple compounds having solubility greater than or equal to 1 mg/ml across a range of buffers and pH values.
Boss teaches all of its solubility buffers comprising 2.7 mg/ml m-cresol, paras 358-360, see also para 365 teaching the same concentration in chemical stability buffers, falling within the range of rendering obvious claim 16.
Claim 2 is rejected under 35 U.S.C. 103 as being unpatentable over Larson et al, WO 2018104561, cited and provided in 6/26/23 IDS, (“Larson”) in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”), as applied to claim 1 above, and further in view of Usach et al., Adv Ther (2019) 36:2986–2996 (“Usach”).
Claim 1 is rejected above.
Usach teaches that “Ideally, injectable products should be formulated as isotonic solutions (osmolality of about 300mOsm/kg) and no more than 600 mOs/kg have to be used in order to prevent pain,” Abstract, page 2986.
It would have been obvious to formulate to obtain an isotonic solution because Usach teaches that this is ideal for injectable products.
Accordingly claim 2 is rejected.
Claims 1, 3-15, 17 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Larson et al, WO 2018104561, cited and provided in 6/26/23 IDS, (“Larson”) in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”), as applied to claims 1, 3-11 and 16 above, and further in view of Izutsu (in Therapeutic Proteins (2005), Smales and James, ed. ISBN 1-58829-390-4).
The rejection of claims 1 and 3-11 are set forth above, and the rejections herein for such claims already rejected above are provided to further establish bases for rejection when considering the additional prior art herein.
Izutsu teaches a sequence of steps to develop stabilized polypeptide formulations.
Izutsu describes polypeptide stabilization (title). Changing the polypeptide environment and using appropriate excipients can usually provide stable formulations (p287, 2nd page). Stability is for 1-2 years of storage (p287, 1st paragraph). Preformulation studies survey the stability profile while varying pH and ionic strength, followed by identifying various buffers and excipients that affect protein stability (p289, section 3.1 “preformulation studies”). Among the excipients suggested are phosphate buffer and also NaCl and mannitol as tonicity modifiers (table 2, p288).
Therefore, it would be obvious to optimize the formulations of Larson to optimize their stability, as discussed by Izutsu, to generate formulations with improved stability by evaluating combinations of known and widely used excipients, such as those instantly set forth in the claims. As Izutsu describes how to perform this optimization, with suggested buffers and excipients, an artisan in this field would attempt this optimization with a reasonable expectation of success. As made clear in Izutsu, the optimization is based on evaluating combinations of result-effective variables.
Larson et al describes applicant’s elected polypeptide for treating one or more disorders. Izutsu describes optimizing the pH and ionic strength of a polypeptide formulation for stability, followed by optimizing the buffer and ligand. The reference explicitly describes the excipients used in applicant’s claimed formulation, indicating that they would be included in the optimization. The MPEP states that “Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or working ranges by routine experimentation" In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955); see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382 (“The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.”) (MPEP2144.05.II). Thus, the combination of references renders obvious claims not only claims 1, 3-11 and 16 as set forth above, now bases supplemented by the approach of Izutsu, but also claims 12-15, 17 and 20.
Claim 18 is rejected under 35 U.S.C. 103 as being unpatentable over Larson et al, WO 2018104561, cited and provided in 6/26/23 IDS, (“Larson”) in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”), and Izutsu (in Therapeutic Proteins (2005), Smales and James, ed. ISBN 1-58829-390-4) as applied to claims 1 and 10 above, and further in view of Gupta et al., Molecules 2018, 23, 1719, 15 pages (“Gupta”).
Claim 1 and 10 are rejected above.
Gupta, providing a review of salts of therapeutic agents, see Title, teaches that “The most commonly used anions for oral dosage forms are chloride, sulfate, and maleate; chloride, sulfate, and acetate were the three top anions used for injectable dosage forms,” page 8.
One of ordinary skill in the art reasonably would have evaluated, and reasonably selected, a chloride salt based on selecting from among a short list of the most common salts used for two dosage forms, and also from evaluating formulations as part of routine optimization such as following the teachings of Izutsu.
Accordingly, claim 18 would have been obvious and is rejected under this section.
Claim 19 is rejected under 35 U.S.C. 103 as being unpatentable over Larson et al, WO 2018104561, cited and provided in 6/26/23 IDS, (“Larson”) in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”), as applied to claims 1, 3-11 and 16 above, further in view of Izutsu (in Therapeutic Proteins (2005), Smales and James, ed. ISBN 1-58829-390-4), rejecting claims 13 and 14 above, and further with evidentiary support from the Byju’s chemistry webpage (cited and provided in 1/13/25 IDS).
Claims 1, 13 and 14 are rejected above.
Claim 19 introduces that “the mannitol comprises D-mannitol” and states that this is “present in the composition at a concentration of from about 130 mM to about 330 mM.”
The range of claim 19 would reasonably be obtained, and/or a narrower range or value within the claimed range, by routine optimization as taught in Izutsu, and as evidenced by the Byju chemistry web page, mannitol and d-mannitol are synonyms, rendering obvious claim 19.
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 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 6, 9-16, 19, and 20 of copending Application No. 18/039,857 (US 20240024425) in view of Izutsu (in Therapeutic Proteins (2005), Smales and James, ed. ISBN 1-58829-390-4).
Competing claim 1 specifies a GLP-1/GLP-2 dual agonist in tris buffer and one or more preservative comprising or is m-cresol and/or phenol, and competing claim 9 is directed to a polypeptide species with different C-terminus alternatives corresponding to instant claim 10. Competing claim 2 specifies an isotonic parenteral formulation, corresponding to instant claim 2. Competing claims 3 and 4 correspond to instant claims 3 and 4. Competing claim 6 specifies the pH to be between about 6 and 8.5, corresponding to instant claim 7. Competing claim 8 corresponds with instant claim 9. Competing claims 10 and 11 specify the polypeptide is at a concentration of at least 1 mM, or about 2 or 15 mM, corresponding to instant claims 11 and 12. Competing claim 12 specifies one or more tonicity agents, which competing claim 13 states includes mannitol, which competing claim 14 specifies a concentration of between about 130 and 330 mM, and competing claim 15 specifies the tonicity agent is NaCl which competing claim 20 specifies at a concentration between about 50 and 450 mM. These correspond to instant claims 13-15. Competing claims 16 and 17 correspond to instant claims 16 and 17. Competing claim 18 is directed to a chloride salt of two specified peptides, these falling within and anticipatory for instant claim 18. Competing claim 19 is directed to D-mannitol, the normal kind, and this corresponds to instant claim 19 but for the latter’s concentration range, which is rendered obvious by the range of competing claim 14. Competing and instant claim 20 are identical. Note that the concentration ranges specified are the same or very similar to those of the examined claims that do not specify a buffer, using the same excipients, so those claim limitations are anticipated.
The difference between the competing claims and the examined claims is that the competing claims do not specify phosphate buffer.
The level of ordinary skill in the pertinent art is high, and there is great interest in developing more effective and improved formulations of the receptor agonists in this art.
Izutsu describes polypeptide stabilization (title). By changing the polypeptide environment and using appropriate excipients can usually provide stable formulations (p287, 2nd page). Stability is for 1-2 years of storage (p287, 1st paragraph). Preformulation studies survey the stability profile while varying pH and ionic strength, followed by identifying various ligands that affect protein stability (p289, section 3.1 “preformulation studies”). Among the excipients suggested are phosphate buffer and NaCl and mannitol as tonicity modifiers (table 2, p288). Note that, as evidenced by the Byju chemistry web page, mannitol is a synonym for d-mannitol
Therefore, it would be obvious to optimize the formulations claimed by the reference application to optimize their stability, as discussed by Izutsu, to generate formulations with improved stability. As Izutsu describes how to perform this optimization, with suggested buffers and excipients, an artisan in this field would attempt this optimization with a reasonable expectation of success.
second rejection
Claims 1-17, 19 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 8-13, 15, 16, 25-27 of copending Application No. 17/617,670 (US 20230212227, allowed) in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”), and Izutsu (in Therapeutic Proteins (2005), Smales and James, ed. ISBN 1-58829-390-4).
Competing claim 1 claims an isotonic parenteral composition comprising a GLP-1/GLP-2 dual agonist species encompassed by instant claim 1’s genus, in a buffer formulation at pH 6-8.2, including about 5 to about 50 mM phosphate buffer component, with mannitol, and a solvent. Competing claim 2 specifies that the mannitol is d-mannitol, while competing claim 6 specifies that the buffer is a sodium phosphate buffer. Other competing claims set forth above additionally set forth limitations found in the instant dependent claims, however none of the competing claims set forth m-cresol or phenol preservatives.
The level of ordinary skill in the pertinent art is high, and there is great interest in developing more effective and improved formulations of the receptor agonists in this art.
Boss, however, clearly teaches these in similar pharmaceutical compositions, see paras 43, 191 and 192, so these additions would have been obvious based on one of ordinary skill in the art reasonably being motivated to combine the elements of separate references by known methods, such that in combination, each element merely performs the same function as it does separately.
Additionally, Izutsu teaches a sequence of steps to develop stabilized polypeptide formulations, and teaches several specific excipients.
Izutsu describes polypeptide stabilization (title). Changing the polypeptide environment and using appropriate excipients can usually provide stable formulations (p287, 2nd page). Stability is for 1-2 years of storage (p287, 1st paragraph). Preformulation studies survey the stability profile while varying pH and ionic strength, followed by identifying various buffers and excipients that affect protein stability (p289, section 3.1 “preformulation studies”). Among the excipients suggested are phosphate buffer and also NaCl and mannitol as tonicity modifiers (table 2, p288).
Therefore, it would be obvious to optimize the formulations of the reference application claims to optimize their stability, as discussed by Izutsu, to generate formulations with improved stability by evaluating combinations of known and widely used excipients, such as those instantly set forth in the claims. As Izutsu describes how to perform this optimization, with suggested buffers and excipients, an artisan in this field would attempt this optimization with a reasonable expectation of success. As made clear in Izutsu, the optimization is based on evaluating combinations of result-effective variables.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 8-13, 15, 16, 25-27 of copending Application No. 17/617,670 (US 20230212227, allowed) in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”), Izutsu (in Therapeutic Proteins (2005), Smales and James, ed. ISBN 1-58829-390-4), as applied to claims 1 and 10 above, and further in view of Gupta et al., Molecules 2018, 23, 1719, 15 pages (“Gupta”).
Claim 1 and 10 are rejected above.
Gupta, providing a review of salts of therapeutic agents, see Title, teaches that “The most commonly used anions for oral dosage forms are chloride, sulfate, and maleate; chloride, sulfate, and acetate were the three top anions used for injectable dosage forms,” page 8.
One of ordinary skill in the art reasonably would have evaluated, and reasonably selected, a chloride salt based on selecting from among a short list of the most common salts used for two dosage forms, and also from evaluating formulations as part of routine optimization such as following the teachings of Izutsu.
Accordingly, claim 18 is rejected under this section.
third rejection
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 28 of copending Application No. 17/834,062 in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”) and Izutsu (in Therapeutic Proteins (2005), Smales and James, ed. ISBN 1-58829-390-4) with evidentiary support from the Byju’s chemistry webpage (cited and provided in 1/13/25 IDS).
Competing claim 1 describes a method of treating a Markush group of disorders, including obesity, using a genus of polypeptides. Competing claim 28 describes a Markush group of polypeptides used in this method, including H[Aib]EGSFTSELATILD[K{17 carboxy-heptadecanoyl}isoGlu)]QAARDFIAWLIQHKITD.
The difference between the competing claims and the examined claims is that the competing claims do not specify a formulation that includes those non-peptide components of the instant claims.
The level of ordinary skill in the pertinent art is high, and there is great interest in developing more effective and improved formulations of the receptor agonists in this art.
As to the instant claims’ m-cresol and phenol, Boss clearly teaches these in similar pharmaceutical compositions, see paras 43, 191 and 192, so these additions would have been obvious based on one of ordinary skill in the art reasonably being motivated to combine the elements of separate references by known methods, such that in combination, each element merely performs the same function as it does separately.
Additionally, as to other components and formulation limitations, Izutsu teaches a sequence of steps to develop stabilized polypeptide formulations, and teaches several specific excipients.
Izutsu describes polypeptide stabilization (title). Changing the polypeptide environment and using appropriate excipients can usually provide stable formulations (p287, 2nd page). Stability is for 1-2 years of storage (p287, 1st paragraph). Preformulation studies survey the stability profile while varying pH and ionic strength, followed by identifying various buffers and excipients that affect protein stability (p289, section 3.1 “preformulation studies”). Among the excipients suggested are phosphate buffer and also NaCl and mannitol as tonicity modifiers (table 2, p288).
Therefore, it would be obvious to optimize the formulations of the reference patent to optimize their stability, as discussed by Izutsu, to generate formulations with improved stability by evaluating combinations of known and widely used excipients, such as those instantly set forth in the claims. As Izutsu describes how to perform this optimization, with suggested buffers and excipients, an artisan in this field would attempt this optimization with a reasonable expectation of success. As made clear in Izutsu, the optimization is based on evaluating combinations of result-effective variables.
Finally, with regard to claim 19 “the mannitol comprises D-mannitol” and states that this is “present in the composition at a concentration of from about 130 mM to about 330 mM,” the range of claim 19 would reasonably be obtained, and/or a narrower range or value within the claimed range, by routine optimization as taught in Izutsu, and as evidenced by the Byju chemistry web page, mannitol and d-mannitol are synonyms, supporting the rejection under this section of instant claim 19.
fourth rejection
Claims 1-17, 19 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 6-8, 11-15, 20, and 21 of copending Application No. 18/037,795 (US 20230405088) in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”).
Competing claim 1 specifies a GLP-1/GLP-2 dual agonist in phosphate buffer, while competing claim 11 specifies applicant’s elected polypeptide. Competing claim 2 specifies an isotonic formulation, while competing claims 6-8 specify the buffer concentration is from about 5-50 mM, the buffer is sodium phosphate, and the formulation has a pH between about 6 to 8.5. Competing claims 12 and 13 specifies the polypeptide is at a concentration of at least 1 mM, or about 1 or 10 mM. Competing claim 14 specifies one or more tonicity agents, which competing claim 15 states includes NaCl, which competing claim 21 specifies a concentration of between about 50 and 450 mM, and competing claim 20 specifies the tonicity agent is d-mannitol at a concentration between about 130 and 330 mM. Note that the concentration ranges specified are very similar to those of the examined claims, using the same excipients, so the claims are anticipated.
The level of ordinary skill in the pertinent art is high, and there is great interest in developing more effective and improved formulations of the receptor agonists in this art.
While the competing claims do not specify m-cresol or phenol (its claims 3-5 directed to other preservatives), Boss clearly teaches m-cresol and phenol in similar pharmaceutical compositions, see paras 43, 191 and 192, so these additions would have been obvious based on one of ordinary skill in the art reasonably being motivated to combine the elements of separate references by known methods, such that in combination, each element merely performs the same function as it does separately, as well as by routine substitution of compounds having similar known properties.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 6-8, 11-15, 20, and 21 of copending Application No. 18/037,795 (US 20230405088) in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”), as applied to claims 1 and 10 above, and further in view of Gupta et al., Molecules 2018, 23, 1719, 15 pages (“Gupta”).
Claim 1 and 10 are rejected above.
Gupta, providing a review of salts of therapeutic agents, see Title, teaches that “The most commonly used anions for oral dosage forms are chloride, sulfate, and maleate; chloride, sulfate, and acetate were the three top anions used for injectable dosage forms,” page 8.
One of ordinary skill in the art reasonably would have evaluated, and reasonably selected, a chloride salt based on selecting from among a short list of the most common salts used for two dosage forms, and also from evaluating formulations as part of routine optimization such as following the teachings of Izutsu.
Accordingly, claim 18 is rejected under this section.
fifth rejection
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 6, 7, 9, 11-15, 19, and 20 of copending Application No. 19/236746, in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”) and Izutsu (in Therapeutic Proteins (2005), Smales and James, ed. ISBN 1-58829-390-4).
Competing claim 1 claims an isotonic parenteral composition comprising a GLP-1/GLP-2 dual agonist species encompassed by instant claim 1’s genus, in a buffer formulation about pH 6-8.2, including about 200 mM buffer component and about 500 mM of one or more tonicity agent, and a solvent. Competing claim 2 specifies that the mannitol is d-mannitol, while competing claim 7 specifies that the buffer is selected from a small group including a phosphate buffer, competing claim 8 specifies phosphate buffer, and competing claim 9 specifies sodium phosphate buffer. Other competing claims such as claims 11-13, 15, 20, 22 and 38-42 set forth above additionally set forth limitations found in the instant dependent claims, including in claim 22 that the dual agonist includes a chloride salt thereof, however none of the competing claims set forth m-cresol or phenol preservatives.
The level of ordinary skill in the pertinent art is high, and there is great interest in developing more effective and improved formulations of the receptor agonists in this art.
Boss clearly teaches these in similar pharmaceutical compositions, see paras 43, 191 and 192, so these additions would have been obvious based on one of ordinary skill in the art reasonably being motivated to combine the elements of separate references by known methods, such that in combination, each element merely performs the same function as it does separately.
Additionally, Izutsu teaches a sequence of steps to develop stabilized polypeptide formulations, and teaches several specific excipients.
Izutsu describes polypeptide stabilization (title). Changing the polypeptide environment and using appropriate excipients can usually provide stable formulations (p287, 2nd page). Stability is for 1-2 years of storage (p287, 1st paragraph). Preformulation studies survey the stability profile while varying pH and ionic strength, followed by identifying various buffers and excipients that affect protein stability (p289, section 3.1 “preformulation studies”). Among the excipients suggested are phosphate buffer and also NaCl and mannitol as tonicity modifiers (table 2, p288).
Therefore, it would be obvious to optimize the formulations of the reference application claims to optimize their stability, as discussed by Izutsu, to generate formulations with improved stability by evaluating combinations of known and widely used excipients, such as those instantly set forth in the claims. As Izutsu describes how to perform this optimization, with suggested buffers and excipients, an artisan in this field would attempt this optimization with a reasonable expectation of success. As made clear in Izutsu, the optimization is based on evaluating combinations of result-effective variables.
sixth rejection
Claims 1-17, 19 and 20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of US Patent No. 10,905,745 in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”) and Izutsu (in Therapeutic Proteins (2005), Smales and James, ed. ISBN 1-58829-390-4) with evidentiary support from the Byju’s chemistry webpage (cited and provided in 1/13/25 IDS).
Competing claim 1 describes a genus of GLP-1/GLP-2 dual agonists, with competing claims 2 and 3 narrowing to particular species, these corresponding to those of instant claims’ genus and species, and competing claims 4 and 5 set forth that these are in admixture with a carrier, excipient or vehicle.
The difference between the competing claims and the examined claims is that the competing claims do not specify a formulation that includes those non-peptide components of the instant claims.
The level of ordinary skill in the pertinent art is high, and there is great interest in developing more effective and improved formulations of the receptor agonists in this art.
As to the instant claims’ m-cresol and phenol, Boss clearly teaches these in similar pharmaceutical compositions, see paras 43, 191 and 192, so these additions would have been obvious based on one of ordinary skill in the art reasonably being motivated to combine the elements of separate references by known methods, such that in combination, each element merely performs the same function as it does separately.
Additionally, as to other components and formulation limitations, Izutsu teaches a sequence of steps to develop stabilized polypeptide formulations, and teaches several specific excipients.
Izutsu describes polypeptide stabilization (title). Changing the polypeptide environment and using appropriate excipients can usually provide stable formulations (p287, 2nd page). Stability is for 1-2 years of storage (p287, 1st paragraph). Preformulation studies survey the stability profile while varying pH and ionic strength, followed by identifying various buffers and excipients that affect protein stability (p289, section 3.1 “preformulation studies”). Among the excipients suggested are phosphate buffer and also NaCl and mannitol as tonicity modifiers (table 2, p288).
Therefore, it would be obvious to optimize the formulations of the reference patent to optimize their stability, as discussed by Izutsu, to generate formulations with improved stability by evaluating combinations of known and widely used excipients, such as those instantly set forth in the claims. As Izutsu describes how to perform this optimization, with suggested buffers and excipients, an artisan in this field would attempt this optimization with a reasonable expectation of success. As made clear in Izutsu, the optimization is based on evaluating combinations of result-effective variables.
Finally, with regard to claim 19 “the mannitol comprises D-mannitol” and states that this is “present in the composition at a concentration of from about 130 mM to about 330 mM,” the range of claim 19 would reasonably be obtained, and/or a narrower range or value within the claimed range, by routine optimization as taught in Izutsu, and as evidenced by the Byju chemistry web page, mannitol and d-mannitol are synonyms, supporting the rejection under this section of instant claim 19.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5 of US Patent No. 10,905,745 in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”) and Izutsu (in Therapeutic Proteins (2005), Smales and James, ed. ISBN 1-58829-390-4) with evidentiary support from the Byju’s chemistry webpage (cited and provided in 1/13/25 IDS), as applied to claims 1 and 10 above, and further in view of Gupta et al., Molecules 2018, 23, 1719, 15 pages (“Gupta”).
Claim 1 and 10 are rejected above.
Gupta, providing a review of salts of therapeutic agents, see Title, teaches that “The most commonly used anions for oral dosage forms are chloride, sulfate, and maleate; chloride, sulfate, and acetate were the three top anions used for injectable dosage forms,” page 8.
One of ordinary skill in the art reasonably would have evaluated, and reasonably selected, a chloride salt based on selecting from among a short list of the most common salts used for two dosage forms, and also from evaluating formulations as part of routine optimization such as following the teachings of Izutsu.
Accordingly, claim 18 is rejected under this section.
seventh rejection
Claims 1-20 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 40, 41, and 45 of US Patent No. 11,395,847 in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”) and Izutsu (in Therapeutic Proteins (2005), Smales and James, ed. ISBN 1-58829-390-4) with evidentiary support from the Byju’s chemistry webpage (cited and provided in 1/13/25 IDS).
Competing claims 1, 40, and 41 describe a genus of GLP-1/GLP-2 dual agonists, with competing claim 41 comprising a Markush group containing species of instant claims 9 and 10.
The difference between the competing claims and the examined claims is that the competing claims do not specify a formulation that includes those non-peptide components of the instant claims.
The level of ordinary skill in the pertinent art is high, and there is great interest in developing more effective and improved formulations of the receptor agonists in this art.
As to the instant claims’ m-cresol and phenol, Boss clearly teaches these in similar pharmaceutical compositions, see paras 43, 191 and 192, so these additions would have been obvious based on one of ordinary skill in the art reasonably being motivated to combine the elements of separate references by known methods, such that in combination, each element merely performs the same function as it does separately.
Additionally, as to other components and formulation limitations, Izutsu teaches a sequence of steps to develop stabilized polypeptide formulations, and teaches several specific excipients.
Izutsu describes polypeptide stabilization (title). Changing the polypeptide environment and using appropriate excipients can usually provide stable formulations (p287, 2nd page). Stability is for 1-2 years of storage (p287, 1st paragraph). Preformulation studies survey the stability profile while varying pH and ionic strength, followed by identifying various buffers and excipients that affect protein stability (p289, section 3.1 “preformulation studies”). Among the excipients suggested are phosphate buffer and also NaCl and mannitol as tonicity modifiers (table 2, p288).
Therefore, it would be obvious to optimize the formulations of the reference patent to optimize their stability, as discussed by Izutsu, to generate formulations with improved stability by evaluating combinations of known and widely used excipients, such as those instantly set forth in the claims. As Izutsu describes how to perform this optimization, with suggested buffers and excipients, an artisan in this field would attempt this optimization with a reasonable expectation of success. As made clear in Izutsu, the optimization is based on evaluating combinations of result-effective variables.
Finally, with regard to claim 19 “the mannitol comprises D-mannitol” and states that this is “present in the composition at a concentration of from about 130 mM to about 330 mM,” the range of claim 19 would reasonably be obtained, and/or a narrower range or value within the claimed range, by routine optimization as taught in Izutsu, and as evidenced by the Byju chemistry web page, mannitol and d-mannitol are synonyms, supporting the rejection under this section of instant claim 19.
eighth rejection
Claims 1-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 16 of copending Application No. 18/275,195 (US 20240316155) in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”) and Izutsu (in Therapeutic Proteins (2005), Smales and James, ed. ISBN 1-58829-390-4) with evidentiary support from the Byju’s chemistry webpage (cited and provided in 1/13/25 IDS).
Competing claim 1 describes a method of treating a Markush group of digestive disorders, using a composition with a dual GLP-1/GLP-2 agonist. Competing claim 16 describes a Markush group of polypeptides used in this method, including H[Aib]EGSFTSELATILD[K{17 carboxy-heptadecanoyl}isoGlu)]QAARDFIAWLIQHKITD.
The difference between the competing claims and the examined claims is that the competing claims do not specify a formulation.
The level of ordinary skill in the pertinent art is high, and there is great interest in developing more effective and improved formulations of the receptor agonists in this art.
As to the instant claims’ m-cresol and phenol, Boss clearly teaches these in similar pharmaceutical compositions, see paras 43, 191 and 192, so these additions would have been obvious based on one of ordinary skill in the art reasonably being motivated to combine the elements of separate references by known methods, such that in combination, each element merely performs the same function as it does separately.
Additionally, as to other components and formulation limitations, Izutsu teaches a sequence of steps to develop stabilized polypeptide formulations, and teaches several specific excipients.
Izutsu describes polypeptide stabilization (title). Changing the polypeptide environment and using appropriate excipients can usually provide stable formulations (p287, 2nd page). Stability is for 1-2 years of storage (p287, 1st paragraph). Preformulation studies survey the stability profile while varying pH and ionic strength, followed by identifying various buffers and excipients that affect protein stability (p289, section 3.1 “preformulation studies”). Among the excipients suggested are phosphate buffer and also NaCl and mannitol as tonicity modifiers (table 2, p288).
Therefore, it would be obvious to optimize the formulations of the reference patent to optimize their stability, as discussed by Izutsu, to generate formulations with improved stability by evaluating combinations of known and widely used excipients, such as those instantly set forth in the claims. As Izutsu describes how to perform this optimization, with suggested buffers and excipients, an artisan in this field would attempt this optimization with a reasonable expectation of success. As made clear in Izutsu, the optimization is based on evaluating combinations of result-effective variables.
Finally, with regard to claim 19 “the mannitol comprises D-mannitol” and states that this is “present in the composition at a concentration of from about 130 mM to about 330 mM,” the range of claim 19 would reasonably be obtained, and/or a narrower range or value within the claimed range, by routine optimization as taught in Izutsu, and as evidenced by the Byju chemistry web page, mannitol and d-mannitol are synonyms, supporting the rejection under this section of instant claim 19.
ninth rejection
Claims 1-17, 19 and 20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 15, 17, 18, and 19 of copending Application No. 18688026 in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”), and Izutsu (in Therapeutic Proteins (2005), Smales and James, ed. ISBN 1-58829-390-4), with evidentiary support from the Byju’s chemistry webpage (cited and provided in 1/13/25 IDS).
Competing claim 1 claims a method for a range of conditions and diseases, comprising administering a GLP-1/GLP-2 dual agonist that falls within instant claim 1’s genus, claim 15 adds in the form of a composition in admixture with a carrier, claim 17 adds that the composition is a pharmaceutical composition and the carrier is a pharmaceutically acceptable carrier, claim 18 further refines that the pharmaceutical composition is an isotonic parenteral composition, and claim 19 claims that the claim 18 isotonic parenteral composition comprises:
PNG
media_image1.png
204
821
media_image1.png
Greyscale
These meet or overlap limitations of the instant claims – part (c) of instant claim 1, claim 2, claim 5, claim 7’s pH range, claims 9, 10, 13, 14, and 19. Administering the compound or composition comprising it, in various formulations, provides a teaching of such formulations and combinations. However, the reference application claims do not set forth other limitations such as the inclusion of preservatives m-cresol and/or phenol.
The level of ordinary skill in the pertinent art is high, and there is great interest in developing more effective and improved formulations of the receptor agonists in this art.
Boss clearly teaches inclusion of preservatives m-cresol and/or phenol in similar pharmaceutical compositions, see paras 43, 191 and 192, so these additions would have been obvious based on one of ordinary skill in the art reasonably being motivated to combine the elements of separate references by known methods, such that in combination, each element merely performs the same function as it does separately.
Additionally, Izutsu teaches a sequence of steps to develop stabilized polypeptide formulations, and teaches several specific excipients.
Izutsu describes polypeptide stabilization (title). Changing the polypeptide environment and using appropriate excipients can usually provide stable formulations (p287, 2nd page). Stability is for 1-2 years of storage (p287, 1st paragraph). Preformulation studies survey the stability profile while varying pH and ionic strength, followed by identifying various buffers and excipients that affect protein stability (p289, section 3.1 “preformulation studies”). Among the excipients suggested are phosphate buffer and also NaCl and mannitol as tonicity modifiers (table 2, p288).
Therefore, it would be obvious to optimize the formulations of the reference application claims to optimize their stability, as discussed by Izutsu, to generate formulations with improved stability by evaluating combinations of known and widely used excipients, such as those instantly set forth in the claims. As Izutsu describes how to perform this optimization, with suggested buffers and excipients, an artisan in this field would attempt this optimization with a reasonable expectation of success. As made clear in Izutsu, the optimization is based on evaluating combinations of result-effective variables.
Claim 18 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 8-13, 15, 16, 25-27 of copending Application No. 18688026 in view of US Publication No. 2018/0155406, Bossart et al., published 6/7/18 (“Boss”), Izutsu (in Therapeutic Proteins (2005), Smales and James, ed. ISBN 1-58829-390-4), as applied to claims 1 and 10 above, and further in view of Gupta et al., Molecules 2018, 23, 1719, 15 pages (“Gupta”).
Claim 1 and 10 are rejected above.
Gupta, providing a review of salts of therapeutic agents, see Title, teaches that “The most commonly used anions for oral dosage forms are chloride, sulfate, and maleate; chloride, sulfate, and acetate were the three top anions used for injectable dosage forms,” page 8.
One of ordinary skill in the art reasonably would have evaluated, and reasonably selected, a chloride salt based on selecting from among a short list of the most common salts used for two dosage forms, and also from evaluating formulations as part of routine optimization such as following the teachings of Izutsu.
Accordingly, claim 18 is rejected under this section.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH FISCHER whose telephone number is (571)270-7925, and whose direct facsimile number is (571)270-8925. The examiner can normally be reached on Monday to Friday, 9:00 AM to 5:00 PM, however noting that the examiner will not normally be working on Monday/Tuesday and on Wednesday-Friday on alternating weeks, but will promptly answer messages upon his return to work.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached on 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Joseph Fischer/
Examiner, Art Unit 1658