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 .
Response to Election/Restriction filed on March 1, 2026 is acknowledged.
Claims 1-14 are pending in this application.
Instant application is a CON of a PCT application.
Priority
Applicant claims foreign priority to KOREA 10-2020-0059322 (5/18/2020). The certified copy has been received by the Office. However, a certified English translation has not been provided. Therefore, the foreign priority date has not been perfected. Thus, the effective filing date of instant application is 5/18/2020 until the foreign priority date is perfected.
Restriction
6. Applicant's election with traverse of 1-ethyl-3-methylimidazolim ethyl sulfate as the species of ionic liquid, and PyBOP ((benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate) as the species of a coupling agent in the reply filed on March 1, 2026 is acknowledged. The traversal is on the ground(s) that there is lack of undue search burden and the shared general functional role of the listed coupling agents. This is not found persuasive because instant application is a 371 of a PCT. Therefore, search burden does not play a role in the lack of unity of species election.
The requirement is still deemed proper and is therefore made FINAL. A search was conducted on the elected species and prior art was found. Claims 1-14 are examined on the merits in this office action.
Objections
7. The abstract is objected to for the following minor informality:
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words. It is important that the abstract not exceed 150 words in length since the space provided for the abstract on the computer tape used by the printer is limited. The form and legal phraseology often used in patent claims, such as "means" and "said," should be avoided. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, "The disclosure concerns," "The disclosure defined by this invention," "The disclosure describes," etc.
In the instant case, the abstract recites, “Proposed is a novel method for preparing liraglutide by means of...” at lines 1-2 of the abstract. The abstract contains legal phraseology “means” and this should be avoided. Additionally, the abstract recites, “Provided is a novel…” Applicant should correct these informalities. See MPEP 608.01(b). For example, Applicant is advised to amend the abstract to recite, “A method for preparing liraglutide…is described.”
8. The drawings are objected to because the drawings comprise peptide sequences without the corresponding sequence identifiers associated with them being present in the drawings and/or the description of the drawings. Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
9. The specification is objected to for the following: The “Brief Description of the Drawings” does not provide clear description of each figures. Applicant is required to correct this issue.
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant’s cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
10. Sequence disclosure is objected to for the following: Claims recite SEQ ID NOs: 2-4. However, the sequence listing does not recite the same sequence as those recited in the claim.
11. Claims 1 and 5-6 are objected to for the following: Claims 1 and 5-6 do not end with a period at the end of the claims. Additionally, the correct way to recite a sequence identifier is “SEQ ID NO:”. These errors must be corrected.
12. Claim 7 is objected to for the following minor informality: claim 7 contains the acronyms “PyBOP,” “PyAOP,”…”EDC”, and an acronym in the first instance of claims should be expanded upon/spelled out with the acronym indicated in parentheses, i.e., (benzotriazole-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP). The abbreviations can be used thereafter.
Rejections
U.S.C. 112(b)
13. 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.
14. Claims 1-14 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.
15. Claim 1 recites, “A method of preparing liraglutide (SEQ ID NO 10), comprising subject fractionated peptide 1 represented by Chemical Formula 1 below and fractionated peptide 2 represented by Chemical Formula 2 below to a coupling reaction using an ionic liquid or a eutectic solvent.” The metes and bounds of the claim is unclear because the active method steps are not clearly defined in the claims. It is also unclear what are meant by “fractionate” peptide 1 and “fractionated” peptide 2. Because claims 2-14 depend from indefinite claim 1 and do not clarify the point of confusion, these claims are also rejected. Claims should be amended to recite active method steps, e.g., reacting SEQ ID NO: 5 and SEQ ID NO: 9 with a coupling agent in an ionic liquid or an eutectic solvent…” (Additionally, for example claims 7-14 should be amended to “…performing the coupling reaction.”).
16. Claim 5 recites, “The method according to claim 1, wherein the fractionated peptide 1 is synthesized through a coupling reaction of peptide 1-1…” The chronological order of the method step recited in claim 5 appears to be prior to what is recited in claim 1. Therefore, the order of reaction is unclear. Additionally, the method step is unclear since the active method step is missing (e.g., reacting peptide 1-1 and peptide 1-2…with a coupling agent…).
17. Claim 6 recites, “The method according to claim 1, wherein the fractionated peptide 2 is synthesized through a coupling reaction of peptide 2-1…” The chronological order of the method step recited in claim 6 appears to be prior to what is recited in claim 1. Therefore, the order of reaction is unclear. Additionally, the method step is unclear since the active method step is missing (e.g., reacting peptide 2-1 and peptide 2-2…with a coupling agent…).
18. Claims 5 and 12 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, for referring to “skipped sequences” in the sequence listing. Instant SEQ ID NOs: 2-4 are “skipped” in the sequence listing: e.g.,
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. Applicant should amend the claims to replace all relevant SEQ ID NOs with the actual sequences. Because claim 12 depends from claim 5, claim 12 also is rejected.
19. Claim 7 recites, “The method according to claim 1, wherein the coupling reaction…is performed using at least one coupling agent selected from…” Claim 7 depends from claim 1. Claim 1 recites, “…to a coupling reaction using an ionic liquid or a eutectic solvent”. Therefore, there is lack of antecedent basis for “using at least one coupling agent…”
U.S.C. 112(d)
20. The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
21. Claim 7 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
22. Claim 7 recites, “The method according to claim 1, wherein the coupling reaction of fractionated peptide 1…is performed using at least one coupling agent selected from among PyBOP…and EDC.” Claim 7 depends from claim 1. Claim 1 recites, “…to a coupling reaction using an ionic liquid or a eutectic solvent”. Therefore, claim 7 recites agents that are outside (broader than) the agents recited in claim 1 (i.e., ionic liquid and eutectic solvent).
U.S.C. 103
23. 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.
24. 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.
25. 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.
26. 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.
27. Claim(s) 1, 3-4, 7-8, 10-11 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lonza LTD reference (EP 3196206) in view of Schatte et al (US 2019/0040436) and Wolczanski et al (Tetrahedron Letters, 2019, 60: 1814-1818).
28. Lonza LTD reference teaches a method of preparing liraglutide by liquid phase condensation of two protected fragments (see abstract).Lonza LTD reference teaches that one of the C-terminal fragment carries the Palmitoyl-Glu-OtBu residue on the Lys and is protected on its C-terminal COOH by a psWang linker (see paragraph [0001]). Lonza LTD reference teaches the Liraglutide of instant SEQ ID NO: 10 (see paragraph [0002]), and the FRAG1 and FRAG2 that is the same as instant SEQ ID NOs: 5 and 9, respectively, with the psWang linker attached to the FRAG2 (see paragraph [0010]) meeting the limitation of instant SEQ ID NO: 9. This meets the limitation of instant claim 1. As evidenced by instant specification, “if there is no special explanation or specific content, “linker” is a P. Wang linker” (see paragraph [0025] of instant specification US 2023/0047729). Lonza LTD reference teaches coupling agent, for example, PyBOP (see throughout the reference, e.g., line 20 of page 3) and other agents, such as FMOC, Boc, TFA and TIS (see p. 3, lines 1-27), meeting the limitation of instant claim 7. Lonza LTD reference teaches synthesis of FRAG1 and FRAG2 (see pp. 5-9, for example, paragraphs [0025]-[0103]).
The differences between the Lonza LTD reference and instant claims are that Lonza LTD reference does not teach coupling reaction in eutectic solvent and under ultrasonic irradiation.
29. However, Schatte et al teach use of a deep eutectic solvent comprising choline chloride and glycerol at a molar ratio of 1:2 and further comprising up to 5% (v/v) aqueous co-solvent as solvent in an enzymatic transamidation reaction catalyzed by a sortase, preferably Sortase A (see paragraph [0040], for example). Schatte et al teach the following: “Deep eutectic solvents (DESs) are water free solutions with melting points below 100° C. DESs are based on hydrogen bonds. In DES the properties of water and organic solvents are combined. Most DESs are liquid at suitable temperatures for biocatalysis. DESs are more hydrophobic than water however in some cases they do not lead to hydrophobicity induced inactivation of the biocatalyst. Additionally deep eutectics solvents can be produced water free and are therefore inert for hydrolysis. Ionic liquids have similar properties as DES, but are more difficult to produce and more harmful to the environment” (see paragraph [0003]). Schatte et al teach that transpeptidation reaction can be performed in deep eutectic solvents and that the reduction or even absence of water is not detrimental to the reaction but suppresses hydrolysis side reaction (see paragraph [0021]). Schatte et al teach that deep eutectic solvents can comprise as first component a strong hydrogen bond donor and as second component a metal salt or a nitrogen salt... For example, in one embodiment, the deep eutectic solvent comprises between 10% and 99% (v/v) of deep eutectic solvent and the remainder is a non-deep eutectic solvent. In one embodiment the second component is a halide-containing salt of an amine or metals. In one embodiment the metal is a transition metal. In one embodiment the first component is selected from the group consisting of hydroxyl, amide, amine, aldehyde, and carboxylic acid. In one embodiment the first component is selected from the group consisting of organic acids, urea, thiourea, amide, hydroxyl groups, diols, glycerol, choline chloride, and combinations thereof. In one embodiment the first component is selected from the group comprising choline chloride, ethyl ammonium chloride, choline bromide, glycerol, tetra butyl ammonium chloride, triethyl benzyl ammonium chloride, zinc chloride, and acetylcholine chloride. In one embodiment the second component is selected from the group consisting of acetamide ethylene glycol, glycerol, urea, malonic acid, formamide, arabinose, glucose, and xylose” (see paragraph [0069]).
30. Furthermore, Wolczanski et al teach that ultrasound is regarded as a green activation technique, using ultrasonic agitation is a faster solid phase peptide synthesis method (see Title and Introduction).
31. Therefore, it would have been obvious to one of ordinary skill in the art to combine the teachings of Lonza LTD reference, Schatte et al and Wolczanski et al to arrive at instant method of preparing liraglutide, since Lonza LTD reference and Schatte et al and Wolczanski et al teach peptide synthesis. One of ordinary skill in the art would have been motivated to combine with a reasonable expectation of success, since using deep eutectics solvents can be produced water free and are therefore inert for hydrolysis, and using ultrasonic agitation is a faster solid phase peptide synthesis method. One of ordinary skill in the art would expect that using eutectic solvents and ultrasonic agitation will produce more stable peptides at a faster synthesis process.
32. Claim(s) 1-2, 7-9 and 14 is/are rejected under 35 U.S.C. 103 as being unpatentable over Lonza LTD reference (EP 3196206) in view of Tietze et al (Molecules, 2012, 17(4): 4158-4185) and Wolczanski et al (Tetrahedron Letters, 2019, 60: 1814-1818).
33. Lonza LTD reference teaches a method of preparing liraglutide by liquid phase condensation of two protected fragments (see abstract).Lonza LTD reference teaches that one of the C-terminal fragment carries the Palmitoyl-Glu-OtBu residue on the Lys and is protected on its C-terminal COOH by a psWang linker (see paragraph [0001]). Lonza LTD reference teaches the Liraglutide of instant SEQ ID NO: 10 (see paragraph [0002]), and the FRAG1 and FRAG2 that is the same as instant SEQ ID NOs: 5 and 9, respectively, with the psWang linker attached to the FRAG2 (see paragraph [0010]) meeting the limitation of instant SEQ ID NO: 9. This meets the limitation of instant claim 1. As evidenced by instant specification, “if there is no special explanation or specific content, “linker” is a P. Wang linker” (see paragraph [0025] of instant specification US 2023/0047729). Lonza LTD reference teaches coupling agent, for example, PyBOP (see throughout the reference, e.g., line 20 of page 3) and other agents, such as FMOC, Boc, TFA and TIS (see p. 3, lines 1-27), meeting the limitation of instant claim 7. Lonza LTD reference teaches synthesis of FRAG1 and FRAG2 (see pp. 5-9, for example, paragraphs [0025]-[0103]).
The differences between the Lonza LTD reference and instant claims are that Lonza LTD reference does not teach coupling reaction in ionic liquid and under ultrasonic irradiation.
34. However, Tietze et al teach that ionic liquids reduce the ability to form peptide-peptide hydrogen bonds, lowering the risk of protein denaturation through misfolding and aggregation (see p. 4161, 2nd paragraph of “2. Ionic Liquids in Peptide Chemistry”). Tietze et al lists different ionic liquids (see Table 1, pp. 4162, 4163), and explicitly teach the elected species, 1-ethyl-3-methylimidazolium ethyl sulfate (see for example, p. 4176).
35. Furthermore, Wolczanski et al teach that ultrasound is regarded as a green activation technique, using ultrasonic agitation is a faster solid phase peptide synthesis method (see Title and Introduction).
36. Therefore, it would have been obvious to one of ordinary skill in the art to combine the teachings of Lonza LTD reference, Tietze et al and Wolczanski et al to arrive at instant method of preparing liraglutide, since Lonza LTD reference and Tietze et al and Wolczanski et al teach peptide synthesis. One of ordinary skill in the art would have been motivated to combine with a reasonable expectation of success, since using ionic liquids will reduce the ability to form peptide-peptide hydrogen bonds, lowering the risk of protein denaturation through misfolding and aggregation, and using ultrasonic agitation is a faster solid phase peptide synthesis method. One of ordinary skill in the art would expect that using ionic liquid and ultrasonic agitation will produce more stable peptides at a faster synthesis process.
CONCLUSION
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JULIE HA whose telephone number is (571)272-5982. The examiner can normally be reached Monday-Thursday 5:00 am- 6:30 pm EST.
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/JULIE HA/Primary Examiner, Art Unit 1654
4/30/2026
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