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 .
Claim Rejections - 35 USC § 112
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 1-8 and 10 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.
Claim 1 contains numerous grammatical errors that render the claim indefinite. For example, step b) recites deprotection “followed by solid-phase synthesis, amino acids with…”. It is not clear if the phrase that begins with “amino acids with” describes the “solid phase synthesis” because the entire section is not written as a clear, active method step. In addition, it is not clear if the activating agent and solvent at the end of step b are presented in all coupling steps or just the coupling steps for positions 15, 16, 18, 22, 24, 25, 28, and 31.
In addition, the term “highly pure” in claim 1 is a relative term which renders the claim indefinite. The term “highly pure” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
In addition, the term “molar equivalent” is indefinite because it is not clear what component is being referred to.
Dependent claims 2-8 and 10 fail to remedy these issues and are likewise rejected
In addition, claim 3 is indefinite because it appears to recite a list of alternatives however the list is open.
A proposal to overcome this rejection is presented at the end of this action.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim 9 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ganga et al. (WO 2018/104922).
Ganga et al. teach a method wherein crude liraglutide was dissolved in dilute ammonium carbonate solution containing 5-40% ACN at a concentration of 5-75 mg/ml and was loaded onto pre-equilibrated 100-10-C8 column (10mm x 250mm). This was followed by 0.2 CV of the diluent. The bound liraglutide was eluted using a step gradient of the mobile phase (A: 0.1% TFA in water; B: 0.1% TFA in ACN: IPA). Fractions having purity >92% was concentrated under vacuum followed by iso-electric point precipitation. The precipitate was recovered by centrifugation. The recovered precipitate was again subjected to another RP-HPLC step on the column 100-10-C8 column (10mm x 250mm). The bound liraglutide was eluted using gradient elution of the mobile phase composed of viz. A: dilute ammonium acetate; B: ACN. Fractions >98.5% were pooled, concentrated under vacuum, precipitated at iso-electric point & finally lyophilized. See Examples 8-9. The method taught by Ganga et al. meets all of the limitations of independent claim 9.
Allowable Subject Matter
The following claims drafted by the examiner and considered to distinguish patentably over the art of record in this application, are presented to applicant for consideration:
Claim 1 (Currently Amended) An improved process for solid phase synthesis of highly pure Liraglutide, comprising
a) reacting protected glycine with resin in the presence of an activating agent and a solvent to form Fmoc-Gly-resin and followed by capping with acetic anhydride in pyridine;
b) deprotectingthe Fmoc-Gly-resin[[,]] followed by solid-phase synthesis, wherein amino acids with N-terminal Fmoc protection and side chain protection are sequentially coupled based on the sequence of the peptide backbone of liraglutide in the presence of an activating agent and solvent,
wherein purified Fmoc-Lys(Pal-Glu(OtBu)-OH is employed as the lysine amino acid at position 20,[[;]]
wherein the amino acid[[s]] coupling is performed at 25-30°C and involves addition of 2 molar equivalents of the protected amino acid at all positions except for amino acid coupling [[in]]at positions [[at]] 15, 16, 18, 22, 24, 25 28, and 31 wherein coupling is performed at 35-60°C and involves addition of 2 to 3 molar equivalents of the protected amino acid
c) Liraglutide is finally obtained by purification and lyophilizing,[[;]] wherein the purification is performed by a reverse-phase high performance liquid chromatography using a reverse-phase C8 or C18 column using ammonium salts and ammonium buffers in a first purification and followed by 0.10% TFA in water, acetonitrile or mixture thereof in a second purification,
wherein the highly pure Liraglutide has a purity of greater than or equal to 99.5% purity by HPLC.
Claim 2 (Currently Amended) An improved process for solid phase synthesis of highly pure Liraglutide according to claim 1, wherein said step a) involves the use of Wang resin, which is employed as the resin solid phase support, and said Fmoc-Gly-resin has a[[with]] substitution degree in the range from 0.40 to 0.75 mmol/g.
Claim 3 (Currently Amended) An improved process for solid phase synthesis of highly pure Liraglutide according to claim 1, wherein in steps a) and b) the activation agent for coupling of amino acid is selected from the group consisting of DIC (Diisopropylcarbodiimide), DCC (N,N'-Dicyclohexylcarbodiimide) Ethylcyano(hydroxyimino)acetate, DIPEA (Diisopropylethylamine), HCTU (O-(1 H-6-Chlorobenzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate), and HATU (1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate.
Claim 4 (Currently Amended) An improved process for solid phase synthesis of highly pure Liraglutide according to claim 1, wherein in step b) the unreacted or free amino group of amino acid after coupling is protected by acetic anhydride in pyridine.
Claim 5 (Currently Amended) An improved process for solid phase synthesis of highly pure Liraglutide according to claim 1, wherein in said step b) deprotection of Fmoc-Gly-resin involves the use of DMF and piperidine.
Claim 6 (Currently Amended) An improved process for solid phase synthesis of highly pure Liraglutide according to claim 1, wherein said step b) for sequential coupling involves the sequential use of amino acids Fmoc-Arg(Pbf)-OH (Arg), Fmoc-Gly-OH (Gly), Fmoc-Arg(Pbf)-OH (Arg), Fmoc-Val-OH (Val), Fmoc-Leu-OH (Leu), Fmoc-Trp(Boc)-OH (Trp), Fmoc-Ala-OH (Ala), Fmoc-Ile-OH (Ile), Fmoc-Phe-OH (Phe), Fmoc-Glu(OtBu)-OH (Glu), Fmoc-Lys(Pal- Glu(OtBu))-OH, Fmoc-Ala-OH (Ala), Fmoc-Ala-OH (Ala), Fmoc-Gln(Trt)-OH (Gln), Fmoc-Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Leu-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Ser(tBu)-OH (Ser), Fmoc-Val-OH, Fmoc-Asp(OtBu)-OH (Asp), Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-Gly-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Ala-OH and Boc-His(trt)-OH.
Claim 7 (Currently Amended) An improved process for solid phase synthesis of highly pure Liraglutide according to claim 1, wherein in steps a) and b) said solvent is selected from the group consisting of DMF, DCM, NMP, Acetonitrile, TFA, Piperdine, Pyridine, Diethyl Ether, Diisopropyl Ether, Methyl tertiary Butyl Ether, Ethyl acetate, Dimethyl sulphoxide, Diisopropyl ethylamine, hexane, water and combination thereof.
Claim 8 (Previously Presented) An improved process for solid phase synthesis of highly pure Liraglutide, according to claim 1, wherein ammonium salts is selected from ammonium acetate, ammonium chloride, ammonia, ammonium bicarbonate, ammonium carbonate, ammonium formate or combination thereof.
Cancel claim 9.
Claim 10 (Previously Presented) An improved process for solid phase synthesis of highly pure Liraglutide, according to claim 8, wherein ammonium salts is selected from ammonium acetate, ammonium chloride, ammonia, ammonium bicarbonate, ammonium carbonate, or combination thereof.
The following is a statement of reasons for the indication of allowable subject matter: Ganga et al. (WO 2018/104922) teaches a method of making liraglutide by solid phase peptide synthesis comprising a) Loading of C-terminal glycine to a resin solid-phase support in the presence of coupling agent; b) Sequential coupling of Nα- and side chain protected amino acids to prepare backbone of liraglutide, in the presence of coupling agent and an inorganic salt; c) Deprotection of side chain protecting group of lysine; d) Coupling of γ-glutamic acid and palmitic acid in sequential manner to the side chain of lysine in the presence of coupling agent and an inorganic salt; e) Crude liraglutide is obtained by removal of protective groups and cleavage of peptide from the resin; and f) Purification of crude liraglutide (Figure 1). Ganga et al. teach that coupling steps for positions 7-8 and 14-30 are performed at room temperature and that coupling steps for positions 9-13 are performed at 30-45° C (Stages 2-34). Ganga et al. do not teach nor suggest that coupling at positions 15, 16, 18, 22, 24, 25 28, and 31 is performed at 35-60°C and that coupling for all other positions is performed at 25-30°C.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654