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 .
Status of the Claims
Claims 35-38 and 42-53 are pending. Claim 35 was amended, claims 39-41 were cancelled, and claims 46-53 were added in the response filed March 13, 2026.
Claims 42-45 and 51-53 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.
The rejection of claims 39-40 under 35 U.S.C. 112(d) is moot because the claims are cancelled.
The provisional rejection under 35 U.S.C. 101 is withdrawn.
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.
Claim 46 is 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 46 recites the limitation "the thiol" in claim 35. There is insufficient antecedent basis for this limitation in the claim.
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.
Claims 35-38 and 47-48 are rejected under 35 U.S.C. 103 as being unpatentable over Bokvist et al. (U.S. Patent No. 9,474,780 B2) in view of Coskun et al. (LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept. Molecular Metabolism, (2018) 18: 3-14), Frias et al. (Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. The Lancet, (2018) 392: 2180-2193), and Wan et al. (Free-Radical-Based, Specific Desulfurization of Cysteine: A Powerful Advance in the Synthesis of Polypeptides and Glycopolypeptides. Angewandte Chemie International Edition, (2007) 46: 9248-9252)
Determining the scope and contents of the prior art.
Bokvist et al. teach the GIP and GLP-1 co-agonist peptide tirzepatide (SEQ ID NO: 1) (Example 1 in Bokvist et al.). Tirzepatide is a 39 amino acid linear peptide conjugated to a C20 fatty diacid moiety via a linker connected to the lysine residue at position 20. Tirzepatide also contains two non-coded amino acid residues at positions 2 and 13 (Aib, a-amino isobutyric acid), and an amidated C-terminus (structure at top of columns 9-10). Tirzepatide functions as a dual glucose-dependent insulinotropic (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist (column 16, lines 23-31). Bokvist et al. teach that the pharmacokinetic profile of tirzepatide supports once-weekly dosing in humans (column 21, lines 10-30). Bokvist et al. teach that tirzepatide may be useful for treating type 2 diabetes (T2D) (claim 17). Later publication of Phase 1 and Phase 2 clinical trials support the use of tirzepatide as a treatment for T2D (see Coskun et al. and Frias et al.).
Ascertaining the differences between the prior art and the claims at issue.
Neither Bokvist et al., Coskun et al., nor Frias et al. teach a method of making tirzepatide comprising a desulfurization step with a radical initiator.
Resolving the level of ordinary skill in the pertinent art.
Wan et al. teach that native chemical ligation is a convergent synthetic methodology for large peptides and proteins. It involves chemoselective coupling of an C-terminal peptide thioester with an unprotected N-terminal cysteinyl peptide partner and formation of a native amide bond by an irreversible intramolecular S, N-acyl shift (Figure 1a):
PNG
media_image1.png
103
592
media_image1.png
Greyscale
Wan et al. teach that native chemical ligation can be extended to peptides without native cysteine residues by substituting a cysteine in place of a native alanine, conducting the native chemical ligation, and adding a desulfurization step to convert the cysteine to the native alanine in the full-length peptide (Figure 1c):
PNG
media_image2.png
98
593
media_image2.png
Greyscale
Wan et al. developed a milder, metal-free reduction protocol comprising contacting the cysteine-containing peptide with tris(2-carboxyethyl)phosphine (TCEP), a commonly used, water-soluble disulfide reducing agent for peptides, and the water-soluble radical initiator, 2,2′-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (VA-044):
PNG
media_image3.png
610
739
media_image3.png
Greyscale
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to make the tirzepatide taught by Bokvist et al., Coskun et al., and Frias et al. using the native chemical ligation and desulfurization protocol taught by Wan et al. One of ordinary skill in the art would have been motivated to develop and improve alternative synthetic means for tirzepatide given its therapeutic and clinical importance as established by Bokvist et al., Coskun et al., and Frias et al. There would have been a reasonable expectation of success given that Wan et al. conclude that the desulfurization method involving TCEP and VA-044 as the radical initiator can be used with a wide-variety of peptides (pp. 9250-9251).
In applying the method of Wan et al. to the synthesis of the tirzepatide taught by Bokvist et al., Coskun et al., and Frias et al., one of ordinary skill in the art would consider the sequence of tirzepatide and locate four1 native alanines at positions 18, 21, 28, and 35:
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK*AFVQWLIAGG PSSGAPPPS-NH2
The four alanines suggest four possible convergent synthesis strategies according to Figure 1a and 1c of Wan et al.:
1) fragmentation at Ala18/conversion of Ala18 to Cys
Y-Aib-EGTFTSDYSI-Aib-LDKI-C(=O)SR + CQK*AFVQWLIAGG PSSGAPPPS-NH2
Native chemical ligation
Y-Aib-EGTFTSDYSI-Aib-LDKICQK*AFVQWLIAGG PSSGAPPPS-NH2
Desulfurization
with TCEP and VA-044
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK*AFVQWLIAGG PSSGAPPPS-NH2
2) fragmentation at Ala21/conversion of Ala21 to Cys
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK*-C(=O)SR + CFVQWLIAGG PSSGAPPPS-NH2
Native chemical ligation
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK*CFVQWLIAGG PSSGAPPPS-NH2
Desulfurization
with TCEP and VA-044
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK*AFVQWLIAGG PSSGAPPPS-NH2
3) fragmentation at Ala28/conversion of Ala28 to Cys
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK*AFVQWLI-C(=O)SR + CGGPSSGAPPPS-NH2
Native chemical ligation
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK*AFVQWLICGGPSSGAPPPS-NH2
Desulfurization
with TCEP and VA-044
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK*AFVQWLIAGG PSSGAPPPS-NH2
4) fragmentation at Ala35/conversion of Ala35 to Cys
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK*AFVQWLIAGGPSSG-C(=O)SR + CPPPS-NH2
Native chemical ligation
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK*AFVQWLIAGG PSSGCPPPS-NH2
Desulfurization
with TCEP and VA-044
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK*AFVQWLIAGGPSSGAPPPS-NH2
The rationale for obviousness is combining prior art elements according to known methods to yield predictable results (MPEP § 2143.01(A)). The relevant findings for this rationale are as follows.
(1) The prior art included each element claimed, although not necessarily in a single prior art reference, with 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. In the instant case, the only difference between the claimed invention and the primary reference Bokvist et al. is a synthetic scheme for tirzepatide comprising desulfurization with a radical initiator. This difference is found in the prior art of Wan et al. which teaches a method of synthesis of a target peptide lacking a native cysteine comprising native chemical ligation of fragments of the target peptide wherein a native alanine is substituted with a cysteine to facilitate ligation, followed by desulfurization with a radical initiator to restore the native alanine in the full-length peptide. Therefore, the only difference between the claimed invention and the prior art is the actual combination of elements in a single prior art reference.
(2) 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. One of ordinary skill in the art could have applied the method of peptide synthesis comprising desulfurization with a radical initiator taught by Wan et al. to the synthesis of tirzepatide taught by Bokvist et al. using the known method of native chemical ligation and solid phase peptide synthesis of fragments. One of ordinary skill in the art would expect that the radical initiator performs the function of desulfurization of cysteine introduced to the sequence in place of a native alanine to permit native chemical ligation in the combination, which is the same function it performs separate from the combination. Therefore, 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.
(3) One of ordinary skill in the art would have recognized that the results of the combination were predictable. One of ordinary skill in the art would expect that the radical initiator performs the function of desulfurization in the combination because Wan et al. show that it can be used to convert cysteine to alanine in a variety of sequences (Table 1, pp. 9250-9251). Likewise, one of ordinary skill in the art would expect that cysteine performs the function of facilitating native chemical ligation at the site of a native alanine in the target peptide because Wan et al. teach that native chemical ligation is a widely-used convergent synthetic method for peptides (p. 9248, Figure 1). Therefore, one of ordinary skill in the art would have recognized that the results of the combination were predictable.
(4) Whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. The specification discloses a single embodiment of the method on pp. 64-66 wherein SEQ ID NO: 35 (aka tirzepatide cysteine analogue Preparation 36) is contacted with the radical initiator 2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (aka Preparation 37) to undergo desulfurization and to yield tirzepatide (SEQ ID NO: 1). SEQ ID NO: 35 (aka tirzepatide cysteine analogue Preparation 36) was made by native chemical ligation between SEQ ID NO: 33 (aka Preparation 34) and SEQ ID NO: 34 (aka Preparation 35) on pp. 62-64 of the specification. The success of this single reduction to practice is expected in view of the prior art of Wan et al.
The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395; B/E Aerospace, Inc. v. C&D Zodiac, Inc., 962 F.3d 1373, 1379, 2020 USPQ2d 10706 (Fed. Cir. 2020); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atl. & P. Tea Co. v. Supermarket Equip. Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950). "[I]t can be important to identify a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does." KSR, 550 U.S. at 418, 82 USPQ2d at 1396.
Therefore, claim 35 is obvious over the cited art.
Regarding claims 36-38, Wan et al. teach that the radical initiator is a water-soluble, azo radical initiator, 2,2′-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (VA-044) (Table 1, p. 9249, col 2).
Regarding claims 47-48, fragmentation at Ala18/conversion of Ala18 to Cys would yield the intermediate Y-Aib-EGTFTSDYSI-Aib-LDKICQK*AFVQWLIAGG PSSGAPPPS-NH2, which is the same as instant SEQ ID NO: 35, and would be subjected to desulfurization to yield tirzepatide. This route is one of four possible strategies, which is a small, finite number of options.
Claim 46 and 49-50 are rejected under 35 U.S.C. 103 as being unpatentable over Bokvist et al., Coskun et al., Frias et al. and Wan et al., as applied to claims 35-38 and 47-48 above in further view of Thompson et al. (Trifluoroethanethiol: An Additive for Efficient One-Pot Peptide Ligation−Desulfurization Chemistry J. Am. Chem. Soc. 2014, 136, 23, 8161–8164).
It would have been obvious over Bokvist et al., Coskun et al., Frias et al. and Wan et al. to make tirzepatide via the intermediate peptide SEQ ID NO: 35 for the reasons presented above.
Wan et al. teaches
PNG
media_image1.png
103
592
media_image1.png
Greyscale
but does not teach that the thiol additive to make the peptide thioester (-SR group) used in the reaction is 2,2,2-trifluoroethanethiol as required by claim 46.
Thompson et al. also teach native chemical ligation followed by desulfurization for the synthesis of peptides:
PNG
media_image4.png
302
573
media_image4.png
Greyscale
Thompson et al. teach a high-yielding, one-pot ligation−desulfurization protocol that uses trifluoroethanethiol (TFET) as a thiol additive:
PNG
media_image5.png
551
607
media_image5.png
Greyscale
It would have been obvious before the effective filing date of the claimed invention to use TFET taught by Thompson et al. as the thiol additive in the native chemical ligation method taught by Wan et al. and in the synthesis of tirzepatide as taught by Bokvist et al., Coskun et al., Frias et al. The rationale for obviousness is combining prior art elements according to known methods to yield predictable results (MPEP § 2143.01(A)). The relevant findings for this rationale are as follows.
(1) The prior art included each element claimed, although not necessarily in a single prior art reference, with 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. In the instant case, the only difference between the claimed invention and the obvious combination of Bokvist et al., Coskun et al., Frias et al., and Wan et al. presented above is the use of the thiol TFET. This difference is found in the prior art of Thompson et al. which teaches a protocol for native chemical ligation followed by desulfurization for the synthesis of peptides that uses TFET as a thiol additive. Therefore, the only difference between the claimed invention and the prior art is the actual combination of elements in a single prior art reference.
(2) 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. One of ordinary skill in the art could have applied the method of peptide synthesis comprising desulfurization using TFET taught by Thompson et al. to the synthesis of tirzepatide using the known method of native chemical ligation. One of ordinary skill in the art would expect that the TFET would facilitate ligation without disrupting subsequent radical desulfurization in the combination, which is the same function it performs separate from the combination (see Thompson et al. p. 8162, top of col. 1, also col. 2; p. 8164, last para). Therefore, 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.
(3) One of ordinary skill in the art would have recognized that the results of the combination were predictable. One of ordinary skill in the art would expect that the TFET performs the function of facilitating ligations and being present for the desulfurization step without the need for intermediate purification or removal/capture from the reaction mixture because Thompson et al. state: “Given the efficiency and simplicity of ligations employing TFET (a commercially available and affordable reagent), we anticipate that it will find widespread use in the chemical synthesis of proteins and post-translationally modified proteins, greatly improving the efficiency of the processes and reducing handling and purification of intermediates” (p. 8164, last para). In addition, Thompson et al. teach that TFET can be used with the TCEP and VA-044 taught by Wan et al. (see Scheme 3 of Thompson et al.).
Therefore, one of ordinary skill in the art would have recognized that the results of the combination were predictable.
(4) Whatever additional findings based on the Graham factual inquiries may be necessary, in view of the facts of the case under consideration, to explain a conclusion of obviousness. The specification discloses a single embodiment of the method on pp. 64-66 wherein SEQ ID NO: 35 (aka tirzepatide cysteine analogue Preparation 36) is contacted with the radical initiator 2,2'-azobis[2-(2-imidazolin-2-yl)propane]dihydrochloride (aka Preparation 37) to undergo desulfurization and to yield tirzepatide (SEQ ID NO: 1). SEQ ID NO: 35 (aka tirzepatide cysteine analogue Preparation 36) was made by native chemical ligation between SEQ ID NO: 33 (aka Preparation 34) and SEQ ID NO: 34 (aka Preparation 35) on pp. 62-64 of the specification. The success of this single reduction to practice is expected in view of the prior art of Wan et al. and Thompson et al.
The rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395; B/E Aerospace, Inc. v. C&D Zodiac, Inc., 962 F.3d 1373, 1379, 2020 USPQ2d 10706 (Fed. Cir. 2020); Sakraida v. AG Pro, Inc., 425 U.S. 273, 282, 189 USPQ 449, 453 (1976); Anderson’s-Black Rock, Inc. v. Pavement Salvage Co., 396 U.S. 57, 62-63, 163 USPQ 673, 675 (1969); Great Atl. & P. Tea Co. v. Supermarket Equip. Corp., 340 U.S. 147, 152, 87 USPQ 303, 306 (1950). "[I]t can be important to identify a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does." KSR, 550 U.S. at 418, 82 USPQ2d at 1396.
Therefore, claim 46 is obvious over the cited art.
Regarding claim 49, the dependent claim requires that SEQ ID NO: 35 is made by coupling the thioester peptide SEQ ID NO: 34 with SEQ ID NO: 33. As noted in the rejection above over Wan et al., one of the four possible synthetic strategies based on the four native alanines in tirzepatide involves the fragmentation at Ala18/conversion of Ala18 to Cys to yield the intermediate Y-Aib-EGTFTSDYSI-Aib-LDKICQK*AFVQWLIAGG PSSGAPPPS-NH2 (instant SEQ ID NO: 35). In applying the method of Thompson et al. (Scheme 3) to the synthesis of Y-Aib-EGTFTSDYSI-Aib-LDKICQK*AFVQWLIAGG PSSGAPPPS-NH2, which is the same as instant SEQ ID NO: 35, and is required for the method of making tirzepatide by native chemical ligation followed by desulfurization described in the rejection above, one of ordinary skill in the art would consider the sequence of SEQ ID NO: 35 and locate the single cysteine. Thompson et al. teaches that the single cysteine must be at the N-terminus of one of the fragments in order for the transthioesterification step that is critical to the ligation to occur (see Schemes 1 and 3). For SEQ ID NO 35 that means making a C-terminal fragment consisting of the cysteine to the C-terminal amino acid
CQK*AFVQWLIAGGPSSGAPPPS-NH2, which is identical to instant SEQ ID NO: 33.
Thompson et al. teaches that the N-terminal fragment in the ligation reaction consists of the N-terminal amino acid of the final product to the amino acid that is N-terminal to the cysteine, which for SEQ ID NO: 35 is
Aib-EGTFTSDYSI-Aib-LDKI.
The addition of the TFET taught by Thompson et al. would yield Aib-EGTFTSDYSI-Aib-LDKI-SCH2CF3, which is identical to SEQ ID NO: 34 (compare to intermediates show in Scheme 3 of Thompson et al).
Regarding claim 50, the dependent claim requires that SEQ ID NO: 34 is made by contacting the peptide hydrazide SEQ ID NO: 32 Y-Aib-EGTFTSDYSI-Aib-LDKI-N-NH2 with the thiol TFET. Thompson et al. teach that the thioester intermediate required for the native chemical ligation step is made by contacting a peptide hydrazide with TFET (see supporting information S16). Therefore, in applying the method of Thompson et al. to the method of making SEQ ID NO: 35 en route to making tirzepatide, one of ordinary skill in the art would first make the peptide hydrazide corresponding to the fragment consisting of the N-terminal amino acid of the final product to the amino acid that is N-terminal to the cysteine, which for SEQ ID NO: 35 is Aib-EGTFTSDYSI-Aib-LDKI-N-NH2, which is identical to SEQ ID NO: 32. Next, in applying the method of Thompson et al. one of ordinary skill in the art would add TFET to yield Aib-EGTFTSDYSI-Aib-LDKI-SCH2CF3, which is identical to SEQ ID NO: 34 (compare the reaction scheme in S16).
Response to Arguments
Applicant's arguments filed March 13, 2026, have been fully considered but they are not persuasive.
I The Office has not established a prima facie case of obviousness with respect to the location of the native chemical ligation to prepare tirzepatide
Applicant argues that the Office has not pointed to any location in Bokvist, Coskun, Frias, or Wan that teaches a person of ordinary skill in the art where to incorporate the cysteine group that can be altered to be an alanine upon the contact with the radical initiator. This argument is not persuasive. The major development taught by Wan is the extension of native chemical ligation to peptides without native cysteine residues. The method involves substituting a cysteine in place of a native alanine, conducting the native chemical ligation, and adding a desulfurization step to convert the cysteine to the native alanine in the full-length peptide (see Figure 1c of Wan):
PNG
media_image2.png
98
593
media_image2.png
Greyscale
In seeking to apply the method of Wan to other target peptides, including tirzepatide, one of ordinary skill in the art would examine the sequence of the target peptide, locate the native alanines, and design a fragmentation strategy based on the position of the native alanines. Bokvist, Coskun, and Frias teach the amino acid sequence of tirzepatide. One of ordinary skill in the is capable of examining the amino acid sequence of tirzepatide taught in the prior art of Bokvist, Coskun, and Frias and locating the position of alanines by visual inspection and knowledge of the single letter code of amino acids. Using a pencil and paper or a computer, it would be straight-forward to see that there are four alanines in tirzepatide, and to design pairs of fragments that correspond to the fragments in Figure 1 a of Wan et al.: 1) a first fragment that consists of the N-terminal amino acid through the amino acid that is N-terminal to the alanine (corresponding to the fragment in Figure 1a of Wan et al. having the C-terminal thioester, that is shown as Peptide 1 -C(=O)-SR), and 2) a second fragment that consists of the alanine through the C-terminal amino acid (corresponding to the fragment in Figure 1a of Wan et al. having the C-terminal cysteine, that is shown as Cys-Peptide 2, wherein the Cys is in place of the native alanine). Wan et al. provide a model that can be logically extended to other peptides.
Next, Applicant argues that the Office has not pointed to any location in Bokvist, Coskun, Frias, or Wan that teaches a person of ordinary skill in the art the total number of fragments. This argument is not persuasive. One of ordinary skill in the art would understand from Wan et al., and also from Thompson et al., that fragmentation can occur at the position of any native alanine, which in turn is converted to cysteine for the ligation step followed by desulfurization to restore alanine at the native position. In other words, if one of ordinary skill in the art can locate the position of native alanines in the desired peptide, which they readily can by visual inspection, only a simple logical deduction is required to design fragments.
Applicant argues that the Office has not pointed to any location in Bokvist, Coskun, Frias, or Wan that teaches a person of ordinary skill in the art at what time in the process whether the desulfurization from cysteine to alanine to occur. Both Wan et al. and Thompson et al. reduce to practice the protocol for native chemical ligation and desulfurization. Wan et al. illustrates desulfurization as a separate step (see Table 1). Thompson et al. illustrates native chemical ligation and desulfurization as a one-pot reaction without the need for intermediate isolation and purification (Scheme 3). One of ordinary skill in the art would have a reasonable expectation of success with both protocols and would recognize the advantage explicitly taught by Thompson et al. of the one-pot protocol (p. 8164, last para).
Next, Applicant argues that the Office singled out the alanine amino acids at 18 and 21 in the rejection and did not address the alanines at positions 28 and 35. The rejection has been corrected to acknowledge the fact that there are four alanines in tirzepatide. However, neither the obviousness rationale nor the analysis of the prior art changes as a result of this edit. Whether there are two or four alanines and therefore two or four possible convergent synthesis strategies according to Figure 1a and 1c of Wan et al., both offer a finite number of predictable solutions from Wan et al. to the problem of making tirzepatide to one of ordinary skill in the art.
II. Unexpected Results have been demonstrated in the Specification and in Jalan regarding the commercial applicability of this process to prepare tirzepatide
Applicant argues that the application is directed to new methods and intermediates for the commercial scale manufacture of tirzepatide and that even small improvements can lead to hundreds of kg of yield improvement per batch thereby improving access to tirzepatide throughout the world. This argument is not persuasive. The therapeutic and clinical importance of tirzepatide is established by the prior art of Bokvist et al., Coskun et al., and Frias et al. Based on this importance, one of ordinary skill in the art would have significant motivation to develop and improve methods of its manufacture.
Applicant cites the post-filing date reference Jalan as evidence of unexpected results. Jalan discloses Route 2, which involves desulfurization of intermediate SEQ ID NO: 35 (the elected species and subject of claims 47-50), and Route 1, which involves desulfurization of intermediate SEQ ID NO: 39 (the subject of claims 47 and 51-53). Jalan presents evidence that the claimed method can be used for “the first gram-scale synthesis of tirzepatide using ... native chemical ligation/desulfurization strategy” and that this success is unexpected. Applicant cites Jalan as evidence that “This novel green strategy allows unprotected peptide fragments to be coupled in an aqueous buffer at neutral pH- conditions that enhance the solubility of the fragments and the resulting larger peptide product. This NCL methodology, which uses TFF to enable telescoped desulfurization, represents a significant advancement in peptide and protein chemistry, allowing for a one-pot NCL-desulfurization synthesis of peptides...Furthermore, the fragments are also amenable to alternative greener and cost-effective syntheses. The green synthesis of tirzepatide via NCL is a key step in that direction, with fragment ligation and subsequent desulfurization carried out in aqueous buffer. We have demonstrated that the yield of tirzepatide, based on the N-cysteinyl fragment 6, reached as high as 45%, which is competitive with the best yields of other established therapeutic peptides and proteins." See Jalan at page 6.
First, with respect to evidence of gram-scale synthesis of tirzepatide, the claims are not limited to a particular scale. MPEP § 716.02(d) requires that objective evidence of nonobviousness must be commensurate in scope with the claims. In the instant case, the claims encompass both laboratory and industrial scale synthesis of tirzepatide. Therefore, evidence pertaining to gram-scale synthesis is insufficient to overcome the prima face case of obviousness.
Second, with respect to the advantages of a “green synthesis” all of the elements pointed to as characteristics of the green synthesis are taught by the prior art of Wan et al. and Thompson et al. Both Wan et al. and Thompson et al. teach the use of TCEP and VA-044 for desulfurization. Thompson et al. teaches one-pot NCL-desulfurization synthesis using TFET and an aqueous buffered solution near neutral pH (Scheme 3). Given that the elements of the claimed method are taught by the prior art, their advantages are expected, not unexpected.
For these reasons, the rejections are maintained.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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.
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, Lianko G Garyu can be reached at (571) 270-7367. 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.
/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654
1 The previous Office action erroneously indicated that there are two native alanines in tirzepatide. This error was correctly pointed out on page 8 of Applicant’s arguments filed March 13, 2026. The rejection is modified to reflect the fact that there are four alanines in tirzepatide. However, neither the obviousness rationale nor the analysis of the prior art changes as a result of this edit. Whether there are two or four alanines and therefore two or four possible convergent synthesis strategies according to Figure 1a and 1c of Wan et al., both offer a finite number of predictable solutions from Wan et al. to the problem of making tirzepatide to one of ordinary skill in the art.