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 .
Non-Compliant Amendment
A prior response filed 5/01/2026 resulted in a Notice of Non-compliant amendment mailed 6/11/2026. The subsequent response filed 8/03/2026 identifies that relevant “remarks made in the 5/1/2026 response are reiterated herein” (see, e.g., Reply filed 8/03/2026 at 19). Therefore, the response filed 8/03/2026 is considered complete and is addressed and considered herein relative to the examined claim set and Action mailed 1/29/2026.
Claim Status
Per the claim set filed 8/03/2026, claims 1, 6, 9-11, and 15-21 are pending. Claims 2, 5, 8, and 14 were canceled, and claims 1, 9, and 15 were amended in the Reply filed 8/03/2026. Claims 18-19 are withdrawn as direct to a non-elected invention. Claims 9-11, 17, and 20-21 are rejoined following amendment. Claims 1, 6, 9-11, 15-17, and 20-21 are presently considered.
Election/Restrictions
Applicant's election with traverse of Group I (original claims 1-17 and 20-21) and the species of Example I (Dimer 1) in the reply filed on 11/10/2025 was previously acknowledged, but the traversal was not found persuasive for reasons of record, and the requirement was deemed proper and made FINAL.
The originally elected species was understood to be “Dimer 1”, which has the structure of
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Accordingly, the elected species comprises two copies of the native human insulin A chain (i.e., SEQ ID NO: 1; “GIVEQCCTSICSLYQLENYCN”) and two copies of native human insulin B chain (i.e., SEQ ID NO: 2; “FVNQHLCGSHLVEALYLVCGERGFFYTPKT”), wherein the K29 residue of a B-chain in one insulin molecule is conjugated to the G1 of an A-chain in a second insulin molecule via Linker “4”, via the epsilon carbon of the K29 residue, which has the structure
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The N-terminus of the A and B chains of the first insulin molecule are understood to be conjugated to “capping groups” comprising RC(O)-, where R is R’NH- and R’ is H, which yields a capping group of H2N-C(O)-. (i.e., a carbamoyl moiety as recited at claims 5-6). The elected species of Dimer 1 differs from Dimer 3 only with respect to the presence of a B chain Lys29 conjugated to a PEG moiety having the structure of
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This PEG moiety is understood to be conjugated to the epsilon carbon of the B chain Lys29. The curved line is understood to represent a disulfide bond between Cys residue side-chains.
The originally elected species was previously understood to read upon instant claims 1-2, 5-6, 8, and 15-16, but to not read upon previous claims 9-12, 14, 17, and 20-21 for reasons of record (see, e.g., Action mailed 1/29/2026 at 4). However, in the Reply filed 8/03/2026, claim 9 was amended to recite “native insulin”, and is understood to read upon the originally elected species. Accordingly, following the amendments filed 8/03/2026, claims 9-11 and 20-21 are understood to read upon the originally elected species, and claims 9-11 and 20-21 are considered for the first time on record in the instant action. However, claim 17 remains withdrawn as noted on record, because the originally elected species did not recite a GLP-1 receptor agonist.
The amendments to claims 1, 9, and 15, as filed 8/03/2026, are understood to continue reading upon the originally elected species.
Following extensive search and examination, the originally elected species of Dimer 1 was previously deemed free of the prior art. Per MPEP § 803.02(III),
If the examiner determines that the elected species is allowable over the prior art, the examination of the Markush claim will be extended. If prior art is then found that anticipates or renders obvious the Markush claim with respect to a nonelected species, the Markush claim shall be rejected; claims to the nonelected species would still be held withdrawn from further consideration. The prior art search will not be extended unnecessarily to cover all nonelected species.
Accordingly, Examination was previously extended to a non-elected species corresponding to Dimers 1, 2, 8-9, 15, 28 as shown at claim 15, with the understanding that each of Dimers 1-2, 8-8, 15, and 28 have disulfide linkages between the Cys residues as indicated by the lines connecting Cys residues, that any Lysine is modified at the epsilon carbon, that the N-terminus (not side chain) is modified by the capping moieties (see Rejection of claim 15 under 35 USC 112(b) below). Assuming each of these assumptions is correct, each of Dimers 1-2, 8-9, 15, and 28 were previously deemed free of the prior art, wherein the point of novelty was identified as including the combination of at least one modified lysine side chain in addition to the A’1 to B29 (or B28) linkage.
Per MPEP § 803.02(III), examination was extended to Dimer 3 (with the assumption noted above). Following extensive search and examination, the non-elected species was deemed anticipated and/or obvious in view of the prior art as applied below. Per MPEP § 803.02(III), claims directed to other nonelected species have been withdrawn.
Claims 18-19 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/10/2025.
Claim 17 is 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. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/10/2025.
Claims 11, 6, 9-11, 15-16, and 20-21 are presently considered.
Priority
The priority claim to US Provisional Application 63076142 (filed 9/09/2020) is acknowledged.
Information Disclosure Statement
No additional IDS was filed in the Reply submitted 8/03/2026 or 5/01/2026.
Claim Objections
Claims 1 and 9 are objected to because of the following informalities:
Claims 1 and 9 each recite “liner 12”, which should be “Linker 12”.
Appropriate correction is required.
Claim Interpretation
For purposes of examination, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
Claim 1 is representative of the pending claim scope; the applicable claim interpretation is set forth below.
“Comprising” is an open-ended transitional term (see, e.g., MPEP § 2111.03(I)), wherein additional steps or components are not excluded. However, “‘[c]omprising’ is a term of art used in claim language which means that the named elements are essential” (see, e.g., id.; see also Genentech, Inc. v. Chiron Corp., 112 F.3d 495, 501, 42 USPQ2d 1608, 1613 (Fed. Cir. 1997)).
Regarding the preamble of claim 1 and subsequent claims, per MPEP § 2111.02, “where a patentee defines a structurally complete invention in the claim body and uses the preamble only to state a purpose or intended use for the invention, the preamble is not a claim limitation”. Here, the body of claim 1 is understood to recite a structurally complete invention, and therefore the preamble is deemed fully satisfied by prior art that satisfies the steps and structures recited in the body of the claim (see also MPEP § 2111.04(I), noting that “Claim scope is not limited by claim language that suggests or makes optional but does not require steps to be performed, or by claim language that does not limit a claim to a particular structure”).
In view of the Table at pages 71-73 of the Specification filed 2/16/2023, it is understood that Native human insulin has the A chain of instant SEQ ID NO: 1 (GIVEQCCTSICSLYQLENYCN) and the B chain of instant SEQ ID NO: 2 (FVNQHLCGSHLVEALYLVCGERGFFYTPKT); Insulin glargine has the A chain of instant SEQ ID NO: 7 (GIVEQCCTSICSLYQLENYCG) and the B chain of instant SEQ ID NO: 8 (FVNQHLCGSHLVEALYLVCGERGFFYTPKTRR); Insulin lispro has a B chain corresponding to instant SEQ ID NO: 6 (FVNQHLCGSHLVEALYLVCGERGFFYTKPT) and has the same A chain as native human insulin; Insulin aspart has a B chain corresponding to instant SEQ ID NO: 9 (FVNQHLCGSHLVEALYLVCGERGFFYTDKT) and has the same A chain as native human insulin; and that Insulin DesB30 has a B chain corresponding to instant SEQ ID NO: 10 (FVNQHLCGSHLVEALYLVCGERGFFYTPK) and has the same A chain as native human insulin.
Claims 9-11 refer to “a second insulin or insulin analog” and “a first insulin or insulin analog”, wherein claims 1 and 9 identify that “insulin” includes native human insulin, insulin lispro, insulin aspart, desB30 insulin, and insulin glargine (see instant claims 1 and 9)1. The term “insulin” and “insulin analog” are understood to have different meanings (see, e.g., see, e.g., Nystrom v. TREX Co., Inc., 424 F. 3d 1136, 1143 (Fed. Cir. 2005), explaining that "When different words or phrases are used in separate claims, a difference in meaning is presumed"). Upon review of the disclosure, the term “insulin analog” is used inconsistently to refer to insulin lispro, insulin aspart, desB30 insulin, and insulin glargine (see, e.g., Spec. filed 8/03/2026 at lines 15-20), but also more broadly refer to potentially millions of additional compounds (see, e.g., Spec. filed 8/03/2026 at 8 at line 20 to page 9 at line 6). Examiner notes that examination of claim 9 has not proceeded beyond Dimers 1-3, 8-8, 15, and 28.
Claim 15 now recites Dimers 1, 2, 8-9, 15, and 28, wherein the Dimers are associated with SEQ ID NOs. Specifically, Dimer 1 is associated with SEQ ID NOs: 15-18; Dimer 2 is associated with SEQ ID NOs: 19-22; Dimer 8 is associated with SEQ ID NOs: 43-46; Dimer 9 is associated with SEQ ID NOs: 47-50; Dimer 15 is associated with SEQ ID NOs: 71-74; Dimer 28 is associated with SEQ ID NOs: 123-126. This is pertinent because these SEQ ID Numbers include modification fields (i.e., <220>-<223>), identifying the specific placement of intrachain disulfide bonds, modified residues, and interchain disulfide bonds with other sequences. This is understood to clarify the scope of instant claim 15 by addressing the structural ambiguities raised previously on record (see, e.g., Action mailed 1/29/2026 at 4-5 at bridging ¶, 11-12 at rejection of claim 15 under 35 USC § 112(b)).
Additional claim interpretations are set forth in the rejections below.
Withdrawn Claim Rejections
The rejection of claims 1-2, 5-6, 8, and 15-16 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite has been rendered moot with respect to cancelled claims 2, 5, and 8; and successfully traversed in part in view of the amendments to claim 1 and 15 as filed 8/03/2026; however, the revised and amended claim scope has raised additional issues, which are set forth in a maintained, revised, or new rejection below.
Revised or New Claim Rejections Necessitated by Applicant Amendment
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 9-11, 15-16, and 20-21 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.
Amended claim 9 is rendered indefinite in view of claim 9(iii), which recites
(iii) the first insulin and the second insulin heterodimers are independently selected from native human insulin, insulin lispro, insulin aspart, and insulin glargine; and
wherein the amino terminus of at least one of the A-chain polypeptides and the B chain polypeptides of the first insulin polypeptide or second insulin polypeptide is covalently linked to a capping group.
The indefiniteness and confusion arises because it is unclear how the language of claim 9(iii), which refers only to first insulin heterodimer and the second insulin heterodimer is supposed to be interpreted in view of earlier language in claim 9 that refers to “a second insulin or insulin analog heterodimer” and “a first insulin or insulin analog heterodimer”. The term “insulin” is presumed to have a different meaning relative to “insulin analog” (see, e.g., see, e.g., Nystrom v. TREX Co., Inc., 424 F. 3d 1136, 1143 (Fed. Cir. 2005), explaining that "When different words or phrases are used in separate claims, a difference in meaning is presumed"). The scope of “insulin” is recited in the claims, and specifically claims 1 and 9 identify that “insulin” includes native human insulin, insulin lispro, insulin aspart, desB30 insulin, and insulin glargine (see instant claims 1 and 9)2. The term “insulin analog” presumably encompasses billions of variants (see, e.g., Spec. filed 8/03/2026 at 8 at line 20 to page 9 at line 6). Therefore, because “insulin” and “insulin analog” are distinct, and claim 9(iii) only pertains to “insulin” heterodimers, there is a simply question, namely “What does claim 9(iii) suggest about insulin analogs?”. The answer to this question materially alters the pending claim scope. As a possible interpretation, “insulin analog” may just be superfluous language, and redundant in meaning with “insulin”, which would not impact the claim scope. Alternatively, claim 9(iii) may be reasonably interpreted as a required structural limitation limiting the heterodimers to only four possibilities (i.e., the first insulin heterodimer and the second insulin heterodimer must be and can only be selected from native human insulin, insulin lispro, insulin aspart, and insulin glargine). As a third interpretation, claim 9(iii) may be interpreted as a contingent limitation that further defines and limits the scope of insulin heterodimers, but not further limit the scope of insulin analog heterodimers, which would mean the claim scope encompassed potentially billions of analogs (see, e.g., Spec. filed 8/03/2026 at 8 at line 20 to page 9 at line 6). Accordingly, the scope of claim 9 is ambiguous because it is unclear how the claim scope, reading upon insulin analogs, is further limited by claim 9(iii). This rejection could be overcome by amending claim 9 (and its dependents) to remove references to “insulin analogs”; however, such amendments might result in claim 9 being objected as a substantial duplicate of instant claim 1, and therefore amending claim 9 to read “A composition comprising the insulin dimer of claim 1” and removing the reference to “insulin analogs” at claims 10-11 could resolve the instant rejection and avoid a potential objection, while simplifying the claim scope.
Amended claim 9 is rendered indefinite in view of claim 9(i), which recites structural limitations, but only for “the first insulin heterodimer” (see, e.g., instant claim 9(i)), which raises a material concern regarding the scope of the pending claim as it pertains to a first or second “insulin analog heterodimer” (see instant claim 9 at lines 1-6). The answer to this question is unknown but materially and substantially alters the pending claim scope. More specifically, because claim 9(i) only refers to a first insulin heterodimer, it is unclear if claim 9(i) actually (A) requires a “first insulin heterodimer” (i.e., a first insulin analog heterodimer is excluded) or (B) is a contingent limitation that does not exclude the presence of a first insulin analog heterodimer, but rather only applies and further defines structural limitations pertinent if a first insulin heterodimer is present. The indefiniteness and confusion arises because “insulin” is presumed to have a different meaning relative to “insulin analog” (see, e.g., see, e.g., Nystrom v. TREX Co., Inc., 424 F. 3d 1136, 1143 (Fed. Cir. 2005), explaining that "When different words or phrases are used in separate claims, a difference in meaning is presumed"), and therefore whether or not an “insulin” or “insulin analog” is being referenced alters the pending claim scope. Accordingly, claim 9 is rejected as indefinite. This rejection could be overcome by amending claim 9 (and its dependents) to remove references to “insulin analogs”; however, such amendments might result in claim 9 being objected as a substantial duplicate of instant claim 1, and therefore amending claim 9 to read “A composition comprising the insulin dimer of claim 1”, and removing the reference to “insulin analogs” at claims 10-11 could resolve the instant rejection and avoid a potential objection, while simplifying the claim scope.
Claim 11 recites the phrase “near the carboxy terminus” contains the relative term “near”, which renders the claim indefinite. The term “near” 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. It is unclear if “near” means within 2 residues, within 5 residues, within 20 residues, etc. The difference materially alters the pending claim scope (see, e.g., MPEP § 2173.05(b)(I)-(II)).
Claim 11 utilizes possessive language, namely “heterodimer’s A-chain” and “heterodimer’s B chain”, which renders the claim scope indefinite because such language is colloquial and raises substantial and material concern regarding antecedent basis because, for example, it is unclear whether “heterodimer’s A-chain” is introducing a new and distinct claim limitation, or just describing a feature of the heterodimer. Clarification is required.
Claim 20 recites and refers to “the insulin receptor partial agonist” at lines 1-2. There is insufficient antecedent basis for this limitation in the claim. For purposes of applying prior art, Dimer 3 is presumed to satisfy the structural requirements of instant claim 20.
Claims 10-11 and 20-21 depend directly or indirectly from an indefinite base claim and fail to rectify the indefiniteness of the base claim. Accordingly, these claims are rejected as indefinite for the reasons applicable to the base claim.
Claims 9-11 and 20-21 are rejected.
Claim Rejections - 35 USC § 112(d)
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.
Claim 10 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.
Claim 10 depends from claim 9, but restates all possibilities already within the scope of instant claim 9 (i.e., the heterodimers are the same or different). Accordingly, claim 10 fails to further limit the claim upon which it depends. This rejection could be overcome by amending claim 10 to remove one possibility but not the other, such that it further limited the scope of claim 9.
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.
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 1, 6, 9-11, and 20-21 are rejected under 35 U.S.C. 103 as being unpatentable over US20170355743A1 and further in view of Schuttler et al3.
Claim interpretation: The applicable claim interpretation has been set forth in preceding rejections and also in a separate section above, and those discussions and interpretations are incorporated into the instant rejection. Additional claim interpretations are set forth below.
US’743 pertains to insulin receptor partial agonists comprising insulin dimers (see, e.g., US’743 at title, abs, ¶¶[0007], [0017]-[0018], [0023], claims). Regarding instant claims 1, 6, 9-11, 20-21, and the general structure of insulin dimers, US’743 directs artisans to highly similar compounds, such as Dimers 13, 18-20, 24, 28, 32, 54-56, 58, 65, and 83 (see, e.g., US’743 at claim 74). Regarding instant claims 1, 6, 9-11, and 20-21, and native human insulin sequences corresponding to instant SEQ ID NOs: 1 and 2, Dimers 13, 24, 54-56, 58, and 65 (see, e.g., US’743 at claim 74) each comprise the A-chain of SEQ ID NO: 1 and the B-chain of SEQ ID NO: 2 (see, e.g., US’743 at claim 74), which correspond to native human insulin and are identical to instant SEQ ID NOs 1-2, respectively (compare US’743 at SEQ ID NOs: 1 and 2 with instant SEQ ID NOs: 1 and 2, showing 100% identity, respectively; see also US’743 at claim 6). Regarding instant claims 1, 6, 9-11, 20-21, and “Linker No. 4” (i.e., -C(O)-(CH2)6-C(O)-), the prior art of US’743 teaches and discloses the same exact linker (see, e.g., US’743 at ¶[0181], claim 74 showing Dimers 13, 24, 54-56, 58, and 65, Table 3 starting at page 90 showing linker of Dimers 13, 24, 54-56, 58, and 65). Accordingly, “Linker No. 4” as recited in the claims is a prior art element that was specifically taught in the prior art for use in conjugating insulin dimers together. Regarding instant claims 1, 6, 9-11, 20-21, and the “capping group” of -C(O)NH2 located at the N-terminus of “at least one of the first or second A chain or B-chain polypeptides”, the prior art of US’743 teaches and discloses insulin receptor partial agonists comprising substituents such as -C(O)-NH2 moieties (i.e., a carbamoyl group) at the amino terminus of at least one of the A and/or B chain termini (see, e.g., US’743 at claims 1 and 4). Furthermore, US’743 exemplifies the usage of such “capping groups” in claimed Dimer 24, 28, 32, and 54 (see, e.g., US’743 at claim 74). Accordingly, the usage of such moieties at the N-terminus of one or more of the insulin polypeptides was already known and taught in the prior art, and therefore does not weigh in favor of a determination of non-obviousness. Regarding instant claims 1, 6, 9-11, and 20-21, and the conjugation of Lys29 of a B-chain of native human insulin to another insulin molecule via “Linker No. 4”, US’743 teaches and discloses insulin receptor partial agonists that comprise instant “Linker No. 4” (i.e., -C(O)-(CH2)6-C(O)-) conjugated to Lys29 of a B-Chain of native human insulin, wherein the linker connects one native human insulin to another (see, e.g., US’743 at claim 74 at Dimers 24, 32, and 54). Regarding instant claims 20-21 and the presence of a pharmaceutical excipient and treatment of diabetes, US’743 explicitly teaches, discloses, and directs artisans to utilize the disclosed compounds in combination with a pharmaceutical excipient (see, e.g., US’743 at claim 74-75), and informs artisans that such compounds could be predictably utilized to treat type 1 and Type 2 diabetes, as well as gestational diabetes (see, e.g., US’743 at ¶¶[0002]. Claims 75-77).
The teachings of the primary reference differ from the instantly claimed invention as follows: The singular difference between the compounds of US’743 (e.g., Dimers 24, 32, and 54) and the instantly claimed invention is that the Linker (i.e., -C(O)-(CH2)6-C(O)-) of US’743 connects the B29 Lys with the B’29 Lys in US’743, wherein the instant claims require that the same linker connects the B29 Lys with the A’1 Gly in the instant claims. Therefore, the relevant issue is whether or not it would have been obvious to one of ordinary skill in the art that the covalently conjugated dimers of US’743 could be modified by simply substituting one A1 Gly in place of a B29 Lys as a point of attachment covalently linking the insulins.
One of ordinary skill in the insulin arts would readily appreciate the need for optimizing and developing long-acting insulins (see, e.g., US’743 at ¶¶[0004], [0137]). US’743 identifies that one potential solution to address such need is to covalently link two insulin molecules to form a covalently linked insulin dimer (see, e.g., US’743 at ¶[0137]). Accordingly, an artisan would reasonably review the prior art pertaining to covalently linked insulin molecules to review known alternative linkage arrangements among A, B, A’, and B’ chains.
Schuttler pertains to the preparation of covalently linked insulin dimers (see, e.g, Schuttler at title, abs). Schuttler identifies six basic arrangements for covalently linking two insulin molecules to form covalently linked insulin dimers, namely
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(see, e.g., Schuttler at 321 at Fig. 1(A))
and
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(see, e.g., Schuttler at 321 at Fig. 1(C)).
Notably, the arrangement taught and claimed by US’743 are represented by Formula (III) of Schuttler (compare US’743 at claims 1, 4, and 74 with Schuttler at Fig. 1(A) at III). Notably, Schuttler identifies that another obvious arrangement includes A1 conjugated to B’29 as shown at Formula VII (see, e.g, Schuttler at Fig. 1(C) on 321). Accordingly, the instantly claimed arrangement of insulin (i.e., forming a covalently linked insulin dimer by covalently linking an A1 to a B’29 residues or equivalently an A’1 to a B29 residue via a linker), was already known and taught in the prior art (see, e.g, Schuttler at Fig. 1(A) and (C) on 321). The arrangement was shown to yield functional insulin (see, e.g., Schuttler at 325 to 326 at bridging ¶, 326 at Fig. 8, Table 2 at 326, 328 at Table 3, 327-328 at bridging ¶ noting that all dimers “elicit normal maximal responses”). Schuttler provides guidance and motivation to continue using all “interesting” insulin derivatives and refers to them as “useful tools” (see, e.g. Schuttler at 329 at col I at 3rd full ¶).
Therefore, it would have been obvious to one of ordinary skill in the art, either before the effective filing date of the claimed invention (AIA ) or otherwise at the time the invention was made (pre-AIA ), to arrive at the instantly claimed invention in view of the prior art for at least the following reason(s):
First, the invention is the simple substitution of the one point of conjugation (i.e., B’29) for another (i.e., A’1 as taught by Schuttler) in the prior art compounds of US’743, wherein such substitution would yield predictable and expected results, namely covalently linked insulin dimers identical to those disclosed by the primary reference except instead of a linker between B29 and B’29, the linker would be between B29 and A’1 (or B’29 and A1), wherein such dimers would predictably and expectedly function as insulin receptor partial agonists and be usable in the same methods and applications as the compounds of US’743 (see, e.g., MPEP § 2143(I)(B)).
Second, additionally or in the alternative to the rationale above, the invention is obvious to try as the prior art teaches a finite number of known, predictable arrangements for conjugating two insulins to form an insulin dimer via a linker (i.e., 6 arrangements as taught by Schuttler), wherein as shown by US’743, it is typical in the insulin dimer arts to make and test dozens of compounds, and wherein one of ordinary skill in the art could have pursued the known potential solutions and arrangements taught by Schuttler with a reasonable expectation of success since the arrangements were all shown to be functional (see, e.g., MPEP § 2143(I)(E)).
Third, additionally or in the alternative to the rationales above, the same field of endeavor as that of the applicant’s invention (i.e., covalently linked insulin dimers) included analogous and highly similar compounds differing with respect to a single linkage point (i.e., the compounds of US’743); there was incentives identified by US’743 directing artisans to develop and optimize long-acting insulins; the difference between the claimed invention and the prior art were encompassed by known variations in linkage points already known, taught, and exemplified by the prior art of Schuttler; accordingly, an artisan, in view of the incentive to develop and optimize long-acting insulins, could have implemented the claimed variation of the prior art (i.e., linkage arrangements), and the claimed variations would have been predictable to one of ordinary skill in the prior art, wherein such variations would be predicted and expected to have the same utility and applications taught and disclosed for the compounds of US’743 (see, e.g., MPEP § 2143(I)(F)).
Furthermore, there would be a reasonable expectation of success because the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Furthermore, it is well-within the ordinary skill in the art to make known arrangements of known polypeptides using known linkers and known capping moieties to arrive at modified dimers of US’743 conjugated in the manner taught by Schuttler, wherein such compounds would be reasonably expected and predicted to be functional and usable in the methodologies and applications taught and disclosed by US’743 for highly similar compounds.
Zero evidence of unexpected results commensurate in scope with the requirements discussed at MPEP §§ 716, 716.01, and 716.02 have been placed on record to date.
Accordingly, claims 1, 6, 9-11, and 20-21 are rejected.
Response to Arguments
Applicant's arguments filed 8/03/2026 have been fully considered but they are not persuasive.
As an initial matter, Examiner notes that Applicant does not dispute, with specificity, the rationales relied upon by the Examiner to establish obviousness (e.g., MPEP §§ 2143(I)(B), (E), (F)). Accordingly, all findings and rationales not specifically addressed are presently undisputed on record, and for at least these reasons, the rejection under 35 USC 103, as revised above, is maintained.
It is the Examiner’s understanding that Applicant traverses the rejection under 35 USC 103 (revised above in view of Applicant’s amendments) because “there is no suggestion in the prior art to modify US20170355743A1 by changing both the type of insulin and the capping group” (see, e.g., Reply filed 8/03/2026 at 20 at final ¶). The basis for this argument is unknown as Applicant does not elaborate. However, the Applicant does not dispute that US’743 teaches and discloses insulin receptor partial agonists comprising substituents such as -C(O)-NH2 moieties (i.e., a carbamoyl group) at the amino terminus of at least one of the A and/or B chain termini (see, e.g., US’743 at claims 1 and 4), and therefore it is undisputed that US’743 exemplifies the usage of such carbamoyl “capping groups” as presently claimed in the claimed Dimers 24, 28, 32, and 54 (see, e.g., US’743 at claim 74). Furthermore, regarding the “type of insulin”, Dimers 13, 24, 54-56, 58, and 65 (see, e.g., US’743 at claim 74) each comprise the A-chain of SEQ ID NO: 1 and the B-chain of SEQ ID NO: 2 (see, e.g., US’743 at claim 74), which correspond to native human insulin and are identical to instant SEQ ID NOs 1-2, respectively (compare US’743 at SEQ ID NOs: 1 and 2 with instant SEQ ID NOs: 1 and 2, showing 100% identity, respectively; see also US’743 at claim 6). In sum, US’743 teaches and directs artisans to dimeric insulin heterodimers that are explicitly identified and taught as varying with respect to both the “type of insulin and the capping group” (see, e.g., US’743 at claims, see also Rejection under 35 USC 103, above). Accordingly, there is an explicit teaching in the art to vary both the insulin and the capping group of such structures. As noted in the difference statement of the rejection, “The singular difference between the compounds of US’743 (e.g., Dimers 24, 32, and 54) and the instantly claimed invention is that the Linker (i.e., -C(O)-(CH2)6-C(O)-) of US’743 connects the B29 Lys with the B’29 Lys in US’743, wherein the instant claims require that the same linker connects the B29 Lys with the A’1 Gly in the instant claims”; critically, this statement is not disputed, acknowledged, or addressed by the Applicant. Accordingly, such arguments are not persuasive in view of the facts of record since the prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)).
It is the Examiner’s understanding that Applicant traverses the rejection under 35 USC 103 (revised above in view of Applicant’s amendments) because “the prior art does not provide the skilled artisan with any reassurance that making these changes would lead to insulin dimers which are biologically active”, wherein “The present application demonstrates that the claimed dimers are active in an insulin receptor AKT-phosphorylation assay (Example 16)” (see, e.g., Reply filed 8/03/2026 at 20 at final ¶). First, Example 16 is limited to Dimer Nos: 1-17, which do not extend to the full scope of claimed structures at instant claims 1, 9, or 15; accordingly, such data fails to meaningfully distinguish a property of the claimed inventions relative to the prior art. Furthermore, no unexpected results commensurate in scope with the requirements of MPEP § 716.02 have been placed on record at this time. Second, prior art is presumed fully enabled (see, e.g., MPEP § 2121(I)) for all that it discloses (see, e.g., MPEP §§ 2123(I)-(II)). Here, the insulins would be predicted and expected to simply retain their normal function as “insulin” in the absence of evidence to the contrary, and no evidence to the contrary has been presented. Third, the prior art actually identifies that multiple arrangements were known and would be expected to yield functional insulin (see, e.g., Schuttler at 325 to 326 at bridging ¶, 326 at Fig. 8, Table 2 at 326, 328 at Table 3, 327-328 at bridging ¶ noting that all dimers “elicit normal maximal responses”), but Applicant fails to acknowledge or address such disclosures. Fourth, If Applicant means to suggest the existence of skepticism of experts, such evidence should be filed per MPEP § 716.05 as evidence is required to establish skepticism of experts. In the absence of such evidence, such statements are understood to be unsupported conjecture of counsel. Fifth, if Applicant is attempting to allege that the prior art is not enabling or inoperable Applicant is directed to MPEP § 2121(I), which notes that the prior art is presumed fully enabled for all that it discloses, and the burden is on the Applicant to rebut the presumption of operability (see, e.g., MPEP § 2121(I); MPEP § 716.07). No evidence of inoperability commensurate in scope with the requirements of MPEP § 716.07 have been placed on record at this time; critically, arguments of counsel cannot take the place of evidence in the record (see, e.g., In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965), and evidence is required to rebut the presumption of operability. In sum, the prior art teaches insulin dimers and heterodimers, and teaches that such components may be connected using different linkers connecting different points of the insulin polypeptides, wherein such compounds may retain insulin function and be predictably and expectedly utilized as insulins.
Accordingly, all applicable arguments raised on record have been fully considered but not found persuasive. Accordingly, the claims remain rejected in view of the new and revised rejections above, wherein all new or revised rejections were necessitated by Applicant’s amendments.
Allowable Subject Matter
The amendments to claim 15 are understood to limit claim 15 to Dimers 1-2, 8-9, 15, and 28, wherein the new sequence listing clarifies the specific bond arrangements of the modifications and linkages of those dimers.
Accordingly, claims 15-17 are allowed.
Applicant is advised that after-final amendments canceling all claims other than claims 15-17 could place the Application in form for allowance.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US201502748024 pertains to covalently conjugated insulin dimers (see, e.g., US’802 at title, abs, Fig. 11E, passim).
US 10,183,981 B25 pertains to covalently conjugated insulin dimers (see, e.g., US’981 at title, abs, claims).
Conclusion
Claims 15-17 are in form for allowance. Claims 1, 6, 9-11, and 20-21 are rejected.
Applicant's amendment necessitated the new or revised 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 RANDALL L BEANE whose telephone number is (571)270-3457. The examiner can normally be reached Mon.-Fri., 7 AM to 2 PM ET.
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.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 At claim 1(iii), stating “the first insulin and the second insulin heterodimers are independently native human insulin, insulin lispro, insulin aspart, desB30 insulin, or insulin glargine”; see also at claim 9(iii), stating that “the first insulin and the second insulin heterodimers are independently selected from native human insulin, insulin lispro, insulin aspart, and insulin glargine”.
2 At claim 1(iii), stating “the first insulin and the second insulin heterodimers are independently native human insulin, insulin lispro, insulin aspart, desB30 insulin, or insulin glargine”; see also at claim 9(iii), stating that “the first insulin and the second insulin heterodimers are independently selected from native human insulin, insulin lispro, insulin aspart, and insulin glargine”.
3 Schüttler et al., Preparation and properties of covalently linked insulin dimers. Hoppe Seylers Z Physiol Chem. 1982 Mar;363(3):317-30. doi: 10.1515/bchm2.1982.363.1.317. PMID: 7042509; hereafter “Schuttler”; cited in IDS filed 4/28/2023 as cite No. 12.
4 Cited in previous action.
5 Cited in previous action.
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