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 Status
Claims 1-2, 5-6, 8-12, and 14-21 are pending. Claims 1, 5, 9, 14, and 15 were amended in the Reply filed 11/10/2025. Claims 18-19 are withdrawn as direct to a non-elected invention. Claims 9-12, 14, 17, and 20-21 are withdrawn as directed to non-elected species. Accordingly, claims 9-12, 14, 17-21 are withdrawn. Claims 1-2, 5-6, 8, and 15-16 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 is acknowledged. The traversal is on the grounds that unity of invention exists and/or “no serious burden for examination is present” (see, e.g., Reply field 11/10/2025 at 18 at 5th full ¶ to 19 at 1st full ¶). The assertion that unity of inventio exists is not persuasive as no single, common required consensus structure constituting a point of novelty or otherwise an inventive step exists in view of the prior art, as evidenced by the rejections below. Regarding the assertion regarding “no serious burden”, this is not credible in view of claims directed to thousands of species of compounds in the absence of any admission that such all such species are obvious variants of one another.
The requirement is still deemed proper and is therefore made FINAL.
The originally elected species is 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. Accordingly, the originally elected species is understood to read upon instant claims 1-2, 5-6, 8, and 15-16.
Applicant did not identify, with specificity, which claims of Group I actually read upon the amended claims as filed 11/10/2025. Upon review, the following claims are understood to be directed to a non-elected species: Claim 9 excludes the originally elected species because it requires insulin lispro, insulin aspart, or insulin glargine (see claim 9 at (iii)), and therefore excludes native human insulin as present in the originally elected species. Claims 10-12, 14, and 20-21 depend directly or indirectly from claim 9, and therefore also exclude the originally elected species for the reasons applicable to claim 9. The originally elected species does not recite a GLP-1 receptor agonist and Applicant has not identified that such embodiments are obvious variants relative to the originally claimed invention, and therefore claim 17 does not read upon the originally elected species. Accordingly, claims 9-12, 14, 17, and 20-21 do not read upon the originally elected species.
Following extensive search and examination, the originally elected species of Dimer 1 has been 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 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 this is correct, each of Dimers 1-2, 8-9, 15, and 28 were deemed free of the prior art. The point of novelty is 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.
Claims 9-12, 14, 17, and 20-21 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. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/10/2025.
Claims 1-2, 5-6, 8, and 15-16 are presently considered.
Priority
The priority claim to US Provisional Application 63076142 (filed 9/09/2020) is acknowledged.
Information Disclosure Statement
The IDS filed 4/28/2023 is acknowledged and presently considered.
Examiner notes that multiple prior art references are enumerated in the disclosure and therefore presumed relevant to the invention, but have not been set forth in an IDS (see, e.g., Spec. filed 2/16/2023 at 8 at lines 15-28, p. 12 at lines 15-30, 14 at lines 5-15, p. 15 at lines 1-5, 17 at lines 12-19, 27 at lines 20-31, 29 at lines 5-10). The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Sequence Listing
The instant disclosure is objected to for not complying with 37 C.F.R. 1.821 as detailed in MPEP §§ 2421–2424. Specifically, the instant application does not comply with 37 C.F.R. 1.821(b)-(e). The instant claims and/or disclosure contain references or disclosures of amino acid sequences that should be accompanied by a sequence listing and identified using "SEQ ID NOs” as prescribed (see, MPEP §§ 2421–2424). Specifically, the instant application discloses sequences (see, e.g., Spec. filed 2/16/2023 at 33, at 46-56 at preparative examples, 57-65 at Examples, 66-68 at Table).
Appropriate correction is required.
Claim Objections
Claims 5-6 and 15 are objected to because of the following informalities:
Claims 5-6 recite multiple acronyms (e.g., Me2, AEG, etc.). Each acronym should be completely spelled out at least once in the claim listing.
Claim 6 lists “carbamoyl” twice.
Claim 15 recites sequences corresponding to sequences within the sequence listing (see, e.g., instant SEQ ID NOs: 1-2, 6-10), but such sequences are not recited at claim 15. Accordingly, the claims are objected to for not complying with 37 C.F.R. 1.821 as detailed in MPEP §§ 2421–2424 and 37 C.F.R. 1.821(b)-(e). The instant claims contain references or disclosures of amino acid sequences that should be accompanied by a sequence listing and identified using "SEQ ID NOs” as prescribed (see, MPEP §§ 2421–2424).
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”).
Amended claims 1 and 9 as filed 11/10/2025 appear to substantially and materially overlap in scope, wherein claim 1 recites and requires that the first insulin and the second insulin heterodimers are independently native human insulin, insulin lispro, insulin aspart, desB30 insulin, or insulin glargine (see, e.g., instant claim 1), but wherein claim 9 does not recite native human insulin or desB30 insulin (see, e.g., instant claim 9). 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.
Additional claim interpretations are set forth in the rejections below.
Claim Rejections
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 1-2, 5-6, 8, and 15-16 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 recites “…R’ is H (when R is R’NH-)…” at page 6 at (ii) at subpart d), which renders the claim scope indefinite. It is unclear if the parenthetical is exemplary language or not. Specifically, it is unclear if the parenthetical is an attempt to limit the scope of “R’ is H” to only the situation of when R is R’NH, or if R’ may be hydrogen in all circumstances regardless of whether or not R is R’NH (see, e.g., MPEP § 2173.05(d)). Accordingly, claim 1 is rejected as indefinite.
Claim 1 at (i) on page 6 recites:
(i) at least one of the first or second A chain or B-chain polypeptides is conjugated at its N-terminal amino acid to a capping group or at least the N-terminal amino acids of the first insulin heterodimer molecule are conjugated to a capping group or the N-terminal amino acids of both the first insulin heterodimer and second insulin heterodimer are conjugated to a capping group….
However, claim 1 previously states and requires
An insulin dimer comprising: an epsilon (ε)-amine of a lysine group on the B chain of a first insulin having a first A-chain polypeptide and first B-chain polypeptide and an α-amino group of Al’ residue of a second insulin molecule having a second A'-chain polypeptide and second B'-chain polypeptide conjugated together by a bifunctional linker moiety…..
These limitations appear inconsistent because claim 1 appears to simultaneously require position A1’ (i.e., the N-terminus of an A chain) to be conjugated to an epsilon (ε)-amine of a lysine group on the B chain, but then to subsequently attempt to define an inconsistent claim scope wherein “the N-terminal amino acids of both the first insulin heterodimer and second insulin heterodimer” (i.e., all four N-termini including A1, B1, A1’, and B1’) “are conjugated to a capping group”. This configuration is presumably excluded by the requirement for A1’ to be conjugated via a linker to a Lysine in the B-chain. Accordingly, there are substantial and material concerns regarding the metes and bounds of instant claim 1, which is rejected as indefinite for reciting inconsistent structural arrangements. Applicant may overcome this rejection by amending claim 1 at (i) to delete the phrase “the N-terminal amino acids of both the first insulin heterodimer and second insulin heterodimer are conjugated to a capping group”.
Claim 2 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 15 discloses images of multiple structures identified as Dimers 1-4, 8-9, 12-13, 15, 28, and 31-33; however, these structures conflate peptide nomenclature (i.e., A is alanine, I is isoleucine) with common chemical notation (i.e., straight lines representing carbons), because the modified bonds are shown as simply “sticking out” from a peptide sequence in the complete absence of clarification identifying how the structures “sticking out” are actually chemically conjugated to specific portions of the amino acid residues. This renders the claim scope indefinite because it is unclear what actual chemical structures are included or excluded from the pending claim scope. For example, Dimer 1 comprises
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, and
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; however, in
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, it is unclear if the N-terminal glycine is being modified at the N-terminus (i.e., -NH2 moiety) or at the alpha carbon (i.e., replacing hydrogen in the side chain); furthermore, in the
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linkage structure, it is unclear if the side chain of the Lysine is fully, partially, or wholly replaced by the linker as shown (i.e., it is unknown if a portion of the Lysine side chain is present in the structure but not shown, or if the linker shown is directly attached to the alpha carbon, beta carbon, etc. of Lysine); furthermore, in the structure of
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, it is unclear if the side chain of the Lysine is fully, partially, or wholly replaced by the linker as shown (i.e., it is unknown if a portion of the Lysine side chain is present in the structure but not shown, or if the linker shown is directly attached to the alpha carbon, beta carbon, etc. of Lysine); finally, in the structure of
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, it is unclear if the curved line represents a carbon-carbon bond, a disulfide linkage between Cys side-chains, or something else. No clarification is provided at claim 15 and the art of record is silent regarding the typical interpretation of such structures conflating peptide nomenclature with organic chemistry nomenclature by simply having structures “sticking out” from the peptide. Accordingly, the metes and bounds of the compounds shown at claim 15 are unknown. These examples are not exhaustive and the same or similar issues are present in the structures shown for Dimers 2-4, 8-9, 12-13, 15, 28, and 31-33, as well (see esp. Dimers 8-9, noting that single amino acids are shown with two different moieties “sticking out”). Accordingly, claim 15 is rejected as indefinite. For purposes of applying prior art, the curved bond between Cys residues is presumed to be a disulfide linkage, the H2N-C(O)- moiety at an N-terminus is inferred to be a modification of the N-terminus, and lysine residues are understood to be modified at the epsilon moiety of the lysine side chain. Applicant may overcome this rejection by amending claim 15 to contain clarifying information, which might include some or all information set forth at page 40 at lines 1-10 of the specification, or might include information analogous to the information at claim 74 of US20170355743A1 at page 167 at col I.
Claims 2, 5-6, 8, and 16 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 1-2, 5-6, 8, and 15-16 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 8 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 8 depends from claim 1, wherein claim 1 was amended in the Reply filed 11/10/2025 to limit the scope of the claim to native human insulin (SEQ ID NOs: 1-2), insulin glargine (SEQ ID NOs: 7-8), Insulin lispro (SEQ ID NOs: 1 and 6), Insulin aspart (SEQ ID NOs: 1 and 9), and Insulin DesB30 (SEQ ID NOs: 1 and 10). However, claim 8 more broadly recites variable sequences corresponding to an A chain of SEQ ID NO: 3 and a B chain of either SEQ ID NO: 4 or 5. SEQ ID NOs: 3-5 as recited at claim 8 are substantially broader than the limited selection of insulin as required by amended claim 1 since they can vary at multiple positions that are invariant within instant SEQ ID NOs: 1-2 and 6-10. Accordingly, claim 8 is rejected 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.
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 1-2, 5-6, 8, and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over US20170355743A1 and further in view of Schuttler et al1.
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 1-2, 5-6, 8, 15-16, 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 1-2, 5-6, 8, 15-16, 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 1-2, 5-6, 8, 15-16, 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 1-2, 5-6, 8, 15-16, 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 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 1-2, 5-6, 8, 15-16, 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 claim 16 and the presence of a pharmaceutical excipient, 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).
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))
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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 1-2, 5-6, 8, and 15-16 are rejected.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US20150274802 pertains to covalently conjugated insulin dimers (see, e.g., US’802 at title, abs, Fig. 11E, passim).
US 10,183,981 B2 pertains to covalently conjugated insulin dimers (see, e.g., US’981 at title, abs, claims).
Conclusion
No claims are allowed.
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/RANDALL L BEANE/Primary Examiner, Art Unit 1654
1 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.