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 Interpretation
BRI of “binding partner moiety” as amended January 20, 2026, is a moiety that binds to the one or more glucose-binding moieties.
BRI of “wherein by interaction of the glucose-binding moiety with the binding partner moiety” as amended January 20, 2026, is an interaction of the glucose-binding moiety with the binding partner moiety to form a complex between these two element.
Claim Rejections - 35 USC § 112 - withdrawn
The rejection of claims 1-8, 11, 14, 17, 20-22, 29, 35, 41-43, 49-50, and 52 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amendment and arguments filed January 20, 2026.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1, 14, 17, 20-22, 29, 35, 41, 49-50, and 52 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.
In claim 1, the indefinite language is “R and/or R’ comprises…”. The language is indefinite because the both variables are not defined when the conjunction is “or”. That is, if R is selected from i) through vi), the structure of R’ is undefined because no conditional definition for R’ is provided. If R’ is selected from i) through vi), the structure of R is undefined because no conditional definition for R is provided. The claim only defines both variables if R and R’ comprises a structure independently selected from i) through vi).
In addition, in claim 1, part ii) the list of alternatives in the definition of X is not a closed grouping because a conjunction is missing between the last and second to last option in the list of alternatives.
In addition, in claim 1, part v) the list of alternatives in the definition of Z is not a closed grouping because a conjunction is missing between the last and second to last option in the list of alternatives.
Dependent claims 14, 17, 20-22, 29, 35, 41, 49-50, and 52 fail to remedy these issues and are likewise rejected.
Applicant’s remarks that a person having ordinary skill in the art would understand that the "cognate binding partner" is a "binding partner moiety" when referencing the glucose binding moiety and is a "glucose-binding moiety" when referencing the binding partner moiety are acknowledged.
In claim 29, it is not clear whether “wherein the glucose-binding moiety or binding partner moiety of the A chain and the glucose-binding moiety or binding partner moiety of the B chain are bound by cognate binding partners attached through a linker” means that the linker is joining the cognate binding partners to each other or to the insulin. If it is the former, it is not clear how the linker effects the glucose-responsiveness of the insulin.
Claim Rejections - 35 USC § 102 - withdrawn
The rejection of claims 1, 11, 14, 17, 20-21, 41, 49-50, and 52 under 35 U.S.C. 102(a)(1) as being anticipated by Weiss (US 2018/0057559 A1, published March 1, 2018) is withdrawn in view of the amendment and arguments filed January 20, 2026.
The rejection of claims 1-5, 14, 17, 35, 49-50 and 52 under 35 U.S.C. 102(a)(1) as being anticipated by Anderson et al. (US 2015/0320837 A1; published November 12, 2015) is withdrawn in view of the amendment and arguments filed January 20, 2026.
The rejection of claims 1-8, 14, 17, 35, 41-43, 49-50 and 52 under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Kruse et al. (WO 2019/092125 A1; published May 16 2019, effective filing date November 9, 2017; IDS 1/26/2022) is withdrawn in view of the amendment and arguments filed January 20, 2026.
Claim Rejections - 35 USC § 103
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.
Claims 1, 7-8, 14, 17, 20-22, 35, 41, 49-50, and 52 are rejected under 35 U.S.C. 103 as being unpatentable over Weiss (US 2018/0057559 A1, published March 1, 2018) in view of Kruse et al. (WO 2019/092125 A1; published May 16 2019, effective filing date November 9, 2017).
Weiss teaches glucose-responsive insulin-analogues comprising: (i) a monomeric glucose-binding element and (ii) an element that reversibly binds to the monomeric glucose-binding element such that this linkage is displaceable by glucose (abstract). Each element is attached to the insulin analogue. The glucose-binding element may be a phenylboronic acid derivative. The element that reversibly binds to the monomeric glucose-binding element may be N-linked or O-linked monosaccharide, disaccharide, or oligosaccharide such as glucose, mannose, and N-acetyl-galactose (¶ [0011]), which are polyols. The overall structure of the insulin-analogues containing the glucose-binding element and its binding partner is shown in Figure 3:
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Weis teaches that in the absence of exogenous glucose, the glucose-binding element and its binding partner element form a reversible interaction such that the structure of the insulin analogue is stabilized in a closed and less active conformation. Weis teach that in the presence of exogenous glucose, the free glucose binds to the phenylboronic acid moiety, thereby displacing its binding partner element such that insulin analogue binds to the insulin receptor in the blood stream and at target tissues. Accordingly, the insulin analogue is sensitive to the level of glucose in the blood (¶ 0019). The affinity of the analogues for the insulin receptor is higher when dissolved in a solution containing glucose at a concentration above the physiological range (>140 mg/dl; hyperglycemia) than when dissolved in a solution containing glucose at a concentration below the physiological range (<80 mg/dl; hypoglycemia) (¶ [0002]).
Weiss does not teach that the glucose-binding moiety is a multivalent boronic acid of Formula (I).
Kruse et al. teach multivalent boronic acids for use in glucose-sensitive albumin-binding diboron conjugates of blood glucose lowering drugs such as insulin (see page 2; page 7, lines 5-7; Figures 1-2).
Kruse et al. multivalent boronic acid compounds of general formula I’ (page 3, lines 20-22)
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wherein X is (page 4, lines 14-25)
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wherein n is 1-4, and W is a covalent bond or linker to a drug substance such as insulin; and
R1 and R2 are independently selected from (page 6, lines 13-20)
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wherein one to four Y is H, one Y is the attachment point to X, and none, one or two Y are F, Cl, CF2, CF3, SF5, OCF3, SO2CH3 or SO2CF3.
It would have been obvious to substitute the multivalent boronic acids taught by Kruse et al. for the phenylboronic acid derivative in the insulin analogue taught by Weiss. One of ordinary skill in the art would have been motivated to do so given that Kruse et al. teach that the diboron compounds bind glucose with Kd values in the low millimolar range (page 173, lines 29-31; Table 1). Kruse et al. teach that binding of glucose to diboron compounds matches the physiological range of glucose fluctuations, activating insulin in response to higher glucose and avoiding hypoglycemia (page 22, lines 23-32). In addition, the diboron compounds taught by Kruse et al. exhibit a desirable higher affinity for glucose than lactose (page 173, lines 29-31; Table 1). There would have been a reasonable expectation of success given that Kruse et al. teach that the diboronic acid compounds can be conjugated to insulin (see page 2; page 7, lines 5-7; Figure 1).
The resulting insulin analogue would satisfy all of the limitations of claim 1.
With respect to claim 7,it would have been obvious to select the compound recited in this claim given that Kruse et al. disclose the narrow subgenus wherein X is
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and numerous species wherein R1 and R2 are
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(Examples 1, 12, 14, 22, 24)
With respect to claim 8, Kruse et al. teach (Example 40):
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With respect to claim 14, Weiss teaches that the elements are amine-linked. The phenylboronic acid derivative (including a spacer element) may be linked to the α-amino group of glycine at position A1 or optionally at either the ε-amino group of D-Lysine as an amino-acid substitution well tolerated at position A1 or the ε-amino group of L-Lysine as a substitution at position A4. The elements may also be thiol-linked at a cysteine or homocysteine sidechain (¶ [0011]). Kruse et al. teach that the glucose binding component is attached via covalent attachment at a lysine side chain or N-terminal amino and the albumin via noncovalent binding (see page 2; page 7, lines 5-7).
With respect to claim 17, Weiss teaches that the elements may be attached to the insulin via a linker (¶ [0029], [0050]; Figure 3).
With respect to claims 20-21 and 41, Weiss teaches that the phenylboronic acid derivative (including a spacer element) may be linked to the α-amino group of glycine at position A1 or optionally at either the ε-amino group of D-Lysine as an amino-acid substitution well tolerated at position A1 or the ε-amino group of L-Lysine as a substitution at position A4. Each of these options is at or near the N-terminus of the A chain. Weiss teaches that the N-linked or O-linked monosaccharide, disaccharide, or oligosaccharide may be at one or near the C-terminus of the B-chain polypeptide, that is at one or more of the positions B27, B28, B29, B30, or as attached to a peptide extension of the B-chain containing one residue (B31) or two residues (B31-B32). Alternatively, a nonstandard diol-containing amino acid such as L-DOPA or D-DOPA may be substituted at any of B27-B30. (¶ [0011]). When the monosaccharide, disaccharide, oligosaccharide, or polyol are bound to the glucose-binding moiety, binding to the insulin receptor is inhibited.
With respect to claim 22, it would have been obvious to modify the insulin analogue to switch the location of the two components and to attach the phenylboronic acid derivative to the B chain and the diol-containing group to the A chain. One of ordinary skill in the art would expect that the phenylboronic acid derivative would function in the same manner in either location and would bind to its ligand, glucose or binding partner when attached to the A- or B-chain. Likewise, one of ordinary skill in the art would expect that the diol-containing group would function in the same manner in either location and would compete with exogenous glucose for binding to the phenylboronic acid derivative when attached to the A- or B-chain. One of ordinary skill in the art would utilize the conjugation chemistry techniques in Weiss for either orientation.
With respect to claim 35, Kruse et al. teach that the boron-containing compounds also bind to albumin as shown in Figure 1:
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The albumin is also considered a binding partner because it affects insulin activity in a glucose concentration-dependent manner. Kruse et al. teach that the glucose-binding moiety is bound to a chain of the insulin and that the binding partner, albumin, is bound to the glucose-binding moiety (Figure 1). As a result, the two components are bound to the same chain.
With respect to claim 49, Weiss teaches that the insulin may be a mammalian insulin or variant thereof (Figure 1a; ¶ [0039]-[0041]).
With respect to claim 50, Weiss teaches a pharmaceutical composition comprising an effective amount of the insulin analogue, and a pharmaceutically acceptable carrier or excipient, optionally formulated for sub-cutaneous injection (claim 27).
With respect to claim 52, Weiss teaches a method of treating a patient comprising administering the pharmaceutical composition to a patient in need of treatment for lowering blood glucose and/or type 2 diabetes (¶ [0002]).
Response to Arguments
Applicant's arguments filed January 20, 2026, have been fully considered but they are not persuasive.
Applicant traverses the rejection on the grounds that Kruse does not demonstrate the creation of a glucose-responsive insulin, or suggest which of the divergent structures should be selected for modifying Weiss, and that the rejection is a research plan. This argument is not persuasive.
Weiss teaches a glucose-responsive insulin which differs from the claimed glucose-responsive insulin by the substitution of a glucose-binding moiety comprising a phenylboronic acid derivative for a glucose-binding moiety comprising divalent boronic moiety of Formula I. The substituted component and its function was known in the art. Kruse et al. teach a glucose-binding moiety comprising divalent boronic moiety of Formula I. The function of Formula I is known in the art because Kruse et al. teach that the diboron compounds bind glucose with Kd values in the low millimolar range (page 173, lines 29-31; Table 1). One of ordinary skill in the art would expect that the divalent boronic moiety of Formula I performs the function of glucose binding in the combination because Kruse et al. teach that binding of glucose to diboron compounds matches the physiological range of glucose fluctuations, activating insulin in response to higher glucose and avoiding hypoglycemia (page 22, lines 23-32). Therefore, one of ordinary skill in the art could have substituted one known element for another, and the results of the substitution would have been predictable.
Applicant argues that Figures 5A and 5B and Example 6 of the specification provide evidence of unexpected results. However, Applicant has not explained why the data in these portions of the specification are unexpected, not expected in view of the cited art.
For these reasons, the rejection is 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.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654