DETAILED ACTION
Examiner acknowledges receipt of the reply filed 04/06/2026, in response to the non-final office action mailed 01/05/2026.
Claims 4, 6-9, 12, 15-23, 31-36, 44, and 55-73 are pending
Claims 44, 63, 64, 69, 70, and 73 remain withdrawn for the reasons made of record.
Claims 4, 6-9, 12, 15-23, 31-36, 55-62, 65-68, 71 and 72 are being examined on the merits in this office 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 .
Priority
The priority claim to CN201911398378.0 (filed 12/30/2019) and CN202011057926.6 (filed 9/29/2020) are each acknowledged.
Examiner notes that no certified translation of the Foreign Application CN201911398378.0 (filed 12/30/2019) and CN202011057926.6 (filed 9/29/2020) has been placed on record. If applicant wants the application to be accorded benefit of the non-English language application, a certified translation is required (see 35 U.S.C. 119(b)(3), 37 CFR 1.55(g)(1)-(4)). Applicant is advised that any showing of priority that relies on a non-English language application is prima facie insufficient if no certified translation of the application is on file. See 37 CFR 41.154(b).
Sequence Compliance- withdrawn
The objection to the specification for sequence compliance is withdrawn in view of the amendment filed 4/06/2026.
Claim Objections- withdrawn
The objection of claims 4, 6, 7, 16-18, 20-23, 32, 35, 36, and 55 istt6v withdrawn in view of the amendment filed 4/06/2026.
Claim Rejections - 35 USC § 112- withdrawn
The rejection of claims 4, 6, 8, 9, 15-18, and 31-33 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in view of the amendment filed 4/06/2026.
Specification
Please note, the specification has not been checked to the extent necessary to determine the presence of all possible error. Applicant's cooperation is required in correcting any errors of which applicant may become aware in the specification. MPEP § 608.01.
Response to Arguments
Applicant's arguments filed 4/06/2026 have been fully considered but they are not persuasive. An action the merits is set forth herein.
Maintained Rejections
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 4, 6-9, 12, 15-17, 19, 31-34, 55-62, 65-68, 71 and 72 remain/are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 2011/0098439 (Madsen et al- previously cited). The rejection is maintained from the office action mailed 1/05/2026, but has been amended to reflect claims filed 4/06/2026.
Madsen et al discloses acylated insulins acylated insulin wherein an acyl moiety is attached to the parent insulin and wherein said acyl moiety comprises repeating units of alkylene glycol containing amino acids and wherein there is only one lysine residue in the parent insulin, said acyl moiety being connected to an epsilon amino group in said lysine residue (claim 1). The acyl moiety is a group of formula (I):
Acy−AA1n−AA2m−AA3p− (I), wherein n is 0 or an integer in the range 1-3; m is 0 or an integer in the range 1-6, p is an integer in the range 2-30; Acy is a fatty acid or a fatty diacid comprising 8 to 24 carbon atoms from which, formally, a hydroxy group has been removed from the fatty acid and, formally, a hydroxy group has been removed from one of the carboxy groups in the fatty diacid; AA 1 is a neutral cyclic amino acid from which, formally, a hydroxy group has been removed from the carboxy group and a hydrogen atom has been removed from the amino group; AA2 is an acidic amino acid from which, formally, a hydroxy group has been removed from the carboxy group and a hydrogen atom has been removed from the amino group; AA3 is a neutral, alkylene-glycol-containing amino acid from which, formally, a hydroxy group has been removed from the carboxy group and a hydrogen atom has been removed from the amino group; the order in which AA1, AA2 and AA3 appears in the group of formula I can be interchanged independently, and the connections between Acy, AA1, AA2 and/or AA3 are amide bonds (e.g., paras. [0040]-[0050], claims 1, 2 and 6). Preferred parent insulin includes desB30 human insulin (e.g., paras. [0049], Exs 1-2). The neutral, alkylene glycol-containing amino acid (AA3 of Madsen et al, instant Variable I) can be in a range of (p =2-30), preferably in the range of 2-10 (e.g., para. [0122]). Preferred AA3 structures include OEG having the structure of -HN-(CH2)2-O-(CH2)2-CO- (paras. [0022], [0134]-[0137], Ex 2). Instant variable II (AA2 of Madsen et al) is Glu (α or γ, L or D), Asp (α or β, L or D) (e.g., para. [0131], Ex 2, claim 5). The acyl moiety - fatty acid or diacid [instant variable III] can comprise C8-C24, including C20 eicosanedioyl, or C22 (e.g., paras. [0022], [0036], [0042], [0097], [0124-[0126], Ex 2, claims 1 and 7). The neutral, alkylene glycol-containing amino acid (AA3 of Madsen et al, instant Variable I) can be in a range of (p =2-30), preferably in the range of 2-10 (e.g., para. [0122]). Preferred AA3 structures include OEG having the structure of -HN-(CH2)2-O-(CH2)2-CO- (paras. [0022], [0134]-[0137], Ex 2). Example 2 reduced to practice B29K(N(ε)-eicosanedioyl-γGlu-2xOEG), desB30 human insulin, wherein I is OEG, n = 2, II is γGlu, m = 1, and III fatty acid is 20 carbons in length. The A chain is instant SEQ ID NO:1. The insulin B chain is instant SEQ ID NO:2 (see, e.g., Ex 2, claim 7).
Madsen et al differs from the pending claim scope as follows: Madsen et al differs from the pending claim scope only with respect to the number of times OEG is repeated (i.e., 2xOEG compared to 5xOEG-9xOEG).
Madsen et al differs from the originally elected species as follows: Madsen et al only differs with respect to the originally elected species in two respects, namely the specific acyl moiety utilized (i.e., docosanedioyl rather than eicosanedioyl) and the exact number of times OEG is repeated (i.e., 2xOEG compared to 5xOEG-9xOEG).
Repeating OEG 5 to 9 times is obvious in view of Madsen et al: The issue is whether or not it would be obvious to modify prior art embodiments, such as
B29K(N(ε)-eicosanedioyl-γGlu-2xOEG), desB30 human insulin (claim 7, Ex 2)
by extending the OEG moiety, such that OEG is repeated 5-9 times, rather than only twice. Such a difference is obvious for several rationales. First, Madsen et al explicitly teaches general formulas including
Acy-AA10-3-AA20-6-AA32-30-(I)
(see, e.g., paras. [0040]-[0050], [0134]-[0137], claims 1, 2 and 6), and explicitly teaches that the corresponding position of AA3 may be repeated 2-10 times (see para [0122].). Accordingly, such difference in repeating OEG from five to nine times is within the range explicitly taught and claimed by the prior art (see, e.g., id.; see also MPEP § 2144.05(I), noting that where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists). Second, OEG is a known chemical structure, and the only difference is the number of times the known structure is repeated. Per MPEP § 2144.09(I)-(II), a prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities, wherein compounds that are homologs (i.e., compounds differing by the successive addition of the same chemical group, are generally of sufficiently close structural similarity that there is a presumed expectation that such compounds possess similar properties. Here, the compounds are acylated insulins in both the instant claims and Madsen et al:, and the only difference appears to be the successive addition of the same chemical group, namely OEG. Accordingly, such homologs would be presumed to have the same or highly similar properties absent objective evidence to the contrary commensurate in scope with MPEP §§ 716, 716.01, and 716.02. In view of the teachings that AA3 may be repeated 2-10 times, and the exemplification of 2xOEG, (see, e.g., Ex 2 and claim 7), an artisan would readily appreciate that OEG could be repeated in the exemplified structures between 2 and 10 times or otherwise that different lengths of OEG repeats could be simply substituted for other lengths (see, e.g., id.; see also MPEP §§ 2144.05(I), 2144.09(I)-(II), 2144.07, 2143(I)(A),(B)). Accordingly, such simple substitutions or variation in OEG length within the scope of the prior art would reasonably direct artisans to embodiments such as
B29K(N(ε)-eicosanedioyl-γGlu-5-9xOEG), desB30 human insulin,
which reads upon the instant claims.
Substituting a docosanedioyl moiety in place of an eicosanedioyl moiety is obvious in view of Madsen et al: The issue is whether or not it would be obvious to modify prior art embodiments, such as
B29K(N(ε)-eicosanedioyl-γGlu-2xOEG), desB30 human insulin
by simultaneously extending the OEG moiety, such that OEG is repeated 5-9 times, and by substituting docosanedioyl in place of eicosanedioyl. However, such differences are obvious in view of the teachings of Madsen et al. First, Madsen et al. explicitly teaches general formulas including
Acy-AA10-3-AA20-6-AA32-30-(I)
(see, e.g., paras. [0040]-[0050], [0134]-[0137], claims 1, 2 and 6), and explicitly teaches that the corresponding position of AA3 may be repeated 2-10 times (see id.; see discussion in preceding paragraph regarding OEG), and teaches that the Acy moiety may contain 8-24 carbon atoms (see, e.g., claim 1). Madsen et al. explicitly teaches and directs artisans to utilize both eicosanedioyl (20 carbons) and docosanedioyl (22 carbons) (see, e.g., e.g., paras. [0022], [0036], [0042], [0097], [0124-[0126], Ex 2, claims 1 and 7). Variable II (AA2 of Madsen et al) is Glu (α or γ, L or D), Asp (α or β, L or D) (e.g., para. [0131], Ex 2, claim 5). Accordingly, both differences between the prior art embodiments such as
B29K(N(ε)-eicosanedioyl-γGlu-2xOEG), desB30 human insulin
and the originally elected species of
B29K(N(ε)-docosanedioyl-γGlu-6xOEG), desB30 human insulin
B29K(N(ε)-eicosanedioyl-γGlu-6xOEG), desB30 human insulin
fall within the scope of variability explicitly taught and exemplified for acylated insulin moieties as disclosed by Madsen et al. because the differences amount to simply substituting one prior art acyl moiety for another prior art named acyl moiety, and simply extending the OEG repeats to within the range explicitly and expressly taught by Madsen et al. Per Example 2, the A chain is instant SEQ ID NO:1. The insulin B chain is instant SEQ ID NO:2 (see, e.g., Ex 2, claim 7).
Regarding instant claim 15 and a pharmaceutical composition comprising an insulin derivative according to instant claim 4, Madsen et al reasonably informs artisans that the disclosed and obvious embodiments claimed may be utilized in pharmaceutical formulations suitable for use in methods of treating subjects with type 1 and type 2 diabetes (see, e.g., paras. [0051]-[0096]). Madsen et al teach pharmaceutical composition comprising the insulin derivative and one or more pharmaceutically acceptable carriers and additives. Id.
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): The claimed invention is the obvious combination (or substitution) of known prior art components (i.e., known acyl moieties, known human insulin analogues, known linkers (i.e., OEG, γGlu), known linkages via B29K, etc.) according to known methods taught and disclosed by Madsen et al. for constructing acylated insulin analogues exactly as taught and claimed by Madsen et al., wherein such combinations yield only predictable and expected results, such as
B29K(N(ε)-docosanedioyl-γGlu-5-9xOEG), desB30 human insulin
and
B29K(N(ε)-eicosanedioyl -γGlu-5-9xOEG), desB30 human insulin
wherein such compounds would be predicted and expected to have the utilities and benefits disclosed by Madsen et al., including applications in the treatment of Type 1 and 2 diabetes (e.g., paras. [0051]-[0061]; see, e.g., MPEP §§ 2143(I)(A), (B), (G)). Furthermore, each prior art element merely performs its art-recognized function in combination as it does separately.
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 combine known components in known arrangements to obtain a known and expected result having a known and art-recognized utility. In addition or alternatively, it is well-within the ordinary skill in the art to simply substitute known OEG linkers and acyl moieties in exemplified embodiments, with other OEG linkers and acyl moieties explicitly taught by the same reference, to predictably and expectedly obtain variants of the exemplified embodiments expected and predicted to have the same general properties and utilities.
Accordingly, claims 4, 12, 15, 55-62, 65-68, 71 and 72 are rendered obvious.
Regarding claims 6 and 7, the fatty acid or diacid can comprise C8-C24, preferably C20 eicosanedioyl, or C22 (e.g., paras. [0022], [0036], [0042], [0097], [0124-[0126], Ex 2, claims 1 and 7). Variable II is an acidic amino acid wherein m =is 0-6 (e.g., paras. [0036], [0097]-[0158], claim 1). The neutral, alkylene glycol-containing amino acid (AA3 of Madsen et al) can be in a range of (p =2-30), preferably in the range of 2-10 (e.g., para. [0122]). Preferred AA3 structures include OEG having the structure of -HN-(CH2)2-O-(CH2)2-CO- (paras. [0022], [0134]-[0137], Ex 2).
Regarding claims 8 and 9, the acyl moiety is linked to an ε amino group of the lysine residue of lysine (e.g., paras. [0039], [0050], Ex 2, claim 1). Regarding claim 16, the compositions the pH is about 6.5-8.5 (para. [0065]-[0067]). Regarding claim 17, the pharmaceutical compositions can include glycerol, phenol, m-cresol, NaCl and/or Na2HPO4 (e.g., paras. [0065], [0073], [0090]-[0093]). Regarding claim 19, as set forth above, a pharmaceutical composition comprising an insulin derivative of B29K(N(ε)-docosanedioyl-γGlu-5-9xOEG), desB30 human insulin, or B29K(N(ε)-eicosanedioyl-γGlu-5-9xOEG), desB30 human insulin is obvious in view of the teachings of Madsen et al.
Regarding claims 31-34, the pharmaceutical composition can include a mixture of an acylated insulin and a rapid acting insulin analogue selected from the group consisting of AspB28 human insulin; LysB28 ProB29 human insulin and LysB3 GIuB29 human insulin, in a ratio of about 70/30 or about 50/50 (paras. [0051]-[0059]).
Accordingly, claims 4, 6-9, 12, 15-17, 19, 31-34, 55-62, 65-68, 71 and 72 are rendered obvious in view of the teachings of Madsen et al.
Response to Arguments
Applicant traversed the rejection at pp. 16-22 of the reply filed 4/06/2026. Applicant asserts that Madsen discloses a broad genus of insulin derivatives covering “an overwhelmingly large number of options”, e.g. p is 2-30, and fatty acid or fatty diacid comprising 8-24 carbon atoms (p. 17). Applicant asserts that Madsen only exemplified 10 insulin derivatives containing 16, 17, or 20 carbon atoms and 2-4 OEGs, but not the fatty diacid containing 20-26 carbon atoms, or OEG repeated 5-9 times, as instantly claimed. Id. Applicant asserts that Madsen does not provide a finite number of identified, predictable solutions and a motivation/reason for one of ordinary skill in the art to try them to arrive at the presently claimed invention (reply at p. 17).
Applicant asserts unexpected results over the prior art, including compounds of Madsen (reply at pp. 17-22). Applicant asserts that the instantly claimed insulin derivatives combine a certain length (5-9) of neutral and alkylene glycol-containing amino acid residues (OEGs) with a certain length fatty diacid (20-26 carbon atoms) (pp. 17-18). Applicant asserts claimed compound 2 (C20-6xOEG) has improved binding to the insulin receptor in the presence of albumin, as compared to (C20-2xOEG) (Example 2 of Madsen) (reply at p. 18). Applicant asserts that the claimed insulin derivatives [comprising 6OEG] have improved drug effect while maintaining an equivalent or longer duration of action (pp. 18-20). Applicant asserts that the combination of a linker containing 5-9 neutral and alkylene glycol -containing amino acid residues with a specific length of albumin binding moiety (20-26 carbon atoms) [e.g., C20-6xOEG vs C18-2xOEG and C18-6xOEG] had improved hypoglycemic effects (referring to Figs 4a/b and 5a/b). Applicant further referenced Figs 6a/b for the assertion of similar data relating to C22-6xOEG and C22-8xOEG (pp. 21-22).
Examiner has reviewed and considered applicants arguments, but is not persuaded.
With regard to Applicant’s argument referring to a “finite number of predictable solutions”, it is the Examiner’s understanding that Applicant refers to a rationale under MPEP § 2143(I)(E). Examiner did not rely upon the rationale at MPEP § 2143(I)(E), but instead relied upon the exemplary rationales of MPEP §§ 2143(I)(A), (B), and (G) to support a determination of obviousness. Applicant does not address, acknowledge or specifically identify any elements of MPEP §§ 2143(I)(A), (B), and (G) that were not satisfied and addressed on the merits. Accordingly, the rationales of MPEP §§ 2143(I)(A), (B), and (G) are maintained as set forth above.
MPEP § 2143.02(I)-(III) discusses the level of predictability and guidance required to establish a “reasonable expectation of success” sufficient to establish obviousness. As explained at MPEP § 2143.02(II), “Obviousness does not require absolute predictability”, but rather only “at least some degree of predictability”. Here, the predicted and expected applications of the Madsen structures is expressly identified (see, e.g., Madsen at paras. [0051]-[0061], reasonably informing artisans that the disclosed acylated insulins may be predictably utilized in pharmaceutical formulations suitable for use in methods of treating subjects with type 1 and type 2 diabetes). This is pertinent 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)), and the burden is on the Applicant to rebut operability and enablement (see, e.g., MPEP § 2121(I)) commensurate in scope with the requirements of MPEP §§ 716.05 or 716.07. To date, zero evidence of inoperability (MPEP § 716.07) or skepticism of experts (MPEP § 716.05) has been placed on record. Accordingly, because the prior art is presumed fully enabled and no evidence to the contrary exists, then there is a reasonable expectation that the disclosed embodiments of Madsen can be predictably and successfully utilized exactly as disclosed for the exact purpose taught and disclosed by the prior art, e.g., utility in treating diabetes.
It is the Examiner’s understanding that Applicant is alleging that the prior art renders additional species and embodiments obvious (see, e.g., reply at p 17, alleging that the genus of Madsen is broad). The fact that the prior art anticipates and renders obvious additional species and subgenera, which are not currently at issue, does not render the relevant disclosures concerning the instantly claimed invention non-existent (see, e.g., MPEP §§ 2123(I)-(II), explaining that patents are relevant as prior art for all they contain, including nonpreferred and alternative embodiments). If Applicant is suggesting that the disclosure of Madsen “teaches away” from the claimed invention in view of the disclosure of additional compounds and subgenera, this is not persuasive per MPEP § 2123(II), which explicitly notes that disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (see, e.g., MPEP §§ 2123(II)). Furthermore, the Court has stated that
"[W]hen a patent 'simply arranges old elements with each performing the same function it had been known to perform' and yields no more than one would expect from such an arrangement, the combination is obvious."
KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398 , 417 , 127 S. Ct. 1727 , 167 L. Ed. 2d 705 (2007) (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273 , 282 , 96 S. Ct. 1532 , 47 L. Ed. 2d 784 (1976)).
Likewise, the Supreme Court has rejected rigid tests for obviousness and has emphasized that
[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.”
KSR Int’l v. Teleflex Inc., 550 U.S. 398, 415 (2007), at 416.
And has also emphasized that
“If a person of ordinary skill can implement a predictable variation, § 103 likely bars its patentability.”
KSR Int'l v. Teleflex Inc., 550 U.S. 398, 415 (2007), at 417.
Here, as explained in the rejection above, all elements of the invention are prior art elements, and the prior art literally and explicitly teaches how to arrange such prior art elements to form compounds within the instant claim scope, wherein such compounds merely perform the exact applications taught and disclosed by the prior art.
It is the Examiner’s understanding that Applicant is alleging that the prior art is limited to exemplified embodiments (see, e.g., Reply at p17, alleging that Madsen only discloses species that 16, 17, 18, or 20 carbons, and 2 to 4 OEGs). As explained in the rejection, Madsen explicitly identifies that the OEG portion may be preferably repeated 2-10 times, and therefore Applicant’s basis is factually incorrect. Accordingly, it is presumed that Applicant is alleging that prior art is limited to only disclosed and exemplified embodiments (see id); this is incorrect because 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, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments (see, e.g., MPEP §§ 2123(II)).
Regarding Applicant’s assertions of unexpected results, the weight attached to evidence of secondary considerations by the examiner will depend upon its relevance to the issue of obviousness and the amount and nature of the evidence. Note the great reliance apparently placed on this type of evidence by the Supreme Court in upholding the patent in United States v. Adams, 383 U.S. 39,148 USPQ 479 (1966). To be given substantial weight in the determination of obviousness or nonobviousness, evidence of secondary considerations must be relevant to the subject matter as claimed, and therefore the examiner must determine whether there is a nexus between the merits of the claimed invention and the evidence of secondary considerations. Ashland Oil, Inc. v. Delta Resins & Refractories, Inc., 776 F.2d 281, 305 n.42, 227 USPQ 657, 673-674 n. 42 (Fed. Cir. 1985), cert. denied, 475 U.S. 1017 (1986). The term “nexus” designates a factually and legally sufficient connection between the objective evidence of nonobviousness and the claimed invention so that the evidence is of probative value in the determination of nonobviousness. Demaco Corp. v. F. Von Langsdorff Licensing Ltd., 851 F.2d 1387, 7 USPQ2d 1222 (Fed. Cir.), cert. denied, 488 U.S. 956 (1988). See M.P.E.P. § 716.01(b).
The scope of the showing must be commensurate with the scope of claims to consider evidence probative of unexpected results. See, for example, In re Dill, 202 USPQ 805 (CCPA, 1979), In re Lindner 173 USPQ 356 (CCPA 1972), In re Hyson, 172 USPQ 399 (CCPA 1972), In re Boesch, 205 USPQ 215, (CCPA 1980), In re Grasselli, 218 USPQ 769 (Fed. Cir. 1983), and In re Clemens, 206 USPQ 289 (CCPA 1980). In this case, the probative value of the data provided by applicant is not commensurate in scope with the degree of protection sought by the claim.
The results are limited to compounds 1-5 each having the same insulin sequence, either C20 or C22, and one of and 5, 6, or 8 OEG. The results are not commensurate in scope with the genera and subgenera recited in the instant claims as required by MPEP § 716.02(b)(I)-(II), and 716.02(d).
Even if applicant did properly establish unexpected results, recent caselaw reiterated the principle from Newell Cos. v. Kenny Mfg. Co., 9 USPQ2d 1417, 1426 (Fed. Cir. 1988) that the mere presence of secondary considerations does not necessarily overcome a strong case of obviousness. See Pfizer Inc. v. Apotex Inc., 82 U.S.P.Q.2d 1321, 1338-39 (Fed. Cir. 2007) (quoting In re Chupp, 816 F.2d 643, 646 (Fed. Cir. 1987)). Secondary considerations are only one factor in determining obviousness. The cited art establishes the claimed acylated insulins, comprising 2-10 OEG, and 20 or 22 carbons. The claimed acylated insulins reduced to practice are deemed to be obvious to the skilled artisan, for the reasons set forth in the above 103 rejection. Additionally, per MPEP § 716.02(c)(II), “Expected beneficial results are evidence of expected results are evidence of obviousness”, and here the claimed embodiments appear to have the exact applications taught and disclosed by the prior art (i.e., treatment of diabetes), which weighs in favor of a determination of obviousness.
Accordingly, the proffered evidence fails to establish unexpected results commensurate in scope with the requirements of MPEP § 716.02. Upon weighing the data of record per MPEP § 716.02(c)(I)-(II), the proffered data is insufficient to outweigh the evidence of obviousness.
Therefore, the rejection is maintained for the reasons set forth herein.
Claim(s) 4, 6-9, 12, 15-23, 31-36, 55-62, 65-68, 71 and 72 remain/are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 2011/0098439 (Madsen et al- previously cited), as applied to claims 4, 6-9, 12, 15-17, 19, 31-34, 55-62, 65-68, 71 and 72 above, and further in view of Madsen et al (20110105720- previously cited, hereinafter referred to as “US’720”). The rejection is maintained from the office action mailed 1/05/2026, but has been amended to reflect claims filed 4/06/2026.
The teachings of Madsen et al are set forth above. Madsen et al taught pharmaceutical compositions comprising insulin derivatives and excipients, e.g., glycerol, phenol, m-cresol, NaCl and/or Na2HPO4 (e.g., paras. [0065], [0073], [0090]-[0093]). However, Madsen et al do not expressly teach concentrations of the recited excipients.
US’720 teaches acylated insulin analogues of desB30 human insulin comprising point mutations at B25H and A14E or A14H (abstract, claim 5). The acylated moieties comprised Acy-AA10-3-AA20-10-AA31-10-(I), Acy is a fatty acid or a fatty diacid comprising from about 8 to about 24 carbon atoms; AA1 is a neutral linear or cyclic amino acid residue; AA2 is an acidic amino acid residue; AA3 is a neutral, alkylene glycol-containing amino acid residue and I is the protease stabilized insulin; where the order by which AA1, AA2 and AA3 appears in the formula can be interchanged independently; AA2 can occur several times in the formula as the same or different acidic amino acid residues; the connections between Acy, AA1, AA2 and AA3 are amide bonds which; and attachment to the protease stabilized insulin can be from the C-terminal end of a AA1, AA2, or AA3 residue in the formula (I) or from one of the side chain(s) of an AA2 residue present formula (I) (claim 6). Fatty acids include both eicosanedioyl (20 carbons) and docosanedioyl (22 carbons) (see, e.g., paras. [0167], [0377], [0674], claims 6 and 8). US’720 taught OEG as AA3 (e.g., paras [0056]-[0058], [0167], [0375]-[0394]). US’720 teaches pharmaceutical compositions comprising the acylated insulin derivatives (e.g., paras. [0172]-[0327], claims 13-15). The pharmaceutical compositions comprise zinc ions, phenol, cresol, sodium chloride, glycerol, or NA2HPO4 (e.g., paras. [0080], [0091]). The zinc content of the present formulations may be between 0 and about 6 zinc atoms per 6 molecules of insulin. The pH value of the pharmaceutical preparation may be between about 4 and about 8.5, between about 4 and about 5 or between about 6.5 and about 7.5 (para. [0080]). Glycerol can be included at a concentration of 1-50% w/w, for example, 5-40% w/w, for example, 5-30% w/w. Alternatively, the organic polar solvent is present in an amount of 10-30% w/w, for example, 10-25% w/w, for example, in an amount of about 20% w/w or about 15% w/w (e.g., paras. [0242]-[0252]). Preservatives include phenol and m-cresol, or a combination thereof in a concentration of about 0.1 mg/ml to 20 mg/ml (e.g., para.[0186]-[0188], [0287). Sodium chloride can be included as an isotonic agent in a concentration of 1-50 mg/ml (e.g., para [0187]-[0188]). US’720 teaches the use of a preservative and isotonic agents in pharmaceutical compositions are well-known to the skilled person. For convenience reference is made to Remington: The Science and Practice of Pharmacy, 19th edition, 1995 (para. [0186]-[0187]). Buffers include sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate (e.g., para. [0186]-[0189], [0286], Ex 179 teaches 0.1 M). Acylated insulin can be included at about 1-500 mg/ml solution (par [0183]). Acylated protease stabilized insulin may be present in an amount up to about 40% such as up to about 20% by weight of the composition, or from about 0.01% such as from about 0.1%, alternatively, from about 0.01% to about 20%, alternatively, from about 1% to 20% or from about 1% to 10% by weight of the composition, from 0.1% w/w to 30% w/w. (para. [0314]-[0315]). A unit dosage will suitably contain from 0.1 mg to 300 mg acylated protease stabilized insulin polypeptide, e.g., about 0.1 mg, 1 mg, 5 mg, 10 mg, 15 mg, 25 mg, 50 mg, 100 mg, 200 mg, 250 mg, 300 mg, e.g., between 5 mg and 300 mg of the acylated protease stabilized insulin. For example, each unit dosage contains between 10 mg and 300 mg, for example 10 mg and 100 mg or between 20 mg and 300 mg, for example, between 20 mg and 100 mg of the acylated protease stabilized insulin (para. [0316]).
One of ordinary skill in the art would have been motivated to adjust the concentration of components within pharmaceutical compositions comprising the acylated insulin derivatives. Both Madsen et al and US’720 taught acylated insulin comprising the same acidic amino acid residues, fatty acids or diacids, and OEG (instant variables I-III), as well as inclusion of recited excipients, e.g., glycerol, phenol, m-cresol, NaCl and/or Na2HPO4. US’720 further taught specific concentrations of the excipients. The optimization of result effective parameters (e.g., excipient concentrations) is obvious as being within the skill of the artisan. US’720 further teaches that the claimed excipients are well known in pharmaceutical compositions, referring to Remington. The optimization of known effective amounts of known active agents to be administered, is considered well in the competence level of an ordinary skilled artisan in pharmaceutical science, involving merely routine skill in the art. It has been held that it is within the skill in the art to select optimal parameters, such as amounts of ingredients, in a composition in order to achieve a beneficial effect. See In re Boesch, 205 USPQ 215 (CCPA 1980). It is also noted that "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Accordingly, claims 18, 20-23, and 34-36 are rendered obvious.
Claims 4, 6-9, 12, 15-23, 31-36, 55-62, 65-68, 71 and 72 are obvious in view of the teachings of the citied references.
Response to Arguments
Applicant traversed the rejection at pp. 16-22 of the reply filed 4/06/2026. Applicant further stated US’720, does not teach or suggest that the combinations of the linker having 5-9 neutral and alkylene glycol-containing amino acid residues and albumin binding residues of a specific length or a specific number of carbon atoms (20-26 carbons) can achieve the technical effects of the presently claimed compounds (reply at p. 17).
Please refer to examiners counter-arguments und the 103 rejection above which are incorporated herein.
Therefore, the rejection is maintained for the reasons set forth herein.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 4, 6-9, and 12 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 66-74 of copending Application No. 17758108 hereinafter referred to as “the ‘108 application”). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons. The rejection is maintained from the office action mailed 1/05/2026, but has been amended to reflect claims filed 4/06/2026 and claims filed 5/22/2026 in the ‘108 application.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 4, claim 66 of the ‘108 application recites an insulin derivative, wherein the insulin derivative is A14E, B16H, B25H, B29K(N(ε)-eicosanedioyl-yGlu-6xOEG), desB30 human insulin; or A14E, B16H, B25H, B29K(N(ε)-docosanedioyl-yGlu-6xOEG), desB30 human insulin, wherein are embodiments of claim 4. Claims 67, 68, 72, and 73 recite specific desB30 insulin derivatives.
Regarding claim 6, claims 66, 67, and 72 of the ‘108 application recite n1 is 6-9, m is 1-6, and the fatty diacid contains 20-23 carbon atoms.
Regarding claim 7, claim 66 of the ‘108 application recites compounds comprising OEG as variable I.
Regarding claims 8-9, claims 66, 67, and 72 of the ‘108 recite that the acyl moiety is linked to an ε amino group of lysine in the C-terminus.
Regarding claim 12, claim 66 of the ‘108 application recites an insulin derivative, wherein the insulin derivative is B29K(N(ε)-eicosanedioyl-yGlu-6xOEG), desB30 human insulin; and B29K(N(ε)-docosanedioyl-yGlu-6xOEG), desB30 human insulin. Claims 67, 68, 72, and 73 recite specific desB30 insulin derivatives.
Accordingly, claims 4, 6-9, and 12 are anticipated by the claims of the ‘108 application.
Response to Arguments
Applicant requests that the rejection be held in abeyance at p. 22 of the reply filed 4/06/2026.
While a request may be made that objections or requirements as to form not necessary to further consideration of the claims be held in abeyance until allowable subject matter is indicated, the present is a rejection and will not be held in abeyance (see MPEP 714.02). Until a proper Terminal Disclaimer is filed and approved by the Office, the rejection is maintained.
Claims 4, 6-9, and 15-18 remain/are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 and 24 of copending Application No. 18/571461 hereinafter referred to as “the ‘461 application”). Although the claims at issue are not identical, they are not patentably distinct from each other for the following reasons. The rejection is maintained from the office action mailed 1/05/2026, but has been amended to reflect claims filed 4/06/2026.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claims 4 and 15-18, claim 1 of the ‘461 application recites a pharmaceutical composition, comprising: an acylated insulin; 2.3 moles of zinc ions/6 moles of the acylated insulin; 45 mM-65 mM phenol; 0-10 mM m-cresol; 10 mM-20 mM NaCl; 1.5% (weight/weight) glycerol; and 5 mM-10 mM Na2HPO4, wherein, the insulin parent of the acylated insulin is A14E, B16H, B25H, desB30 human insulin or A14E, B16E, B25H, desB30 human insulin, and an acyl moiety of the acylated insulin is linked to an amino group of a lysine residue or an N-terminal amino acid residue of the insulin parent, and the acyl moiety is shown as formula (D):
PNG
media_image1.png
261
628
media_image1.png
Greyscale
Thus, Formula D recites the same limitations of instant formula A. Examiner notes that instant variable III encompasses fatty acids and fatty diacids of 20-26 carbons, whereas W1 encompasses a fatty diacid of C20-24. Claim 6 recites further embodiments of instant claim 4. Claims 6 recite specific desB30 insulin derivatives wherein W2 (instant II) in γGlu. Claims 7-9 further recites specific formulations.
Regarding claim 6, claim 2 of the ‘461 application recites n is 5-9, m is 1-6, and/or the fatty diacid contains 20-23 carbon atoms.
Regarding claim 7, claim 3 of the ‘461 application recites the same compounds for the W3 variable as instant variable I [neutral and alkylene glycol-containing amino acid residue], and/or W2 is a recited acidic amino acid residue.
Regarding claims 8-9, claims 4-5 of the ‘461 application recite the same claim limitations. W3 of the ‘461 application is the same as variable I.
Accordingly, claims 4, 6-9, and 15-18 are anticipated by the claims of the ‘461 application.
Response to Arguments
Applicant requests that the rejection be withdrawn in view of the filing date. Applicant refers to MPEP 1490(VI)(D)(2)(a) for the assertion that a later filed co-pending ODP rejection should be withdrawn if the other case is otherwise allowable.
The instant application has not been allowed. The present rejection will not be held in abeyance (see MPEP 714.02). Until a proper Terminal Disclaimer is filed and approved by the Office, the rejection is maintained.
Application Nos. 17758089 (Pat No 12,576,136), 18/730552, and 19/568449 have been reviewed and considered. The instant claims recite n is 5-9. This is higher than the n variable recited in Application No. 18/730552. Application No. 17758089 recites insulin parent [A14E, B16H, B25H desB30 human insulin] and an acyl moiety of formula D, wherein n2 is 11- 18. Application 19/568449 recite acylated insulin wherein n is equal to or greater than 11.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
U.S. Patent No. 87226200 -previously cited- pertains to acylated insulin analogues, wherein the acyl moiety can vary in length from at least 6-32 carbons (see, e.g., US’742 at title, abs, claims).
U.S. 2014/0228285 -previously cited- pertains to double acylated insulin analogues (see, e.g., US’285 at title, abs, claims).
U.S. 2017/0008945A1-previously cited- pertains to insulins modified with acyl moieties (see, e.g., US’945 at title, abs, claims).
U.S. 2018/0000742A1 -previously cited- pertains to acylated insulin analogues (see, e.g., US’742 at title, abs, claims 1, 9-10, 15-16), including insulin analogues conjugated to docosanedioyl moieties (see id. at paras. 0375]-[0376], [1235]-[1236]).
U.S. 2018/0305431 A1 -previously cited- pertains to acylated derivatives of insulin analogues, wherein insulin analogues are conjugated to acyl moieties via γGlu and OEG linkers, including 10xOEG linkers (see, e.g., US’431 at title, abs, claims 1, 24, 27-32, and 34).
WO2017/032798A1-previously cited- pertains to acylated derivatives of insulin analogues, wherein insulin analogues are conjugated to acyl moieties via γGlu and OEG linkers (WO’798 at title, abs, claim 1-34).
Conclusion
No claims are allowed.
Claims 4, 6-9, 12, 15-23, 31-36, 44, and 55-73 are pending. Claims 44, 63, 64, 69, 70, and 73 are withdrawn.
Claims 4, 6-9, 12, 15-23, 31-36, 55-62, 65-68, 71 and 72 are rejected.
THIS ACTION IS MADE FINAL. 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 KRISTINA M HELLMAN whose telephone number is (571)272-2836. The examiner can normally be reached M-F 9:00 am-5:30 pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, LIANKO GARYU can be reached at 571-270-7367. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KRISTINA M HELLMAN/ Examiner, Art Unit 1654
/JULIE HA/ Primary Examiner, Art Unit 1654
Prosecution Insights