DETAILED ACTION
Examiner acknowledges receipt of the reply filed 08/22/2025, in response to the restriction requirement mailed 06/23/2025.
Claims 4, 6-9, 12, 15-23, 31-36, 44, and 55-73 are pending. Claims 1-3, 10, 11, 24-29, 45, 47-52, and 54 have been cancelled. Claims 55-73 are newly added.
Claims 44, 63, 64, 69, 70, and 73 are withdrawn from further consideration for the reasons set forth below.
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).
Election/Restrictions
Applicant’s election of Group I (claims 4, 6-9, 12, 15-23, 31-36) without traverse in the reply filed on 8/22/2025 is acknowledged.
Claims 44, 63, 64, 69, 70, and 73 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/22/2025.
Examiner notes that claims 45, 47-52, and 54 (Group III) were cancelled in the amendment filed on 8/22/2025.
Applicant’s election of the following species without traverse in the reply filed on 8/22/2025 is acknowledged.
Insulin parent sequence- desB30 human insulin
Linker species: γGlu - 6xOEG, i.e., (II)m-(I)n, wherein I is -HN-(CH2)2-O-(CH2)2-O-CH2-CO- (OEG), II is γGlu, n is 6 and m is 1
Identity of albumin binding residue: a fatty diacid containing 22 carbon atoms, wherein a hydroxyl group has been removed from one of the carboxyl groups in the fatty diacid
Fully defined species of insulin derivative:
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208
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Species of acyl moiety of formula A OR A’: formula A
Identity of GLP-1 compound: moot per amendment filed 8/22/2025 (see reply filed 8/22/2025 at p. 25).
Claims 4, 6-9, 12, 15-23, 31-36, 55-62, 65-68, 71 and 72 read on the elected species.
Upon searching the elected species, an additional species was found e.g. B29K(N(ε)-docosanedioyl-γGlu-6xOEG), desB30 human insulin. Accordingly, for purposes of compact prosecution, the election of species is modified only to the extent of examining this additional species. Otherwise the election of species requirement is still retained.
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.
Sequence Compliance
This application is objected to because the peptide sequences on e.g., pages 41, 45, 49-52, 56, 59-62, 65, and 94 are not associated with a sequence identifier (a SEQ ID NO). All sequences longer than ten nucleotides or four amino acids referenced in the specification must include a SEQ ID NO and must be included in the Sequence Listing. See MPEP § 2421-2422. Applicant must amend the specification in response to this office action and must confirm that all peptide sequences of the specification are included in the sequence listing. Examiner requests that the Applicants review the specification to confirm that all of the peptides, as required, comply with MPEP § 2421-2422.
Claim Objections
Claims 4, 6, 7, 16-18, 20-23, 32, 35, 36, and 55 are objected to because of the following informalities:
Claim 4, line 12 should be amended to recite “III is a fatty acid … atoms, wherein
Claim 6 should be amended to recite “n is 5, 6, 7 or 8;
a hydroxyl group has been removed from one of the carboxyl groups in the fatty diacid; or a combination thereof.”
Claim 7, last 4 lines should be amended to recite:
-HN-(CH2)4-O-(CH2)4-O-CH2-CO-; γGlu, αGlu, βAsp, αAsp, γ-D-Glu, α-D-Glu, β-D-Asp and α-D-Asp; or a combination thereof.”
Claim 16 should be amended to recite “derivative; ; or a combination thereof.”
Claim 17 should be amended to recite “NaCl, 2HPO4; or a combination thereof.”
Claim 18 should be amended to delete multiple recitations of “and/or”, and insert at the end of the claim “or a combination thereof”.
Claim 20, line 4 should be amended to recite “sodium chloride, [[and]] about 0-15 mM m-cresol, and
Claim 21, 4 should be amended to recite “insulin derivative, [[and]] about 20 mM sodium chloride, and
Claim 22, line 4 should be amended to recite “sodium chloride, [[and]] about 0-25 mM m-cresol, and
Claim 23, lines 3-4 should be amended to recite “insulin derivative, [[and]] about 20 mM sodium chloride, about 0-10 mM m-cresol, and
Claim 32 should be amended to recite “insulins selected from the group consisting of”.
Claim 35, lines 4-5 should be amended to recite “chloride, [[and]] about 0-15 mM m-cresol, and
Claim 36, lines 4-5 should be amended to recite “chloride, [[and]] about 10-15 mM m-cresol, and
Claim 55 should be amended to recite “II is .
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).
“Acidic amino acid” is undefined on record. An acidic amino acid is presumably characterized by a negatively charged side chain at a given pH value, wherein the -COOH can donate a proton (H+) to the surrounding environment. For purposes of applying prior art, the term is understood to read upon at least γGlu, αGlu, γ-D-Glu, α-D-Glu, αAsp, βAsp, α-D-Asp, β-D-Asp (see e.g., instant claims 7, 12, 19-23, 34-36).
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 4, 6, 8, 9, 15-18, and 31-33 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 4 recites the term “acidic amino acid residue”, which is not defined on record. The term “acidic amino acid” in claim 4 is a relative term which renders the claim indefinite. The term 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. An acidic amino acid is presumably characterized by a negatively charged side chain at a given pH value, wherein the -COOH can donate a proton (H+) to the surrounding environment. However, no pH value is actually recited in the instant claims and pharmaceutical formulations need not be at physiological pH. Although Glu and Asp are acidic at physiological pH, additional amino acids such as Cysteine (Cys, pKa of sidechain is ~8.37), Tyrosine (side chain pKa of 10.46), may or may not be “acidic amino acid residues” capable of donating a proton to the surrounding environment, depending upon the pH value at issue. It is prima facie unclear what amino acids are included or excluded from the scope of instant claim 4 in the absence of clarification or a limitation pertaining to pH. For purposes of applying prior art, the term is understood to reasonably read upon at least γGlu, αGlu, γ-D-Glu, α-D-Glu, αAsp, βAsp, α-D-Asp, β-D-Asp (see e.g. instant claims 7, 12, 19-23, and 34-36).
Claims 6, 8, 9, 15-18, and 31-33 depend directly or indirectly from claim 4, but fail to address or clarify the indefiniteness of the claim upon which it depends. Accordingly, these claims are also rejected as indefinite for the reasons applied above.
Claim 6 recites two consecutive “and/or” statements, and this grammatical arrangement raises substantial and material concerns regarding what possible combinations are required or optional in the claim scope because it is prima facie unclear if subsequent “and/or” statements are nested within earlier “and/or” statements, or merely intended to provide four alternative possibilities, from which at least one must be true. Applicant should clarify the claim scope by redrafting claim 6 to remove consecutive or potentially nested “and/or” statements.
Claim 18 recites five consecutive “and/or” statements, and this grammatical arrangement raises substantial and material concerns regarding what possible combinations are required or optional in the claim scope because it is prima facie unclear if subsequent “and/or” statements are nested within earlier “and/or” statements, or merely intended to provide four alternative possibilities, from which at least one must be true. Applicant should clarify the claim scope by redrafting claim 18 to remove consecutive or potentially nested “and/or” statements.
Further regarding claim 18, the claim recites the limitation "the content”. There is insufficient antecedent basis for this limitation in the claim.
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 is/are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 2011/0098439 (Madsen et al).
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). 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, including 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). 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).
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.
Claim(s) 4, 6-9, 12, 15-23, 31-36, 55-62, 65-68, 71 and 72 is/are rejected under 35 U.S.C. 103 as being unpatentable over U.S. 2011/0098439 (Madsen et al), 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, hereinafter referred to as “US’720”).
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 stabilised 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 stabilised 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 stabilised 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 stabilised 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 stabilised 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.
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, 15-18, and 31-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 13-18, 26-30, 33, 42-44, 46, 54, and 64-69 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.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Regarding claim 4, claim 13 of the ‘108 application recites an insulin derivative comprising an insulin parent [A14E, B16H, B25H desB30 human insulin] and an acyl moiety of formula C.
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Thus, Formula C 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 Y1 encompasses a fatty diacid of C20-24. Claim 64 and 65 recite further embodiments of claim 4. Claims 18, 30, 66, 67, and 68 recite specific desB30 insulin derivatives.
Regarding claim 6, claim 14 of the ‘108 application recites n1 is 6-9, m is 1-6, and the fatty diacid contains 20-23 carbon atoms.
Regarding claim 7, claim 15 of the ‘108 application recites the same compounds for the Y3 variable as instant variable I [neutral and alkylene glycol-containing amino acid residue].
Regarding claims 8-9, claims 16-17 of the ‘108 application recite the same claim limitations. Y3 of the ‘108 application is the same as variable I.
Regarding claims 15-18, claims 26-29 of the ‘108 application recite the same pharmaceutical composition claim limitations- compounds and amounts. Claim 33 further recites specific excipients, e.g. glycerol, phenol, zinc ions, sodium chloride, m-cresol, and pH range.
Regarding claims 31-33, claims 42-44 of the ‘108 application recite the same pharmaceutical composition claim limitations- further comprising a rapid acting insulin (AspB28, desB30, etc.), and molar ratios. Claim 46 of the ‘108 application recite specific formulations.
Accordingly, claims 4, 6-9, 15-18, and 31-33 are anticipated by the claims of the ‘108 application.
Claims 4, 6-9, and 15-18 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.
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):
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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 claim 4. Claims 6 recite specific desB30 insulin derivatives. 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.
Application Nos. 17758089 and 18/730552 have been reviewed and considered.
The instant claims recite n is 5-9, which is higher than the 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.
Pertinent Prior Art
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
U.S. Patent No. 8722620 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 pertains to double acylated insulin analogues (see, e.g., US’285 at title, abs, claims).
U.S. 2017/0008945A1 pertains to insulins modified with acyl moieties (see, e.g., US’945 at title, abs, claims).
U.S. 2018/0000742A1 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 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 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.
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.
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/KRISTINA M HELLMAN/ Examiner, Art Unit 1654