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 .
Detailed Action
Claims 1-18 are pending in the instant application.
Election/Restrictions
Applicant elected with traverse Group 2 (claims 5-11) drawn to an acylated insulin compound and with traverse COOH(CH3)18CO-L-Lys-CO(CH2)2CO-(OEG)2 as the side chain and human insulin analogue A14E, B16H, B25H, B29K and desB30 human insulin in the response filed June 2, 2026.
Applicants argue that Liu does not break unity and Liu discloses an acylated modifying group attached to human insulin. Applicant argues that analogue does not comprise OEG. Applicants arguments have been fully considered but not found persuasive. The Examiner agrees that the analogue of Liu does not teach OEG. However, the technical feature between Group 1 and Groups 2-4 are the side chain and not an acylated compound. Nevertheless, Madsen in view of Madsen* and Hamley teaches the side chain and thus breaks unity between inventions 1 and 2-4 (see rejection below, given BRI, R can any leaving group). Furthermore, regarding inventions 2-4, Madsen in view of Madsen* and Hamley teaches the acylated insulin compound of the instant claims (see rejection below) and thus, unity of invention is broken for inventions 2-4.
The restriction is deemed proper and is made FINAL in this office action. Claims 1-4, 14-15, 18 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected
invention/species, there being no allowable generic or linking claim.
Claims 5-11 are examined on the merits of this office action.
Claim Objection
Claim 6 is objected to for the following informality: the limitation “structures” should be replaced with -structure-.
Claim 7 is objected to for the following informality: the limitations of “SEQ ID NO.1”, “SEQ ID NO.2” and “SEQ ID. NO.3” should be replaced with -SEQ ID NO:1-, -SEQ ID NO:2- and -SEQ ID: NO.3-.
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 5-11 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.
Regarding claim 5, the phrase "preferably" in lines 12, 15, 17 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). Claims 6-11 are also rejected due to their dependence on claim 5 and not further clarifying this point of confusion.
Claim 5 additionally claims “the linking groups between W, X, Y and Z..” however, this lacks antecedent basis as there is no earlier mention of linking groups. A suggested amendment would be -W, X, Y and Z are linked via amide bonds or peptide bonds”.
Regarding claim 6, the phrase "preferably" in line 6 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Regarding claim 9, the phrase "preferably" on page 13 and “more preferably” on page 14 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 5-11 are rejected under 35 U.S.C. 103 as being unpatentable over Madsen (WO2009115469 A1,cited in Applicant’s IDS) in view of Madsen* (US20090306337) and Hamley (Biomacromolecules 2014, 15, 5, 1543-1559).
*Please note that Claim 5 depends from non-elected claim 1 and is directed to the insulin conjugate produced by acylation of the side-chain compound of claim 1 with a human insulin analog. Although claim 5 incorporates claim 1 by dependency, claim 5 does not claim the side-chain compound of claim 1 per se. Rather, claim 5 recites the resulting insulin conjugate of Formula II, wherein the terminal group R of the side-chain compound has been replaced by the human insulin analog (M) through the recited acylation reaction. Accordingly, the incorporated limitations of claim 1 are considered only to the extent that they define the side-chain structure present in the final insulin conjugate. The recitation “obtained by an acylation reaction” merely describes the preparation of the claimed conjugate and does not distinguish the claimed product from an identical product prepared by another method. Therefore, claim 5 is evaluated based on the structural limitations of the resulting insulin conjugate.
Madsen teaches protease stabilize, long acting acylated insulin analogs tailored for subcutaneous delivery (see claim 1, page 6, first line). Madsen teaches modifying human insulin by introducing amino acid substitutions at position A14 (A14E), B25H combined with deletion of the amino acid at position B30 (desB30) to yield an enzymatic degradation resistant insulin (see Description, page 12, lines 1-15 and specific examples). Madsen teaches conjugation of a lipophilic side chain the epsilon amino group of the B29 lysine residue through an amide bond (see page 14, lines 1-10) and teaches fatty diacids of the formula -CO(CH2)nCOOH, including carbon chain lengths encompassing the claimed range (see claims 1-4, description, page 22). Madsen specifically teaches the A14E, B16E, B25H, desB30 human insulin (see page 20, lines 17-18) as the stabilized insulin analog. Furthermore, Madsen specifically teaches A14E, B25H, B29K (Nε-octadecanedioyl-yGlu-OEG-OEG),desB30 human insulin, thereby teaching attachment of a long chain fatty diacid through y-glutamic acid and an OEG-OEG spacer to the B29lysine residue. Madsen teaches that fatty diacids including octadecanedioic acid and eicosanedioic acid as suitable albumin binding fatty acid moieties (see page 6, lines 18-22). Regarding claim 7, Madsen teaches wherein the A-chain is SEQ ID NO:1 (see SEQ ID NO8) and the B-chain is SEQ ID NO:2 (see SEQ ID NO:17).
Madsen is silent to the specific Lys-CO(CH2)2CO-linker sequence to bridge the insulin to the diacid.
Madsen* teaches PEGylated insulin analogs in which a polyethylene glycol (PEG) moiety is attached to an insulin molecule through a chemical linker. Madsen* teaches that the term “linker” refers to the chemical moiety connecting the amino group of the insulin to the oxygen atom of the PEG moiety (paragraph 34). Madsen* further teaches that PEGylation may be accomplished by acylation of the α-amino group or the ε-amino group of a lysine residue using activated esters to form amide linkages (paragraph 38). Madsen* additionally teaches that the linker is preferably a derivative of a carboxylic acid and identifies representative linker groups including acetic acid (–CH₂CO–), propionic acid (–CH₂CH₂CO–), butyric acid (–CH₂CH₂CH₂CO–), or alternatively a carbonyl (–CO–) group (paragraphs 56–57). Thus, Madsen* teaches carbonyl-containing alkylene linkers attached to lysine through amide bond formation. These linker moieties fall within the claimed genus of Y = –A(CH₂)mB–, wherein A and/or B may be absent or carbonyl groups (–CO–), because the disclosed acetyl, propionyl, butyryl, and carbonyl linkers correspond to embodiments in which Y comprises carbonyl-containing alkylene spacers. Madsen* further teaches that PEG is a polymer composed of repeating ethylene glycol (ethylene oxide) units (paragraphs 35–37). Accordingly, one of ordinary skill in the art would have understood that an oligo(ethylene glycol) (OEG) spacer is merely a shorter ethylene glycol chain within the same class of ethylene glycol-based linkers, and that substitution of a PEG chain with an OEG chain represents routine optimization of linker length while employing the same conjugation chemistry.
Hamley (Section 2.1.1, Coupling Chemistries) teaches that amine groups located at the N-terminus or on lysine side chains are common attachment sites for PEGylation of peptides and proteins. Hamley further teaches that PEG conjugation is routinely accomplished using N-hydroxysuccinimide (NHS) esters, which react with lysine amino groups to form amide linkages. Hamley additionally explains that succinylated PEG reagents are conventional coupling reagents and that the carboxyl group of succinylated PEG has been coupled to peptides using carbodiimide-mediated amide bond formation (Section 2.1.1). A person of ordinary skill in the art would recognize that a succinyl group inherently possesses the structure –CO(CH₂)₂CO–, corresponding to an embodiment of the claimed spacer Y wherein A = CO, B = CO, and m = 2.
It would have been obvious to one of ordinary skill in the art before the effective filing date to employ the lysine-directed PEG/OEG conjugation chemistry taught by Madsen* and Hamley in the insulin analogs of Madsen in place of the yGlu-OEG. Madsen* teaches attachment of ethylene glycol-containing polymers to lysine residues through carboxylic acid-derived linkers and further teaches that the precise linker chemistry is a routine design variable, identifying several representative carboxylic acid-derived linkers and explaining that different linker groups are interchangeable and do not materially affect the biological properties of the PEGylated insulin (paragraph 0083). Hamley corroborates that lysine PEGylation using activated succinylated PEG reagents and NHS ester chemistry was conventional and routinely employed for peptide conjugation. Accordingly, one of ordinary skill in the art would have been motivated to employ a carbonyl-containing alkylene spacer, including a succinyl spacer, to attach an OEG-containing moiety to a lysine with a reasonable expectation of success, as such linker selection merely represents routine optimization from a finite number of known carboxylic acid-derived linker structures.
Regarding claim 6, Madsen in view of Madsen* and Hamley teach the acylated insulin analogue of claim 6 comprising a fatty diacid attached through an amino acid/succinyl linker to an OEG moiety and insulin.
Regarding claim 7, Madsen teaches conjugation of the insulin analog through the epsilon amino group of the B29 lysine residue via an amide bond (see page 6 of Madsen, lines 18-22).
Regarding claims 8-10, Madsen expressly teaches human insulin analogs comprising A14E, B16E or B16H, B25H, desB30, conjugated through LysB29 to octadecanedioic acid (C18) through an amino acid linker and OEG (see above teachings). The combination of Madsen, Madsen* and Hamley render obvious the Lys-succinyl spacer linked to the OEG moiety in the insulin analogue of Madsen (see above rejection). Selection of the disclosed carbon chain lengths (n=14-20), linker lengths (m=1-6), OEG length (p=2) and L or D lysine represents routine optimization of known results effective variables and would have been obvious absent evidence that any particular value is critical.
Regarding claim 11, Madsen teaches pharmaceutical formulations comprising the acylated insulin analog (see claim 11).
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERINNE R DABKOWSKI whose telephone number is (571)272-1829. The examiner can normally be reached Monday-Friday 7:30-5:30 Est.
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.
/ERINNE R DABKOWSKI/ Primary Examiner, Art Unit 1654
Prosecution Insights