DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 7/20/2026 has been entered.
Objections/Rejections Withdrawn
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied, and constitute the complete set presently being applied to the instant application.
Response to Arguments
Applicant’s arguments, see Pg 6, filed 7/20/2026, with respect to the claim rejections under 35 U.S.C. 102 have been fully considered and are persuasive. The rejections have been withdrawn in view of the amended claims.
Applicant's arguments, see Pg 6-7, filed 7/20/2026, with respect to the claim rejections under 35 U.S.C. 103 have been fully considered but they are not persuasive.
Regarding claims 1 and 23-25, Applicant’s position is that there is no teaching or suggestion to substitute position 14 of the A chain of insulin to a glutamate in a non-wild-type amino acid. However, Weiss and Pokorski teach that single chain insulin analogues, including ones comprising a fourth disulfide bridge, may be combined with at least one additional stabilizing modification at position A8, A14, B24, or B29 ([0017]); one such stabilizing modification at position A14 can be a non-beta-branched acidic or polar side chain amino acid ([0008, 0027]). Acidic amino acids include aspartic acid and glutamic acid ([0028]). Thus, the teachings of Weiss and Pokorski still apply.
Regarding claims 4 and 7-9, Applicant’s position is that 1) the instantly claimed peptides show unexpected results in terms of activation of the insulin receptor and 2) the addition of Ala residues to the C-domain connecting polypeptide does not predict that the resulting insulin analogue would have one or more desirable properties or even be active at all.
Regarding 1), MPEP 716.02(b)(I) states that the burden is on the Applicant to establish that the results are unexpected and significant: “The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992).” In the instant application, Figures 5A, 5B, and 6 are cited in Applicant’s arguments to indicate unexpected results; however, these figures do not demonstrate any statistical significance. Thus, this requirement has not been met.
Additionally, per MPEP 716.02(C)(II), “Expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967).” In the instant case, Applicants have demonstrated single-chain insulin analogues activate the insulin receptor. However, insulin analogues are known and expected to activate the insulin receptor; consequently, these results are not unexpected.
Regarding 2), as stated in the prior Office Action, absolute predictability is not required to support a conclusion of obviousness, only some degree of predictability; see MPEP 2143.02(II), which states “Obviousness does not require absolute predictability, but at least some degree of predictability is required. Evidence showing there was no reasonable expectation of success may support a conclusion of nonobviousness. In re Rinehart, 531 F.2d 1048, 189 USPQ 143 (CCPA 1976).”.
At the time of filing, Weiss (US2018/0265560 A1) set forth that the C-domain connecting the B- and A-chains of insulin could comprise a length of 4-11 residues, wherein N-terminal residues C1 and C2 are acidic and C-terminal residues contain two basic residues such as Arg-Arg. The remaining residues between the N- and C-terminal elements, when the domain is 5-11 amino acids, contains a flexible joint; some amino acids contemplated by Weiss that could comprise this flexible join include Gly-Pro, Ser-Pro, Ala, Pro, Gly-Ser, Ser-Ser, Gly-Gly, or Ala-Ala ([0016]). The exactly linker “EEGPRR” is well-known within the art, and at only 6 residues in length, could accommodate up to 5 additional residues selected from those taught by Weiss.
Applicant cites Figure 4 and [0034] of the instant specification to support their position that one could not predict that how the addition of Ala residues to the C-domain would impact the functionality of the peptide. However, this data demonstrates how substituting each of the individual residues in the C-domain “EEGPRR” impacts the functionality of the insulin analogue, which is not the same as introducing additional alanine residues into the C-domain such that domain consists of “EEGAAAPRR”. The further examples given by the Applicant detail the importance of residues “EE”, “RR”, and “P” within the C-domain “EEGPRR”, all of which are present and maintain their relative positioning in the modified C-domains with elongated hinge regions, as taught by Weiss. As stated previously, Weiss does not contemplate removing these residues and instead contemplates the addition of Ala residues in the hinge region, which is in the middle of the sequence, thereby leaving the aforementioned critical residues intact. Moreover, one skilled in the art would recognize a region of a domain deemed to function as a “hinge region,” that could accommodate an additional 5 residues as taught by Weiss, would likely be amenable to the insertion of additional flexible amino acids, such as alanine residues.
Therefore, although not absolutely predictable, Weiss establishes a reasonable expectation of success, and the rejections had been maintained/modified herein.
Applicant's arguments, see Pg 9, filed 7/20/2026, with respect to the double patenting rejections have been fully considered but they are not persuasive. The claims of US ‘429 recite a single-chain insulin comprising a C-domain of from 6-11 amino acid residues comprising at least two acidic residues at the N-terminal side of the C-domain and at least two basic residues at the C-terminal side of the C-domain peptide, wherein the amino acids at the N-terminal side of the C-domain are the amino acids Glu-Glu; a basic amino acid residue at the position corresponding to A8 of human insulin, and an acidic amino acid residue at the position corresponding to A14 of human insulin. The instant SEQ ID NO: 10 anticipates this claim; thus, the instant application is not patentably distinct over US ‘429, and the double patenting rejection has been modified/maintained herein.
Election/Restrictions
Applicant’s election without traverse of Group I: Claims 1-9, drawn to a single-chain insulin analogue in addition to the species of SEQ ID NO: 5, wherein Xaa at position 28 is Pro, and Xaa at positions 29, 44, and 50 are all Glu in the reply filed on 5/5/25 is acknowledged.
Upon further search and examination, the elected species was broadened to include SEQ ID NO: 5, wherein Xaa at position 28 and 29 are any amino acid, and one or both are amino acids other than Pro, Xaa at position 44 is Thr, His, Ser, Glu, or Ala, and Xaa at position 50 is any amino acid; and SEQ ID NO: 6-10, along with previously elected SEQ ID NO: 5, wherein Xaa at position 28 is Pro and Xaa at positions 29, 44, and 50 are all Glu.
Claim Status
Claims 1, 4, 10, and 13 are pending. Claims 10 and 13 are currently withdrawn as non-elected inventions. Claims 1, 4, and 10 are currently amended.
Priority
The application is the 371 of PCT/US20/33493, filed 5/18/20, which claims priority to the provisional application 62/849,363, filed 5/17/19. The priority date of 5/17/19 is acknowledged.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers into the Brief Description of the Drawings, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
See Figure 1A, 1C, 4A, and 4B
Specification
The disclosure is objected to because of the following informalities: [0004], line 2, recites “increased” twice. Appropriate correction is required.
Claim Interpretation
SEQ ID NO: 10 is equivalent to the peptide of claim 1 wherein residue 44 is His; where a rejection is applied to SEQ ID NO: 10, it applies to both claims 1 and 4.
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.
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) 1 and 4 are rejected under 35 U.S.C. 103 as being unpatentable over Weiss (US2018/0265560 A1, published 9/20/2018).
Weiss teaches single-chain insulin polypeptides comprising a C-domain of 6 to 11 amino acid residues, comprising at least two acidic residues at the N-terminal side of the C-domain and at least two basic residues at the C-terminal side of the C-domain peptide, a basic amino acid residue at the position corresponding to A8 of human insulin, and an acidic amino acid residue at the position corresponding to A14 of human insulin (Abstract). The single-chain insulin analogues exhibit enhanced pharmaceutical properties, such as increased thermodynamic stability, augmented resistance to thermal fibrillation above room temperature, decreased mitogenicity, and/or altered pharmacokinetic and pharmacodynamic properties ([0003]).
Weiss teaches a single-chain insulin analogue SEQ ID NO: 8, which is the closest prior art to the instant SEQ ID NO: 10 recited in claim 4; moreover, as stated above in the Claim Interpretation section, SEQ ID NO: 10 is equivalent to the peptide of claim 1 wherein residue 44 is His.
The difference between the peptides is that SEQ ID NO: 8 of Weiss comprises a C-domain “EEGPRR” and does not include 3 Ala residues interspersed between the Gly and Pro.
However, Weiss further teaches that the C-domain 4-11 amino acids in length and consists of two elements: 1) The N-terminal element consists of the first two residues, C1, and C2, that correspond to residues B31 and B32 of an extended insulin B-chain, wherein C1 and C2 contain at least one acidic side chain and a net formal electrostatic charge at pH 7.4 of -1 or -2; and 2) the C-terminal element, which contains two basic residues such as Arg-Arg, Lys-Lys, Arg-Lys, or Lys-Arg. In the case of connecting domains of length greater than 4 (i.e., in the range 5-11), the connection domain contains a flexible joint. In the example of a six-residue connecting domain, such sequences may contain at positions C3 and C4 Gly-Pro, Ser-Pro, Ala, Pro, Gly-Ser, Ser-Ser, Gly-Gly, or Ala-Ala as well as other possibilities (Pg 3, [0016]).
Further, Weiss teaches a C-domain consisting of Y1Y2B1-5RR, wherein Y1 and Y2 can each be Glu or Asp and B1-5 are optional and may be selected from Ala, Asn, Gln, Gly, Pro, Ser, or Thr (see Pg 9, SEQ ID NO: 61 and [0039] of Weiss). A C-domain linker wherein each of Y1 and Y2 are Glu, B1 is Gly, the following 1-3 residues are Ala, and the final residue is Pro reads on the C-domains of the instant SEQ ID NO: 10.
To summarize, Weiss teaches SEQ ID NO: 8 as well as modifications to the length and composition of the C-domain, including the addition of Ala residues within the hinge region interspersed between “EEG” and “PRR” of the well-established C-domain “EEGPRR”. Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to adjust the flexible joint region in the C-domain of SEQ ID NO: 8 of Weiss by adding additional Ala residues between the critical N-terminal and C-terminal elements of the C domain as described above, thereby arriving at the instant SEQ ID NO: 10. One would be motivated to do so with a reasonable expectation of success in order to further augment the flexibility of the hinge region of the C-domain; Ala residues are well-known in the art as having inherent flexibility due to the relatively small size of their side chain, making them an ideal residue to add to the flexible joint region.
Moreover, one of ordinary skill in the art would have been motivated to try adding 1-3 Ala residues as Weiss taught that up to 5 residues could be added between the N-terminal acidic Glu-Glu and the C-terminal basic Arg-Arg sequences; further, Weiss described the intervening region between the N-terminal Glu-Glu and C-terminal Arg-Arg to be a hinge region, which could consist of amino acid sequence such as Ala-Ala. Thus, based on the C-domain length limitations, functionality, and proposed amino acid sequences, it would be obvious to try to insert Ala-Ala-Ala in between “EEG” and “PRR” of the “EEGPRR” linker. One would have a reasonable expectation of success as Weiss established that such linkers could be to improve single-chain insulin analogues as described above.
Claim(s) 1 is rejected under 35 U.S.C. 103 as being unpatentable over Weiss (US2018/0265560 A1, published 9/20/2018) in view of Weiss and Pokorski (WO 2017112952 A1, published 6/29/2017).
The teachings of Weiss have been set forth above. Weiss does not teach substituting the amino acid at position 44 for Glu as recited in claim 1.
Weiss and Pokorski teach insulin analogues containing cysteine substitutions at positions B4 and A10 (to form cystine B4-A10), and one or more additional substitutions selected from the group consisting of: a connecting domain of 5-11 amino acids between insulin A- and B domains; a non-beta-branched amino-acid substitution at position A8; a non-beta-branched acidic or polar side chain at position A14; a halogenic modification of PheB24 at the ortho position; and substitution of lysine at position B29 by Glu, Ala, Val, Ile, Leu, amino-propionic acid, amino-butyric acid, or norleucine (Abstract)
Weiss and Pokorski also teach substitutions at position A8 (equivalent to the instant residue 44 of SEQ ID NO: 5) for non-beta-branched acidic or polar side chain amino acids (Abstract; [0003, 0008]). Weiss and Pokorski indicate that non-beta-branched substitutions at position A8 protect the two-chain insulin analogues and SCIs from both physical and chemical degradation due to their more optimal properties within an alpha-helix and/or at the C-terminal position of an alpha-helix. Examples of stabilizing A8 substitutions are provided by, but not limited to, Arginine, Glutamic Acid and Histidine.
Therefore, it would be prima facie obvious to substitute the residue at position 44 for Glu. One skilled in the art would be motivated to do so in further protect the single-chain insulin analogue from physical and chemical degradation. One would have a reasonable expectation of success as Weiss and Pokorski indicated that such a substitution could be made in conjunction with or without other substitutions in the A- and B- chains to further improve the physical and chemical stability of insulin analogues.
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.
Claim 4 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 13-20 of U.S. Patent No. US 10,392,429 B2 (US ‘429). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims anticipate the composition and method claims of US ‘429.
Claims 1 and 4 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 7, 12-25, 27-33, and 46-47 of copending Application No. 19/641,283 (’283, reference application; claim set filed 6/22/2026). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims anticipate the composition and method claims of copending Application No. ‘238.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
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/SARA E KONOPELSKI SNAVELY/Examiner, Art Unit 1658 /Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
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