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 .
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Applicant cannot rely upon the certified copy of the foreign priority application to overcome prior art rejections because a translation of said application has not been made of record in accordance with 37 CFR 1.55. When an English language translation of a non-English language foreign application is required, the translation must be that of the certified copy (of the foreign application as filed) submitted together with a statement that the translation of the certified copy is accurate. See MPEP §§ 215 and 216.
The effective filing date of claims 1-8 is September 15, 2020.
Notice Regarding Cited Art
CN110551203 cited on the IDS filed 3/25/2022 and on the ISR for PCT/CN2020/115222 is not prior art. CN110551203 was published on December 10, 2019, which is within one year of the effective filing date of claims 1-8. CN110551203 lists the same inventive entity as the instant application, Shuliang Zhou, Peng Wang, and Lan Deng. Therefore, CN110551203 is a grace period inventor-originated disclosure and is disqualified as prior art under 35 U.S.C. 102(b)(1)(A).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 2 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. Claim 2 recites a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug of the exenatide analog structure I of claim 1. However, claim 1 only recites the analog and does not include a pharmaceutically acceptable salt, solvate, chelate, non-covalent complex or prodrug. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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 1-8 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8 of copending Application No. 17/763,985 in view of Yap et al. (Exendin‐4 from Heloderma suspectum venom: From discovery to its latest application as type II diabetes combatant, Basic Clin Pharmacol Toxicol. 2019;124:513–527).
This is a provisional nonstatutory double patenting rejection.
Copending claim 1 recites a GLP-1 analog having the same modifications as the exenatide analog recited in the instant claims:
1) the His-Ala at the N-terminus of the copending GLP-1 analog is replaced with AA1, wherein AA1 of structure I is
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X1 and X2 are each independently selected from the group consisting of H,CH3, CH(CH3)2, C(CH3)3, CH(CH2CH3)2, C(CH2CH3)3, CH(CH2CH2CH3)2, C(CH2CH2CH3)3, CH(CH(CH3))2, C(CH(CH3))3,CH2CH3, CH2CH(CH3)2, CH2C(CH3)3, CH2CH(CH2CH3)2, CH2C(CH2CH3)3, CH2CH(CH2CH2CH3)2, CH2C(CH2CH2CH3)3, CH2CH(CH(CH3))2, and CH2C(CH(CH3))3; and
2) AA2-AA3 is added to the C-terminus, wherein
AA2 is selected from the group consisting of Lys, Dah, Orn, Dab and Dap;
AA3 is NH2 or OH; and
R is HO2C(CH2)n1CO-(yGlu)n2-(PEGn3(CH2)n4CO)n5-, wherein n1 is an integer from 10 to 20, n2 is an integer from 1 to 5, n3 is an integer from 1 to 30, n4 is an integer from 1 to 5, and n5 is an integer from 1 to 5. However, copending Application No. 17/763,985 does not claim analogs of exendin-4.
Yap et al. teach that exendin-4, which is a venom analogue of the physiological mammalian hormone glucagon‐like peptide 1(GLP‐1), is a full agonist for the GLP‐1 receptor on the pancreatic β‐cells (Figure 1; § 2). Exendin-4 exhibits dose‐dependent glucose‐induced secretion of hormone insulin and is used clinically at the antidiabetic drug exenatide (Figure 4; § 2). Yap et al. teach that a drawback for exendin‐4 as an anti‐diabetic drug is its short biological half‐life (1‐4 hours) which necessitates twice daily subcutaneous injection and causes pain, inconvenience, and infection risk for patients (§ 6).
It would have been obvious to apply the modifications to GLP-1 claimed in copending Application No. 17/763,985 to the exendin-4 taught by Yap et al. One of ordinary skill in the art would have been motivated to do so given that Yap et al. teach that modifying the structure of exendin-4 is necessary to overcome the disadvantage of short half-life (§ 6.1). There would have been a reasonable expectation of success given that exendin-4 and GLP-1 share significant sequence and biological properties (Yap et al., Figure 1).
The resulting exendin analogue would satisfy all of the limitations of instant claim 1.
Regarding claims 2-8, claims 2-8 of copending Application No. 17/763,985 recite the same product limitations and methods, respectively.
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.
Claims 1-8 are rejected under 35 U.S.C. 103 as being unpatentable over CN106554404A (cited by Applicant) in view of Donnelly (“The structure and function of the glucagon-like peptide-1 receptor and its ligands,” Br J Pharmacol. 2012 May;166(1):27-41), Coskun et al. (“LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: From discovery to clinical proof of concept,” Molecular Metabolism 18 (2018) 3-14), Wang et al. (“Synthesis of Dehydroamino Acids and Their Applications in the Drug Research and Development,” Progress in Chemistry, 2020, 32(1): 55-71), and Siodłak (“α,β-Dehydroamino acids in naturally occurring peptides,” Amino Acids (2015) 47:1–17).
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.
CN106554404A teaches that exendin-4 (exenatide) is an effective anti‐diabetic drug that is limited by is its short biological half‐life. Exendin-4 must be administered by twice daily subcutaneous injection, which leads to an increased risk of pain, inconvenience, and infection for patients (page 1, English translation).
CN106554404A teaches an improved exendin analog having the structure:
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met- Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Cys(X-PEG-Y)-NH2 wherein X is ethyl succinimide and Y is an aliphatic hydrocarbon of length 6-20 (claim 1).
2. Ascertaining the differences between the prior art and the claims at issue.
There are two differences between exendin-4 taught by CN106554404A and the claimed exendin analogue:
1) the His-Gly at the N-terminus of exendin-4 is replaced with AA1, wherein AA1 is His-a, b-dehydro-a amino acid of the structure
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wherein X1 and X2 are each independently selected from the group consisting of H,CH3, CH(CH3)2, C(CH3)3, CH(CH2CH3)2, C(CH2CH3)3, CH(CH2CH2CH3)2, C(CH2CH2CH3)3, CH(CH(CH3))2, C(CH(CH3))3,CH2CH3, CH2CH(CH3)2, CH2C(CH3)3, CH2CH(CH2CH3)2, CH2C(CH2CH3)3, CH2CH(CH2CH2CH3)2, CH2C(CH2CH2CH3)3, CH2CH(CH(CH3))2, and CH2C(CH(CH3))3; and
2) the C-terminus is extended by AA2-AA3, wherein
AA2 is selected from the group consisting of Lys, Dah, Orn, Dab and Dap;
AA3 is NH2 or OH; and
R is HO2C(CH2)n1CO-(yGlu)n2-(PEGn3(CH2)n4CO)n5-, wherein n1 is an integer from 10 to 20, n2 is an integer from 1 to 5, n3 is an integer from 1 to 30, n4 is an integer from 1 to 5, and n5 is an integer from 1 to 5.
3. Resolving the level of ordinary skill in the pertinent art.
The structure-function of GLP-1 and its natural analogue exendin-4 have been extensively studied, as evidenced by the review by Donnelly. Donnelly report that exendin-4 is 53% identical to GLP-1 but is resistant to DPPIV cleavage, largely due to the substitution of Ala2 by Gly (Figure 1; p. 28, col. 1). Thus, the prior art recognizes that position 2 is critical for resistance to DPPIV cleavage.
It is within the ordinary skill of the art to incorporate non-coded amino acid residues such as a, b-dehydro-a amino acids, and to acylate peptides at lysine residues in order to increase biological half-life.
For example, Coskun et al. teaches that LY3298176 is a 39 amino acid linear peptide GLP-GIP dual agonist suitable for once-weekly dosing in humans. It comprises the non-coded amino acid Aib at positions 2 and 13, and a C20 fatty diacid moiety via a g-Glu-PEG linker connected to a lysine residue at position 20 to enable albumin binding (§ 3.1; Figure 1A).
Wang et al. and Siodłak teach that a, b-dehydro-a amino acids can improve the metabolic stability and bioavailablility of peptides by restricting their conformation (Wang et al. abstract, Figure page 2; Siodłak, p. 1, col. 1).
It would have been obvious to one of ordinary skill in the art to improve the exendin-4 analogue taught by CN106554404A using the techniques and information available in Donnelly, Coskun et al., Wang et al. and Siodłak (rationale in MPEP § 2143(I)(B) Simple Substitution of One Known Element for Another To Obtain Predictable Results, and MPEP § 2143(I)(C) Use of Known Technique To Improve Similar Devices (Methods, or Products) in the Same Way).
First, it would have been obvious to substitute an a, b-dehydro-a amino acid taught by Wang et al. and Siodłak for the glycine at position 2 of the exendin-4 analog taught by CN106554404A. One of ordinary skill in the art would have been motivated to do so given that Wang et al. and Siodłak teach that a, b-dehydro-a amino acids can improve the metabolic stability and bioavailablility of peptides by restricting their conformation (Wang et al. abstract, Figure page 2; Siodłak, p. 1, col. 1). There would have been a reasonable expectation of success given that Donnelly teaches that position 2 is critical for resistance to DPPIV cleavage. (Figure 1; p. 28, col. 1). The rationale to support a conclusion that the claim would have been obvious is that a method of enhancing a particular class of devices (methods, or products) has been made part of the ordinary capabilities of one skilled in the art based upon the teaching of such improvement in other situations. One of ordinary skill in the art would have been capable of applying this known method of enhancement to a "base" device (method, or product) in the prior art and the results would have been predictable to one of ordinary skill in the art.
Second, it would have been obvious to substitute the C20 fatty diacid moiety connected to a lysine residue via a g-Glu-PEG linker taught by Coskun et al. for the acylated cysteine at position 40 of the exendin-4 analog taught by CN106554404A. One of ordinary skill in the art would have been motivated to do so given that to enable albumin binding, thereby extending the half-life, as taught by Coskun et al. (§ 3.1; Figure 1A). There would have been a reasonable expectation of success given that CN106554404A show that the C-terminus of exendin-4 can be extended and acylated. The rationale to support a conclusion that the claim would have been obvious is that the substitution of one known element for another yields predictable results to one of ordinary skill in the art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
The specification presents evidence on the GLP-1R activity (Example 7) and pharmacokinetic properties (Example 8) of six compounds of Structure 1. However, the specification does not include a comparison between the claimed compounds and the closest prior art of CN106554404A. Therefore, there is insufficient evidence to establish that the claimed compounds have properties that are unexpected in view of the prior art.
Regarding claim 1, the resulting exendin-4 would have the structure:
His-( a, b-dehydro alanine or a, b-dehydro glycine)-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met- Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-Lys(AEEA2-g-Glu-C20 diacid)-NH2 satisfying all of the limitations of claim 1 wherein X1 and X2 are H or CH3, AA2 is Lys, AA3 is NH2, n1 is 20, n2 is 1, n3 is 2, n4 is 1, and n5 is 2, satisfying all of the limitations of the claim.
Regarding claim 2, CN106554404A teaches salts of the exendin-4 analog (claim 1).
Regarding claim 3, CN106554404A teaches a pharmaceutical composition of the exendin-4 analog (claim 6).
Regarding claims 4-8, CN106554404A teaches methods of treating and preventing type II diabetes, fatty liver, and weight, and regulating blood glucose in subjects in need thereof (claims 5-7).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTINA MARCHETTI BRADLEY whose telephone number is (571)272-9044. The examiner can normally be reached Monday-Friday, 7 am - 3 pm.
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/CHRISTINA BRADLEY/Primary Examiner, Art Unit 1654