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 .
Election/Restrictions
Applicant’s election without traverse of Group 3 (claims 2, and 4-7 drawn to a fusion protein comprising GLP-1 having amino acid sequence of SEQ ID NO: 2 and IL-1 having amino acid sequence of SEQ ID NO: 8) in the reply filed on 12/8/2025 is acknowledged.
The requirement is still deemed proper and is therefore made FINAL.
Status of Application, Amendments, And/Or Claims
Claims 1-13 and 17-20 are pending.
Claim 1 is withdrawn for being drawn to a non-elected invention (i.e., Group 1) and claim 3 is withdrawn for being drawn to a non-elected GLP-1 sequence of SEQ ID NO: 1.
Claims 2, 4-13, and 17-20 are under consideration to the extent they read on the elected invention.
Information Disclosure Statement
The Information Disclosure Statements (IDSs) filed on 1/9/2023, 3/6/2025 and 12/8/2025 have been considered.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Claim Objections
Claim 4 is objected to because of the following informalities: claim 4 is objected for recited amino acid sequences of non-elected GLP-1 (i.e., SEQ ID NO: 3-4). Appropriate correction is required.
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 2 and 6 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 2, the phrase "wherein the fusion protein comprises an immunoglobulin Fc region" renders the claim indefinite because it is unclear how the Fc region is arranged in relation to a closed language of the claim: a fusion protein comprising a GLP-1 or variant; and interleukin-1 receptor antagonist. See MPEP § 2173.05(d). The examiner suggests that the claim is arranged to something like: A fusion protein comprising: GLP-1 or variant thereof; an interleukin-1 receptor antagonist or fragment thereof; and an immunoglobulin Fc region.
Regarding claim 6, the phrase "variant thereof" after N’-X[linker (1)]n-Fc region fragment; or the phrase "variant thereof" after N’ -Y-[linker(1)]n-Fc region fragment renders the claim indefinite because it is unclear variant thereof is referring to X only or X and Fc; or Y only or Y and -Fc. Therefore, metes and bounds of the claim cannot be determined.
New Matter Rejection
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 18 and 20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. THIS IS A NEW MATTER REJECTION. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the claimed invention. The new claims are not described in the Specification or the Claims as originally filed.
The proscription against the introduction of new matter in a patent application (35 U.S.C. 132 and 251) serves to prevent an applicant from adding information that goes beyond the subject matter originally filed. See In re Rasmussen, 650 F.2d 1212, 1214, 211 USPQ 323, 326 (CCPA 1981). See MPEP § 2163.06 through § 2163.07 for a more detailed discussion of the written description requirement and its relationship to new matter. The claims as filed in the original specification are part of the disclosure and, therefore, if an application as originally filed contains a claim disclosing material not found in the remainder of the specification, the applicant may amend the specification to include the claimed subject matter. In re Benno, 768 F.2d 1340, 226 USPQ 683 (Fed. Cir. 1985). Thus, the written description requirement prevents an applicant from claiming subject matter that was not adequately described in the specification as filed. New or amended claims which introduce elements or limitations which are not supported by the as-filed disclosure violate the written description requirement. See, e.g., In re Lukach, 442 F.2d 967, 169 USPQ 795 (CCPA 1971) (subgenus range was not supported by generic disclosure and specific example within the subgenus range); In re Smith, 458 F.2d 1389, 1395, 173 USPQ 679, 683 (CCPA 1972) (a subgenus is not necessarily described by a genus encompassing it and a species upon which it reads). While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure. MPEP 2105.
In the instant application, there is no support in the specification, as originally filed, for the claim limitation “ fatty liver”. The specification at pages 3 and 18 discloses that GI-210B1 fusion protein dimer has ability to inhibit fat accumulation in hepatocyte caused by palmitate and oleic acid. The specification does define “ fatty liver disease” in the specification. Applicants provide two references: (i) Fabbrini et al. and (ii) Han et al, and they argue that by reading the references, one skill in the art accumulation of fat in hepatocytes can induce fatty liver. However, the rejection is under 35 USC 112-new matter because the specification does not directly or indirectly disclose or support the term “fatty liver” and its treatment. Therefore, claims 18 and 20 are rejected under 35 USC 112, first paragraph-new matter.
Claim Rejections - 35 USC § 112-written description
Claims 2, 4-13 and 17-20 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The written description in this case only sets forth a fusion protein comprising GLP-1 of amino acid sequence of SEQ ID NO: 2 and an IL-1 receptor agonist of SEQ ID NO: 8, the fusion protein further comprising an immunoglobulin Fc region (GLP-1-Fc region-IL-1 Ra, or IL-1 Ra – Fc- GLP-1, see claim 6), and therefore the written description is not commensurate in scope with the claims which read on a fusion protein comprising any variant of GLP-1 or any fragment thereof; any fragment of IL-1 receptor agonist or variant thereof; or any fragment of an Fc or variant thereof (as recited in claim 6).
The claims broadly encompass a fusion protein comprising any variant or any fragment of GLP-1, any variant or any fragment of IL-1 receptor agonist and any variant or fragment of an Fc. The claimed fusion protein is for treating or preventing a metabolic disease. However, the claims do not require that the GLP-1 variants when fused to variants of IL-1 receptor agonist and fused to an Fc variant possess any characteristic or any particular conserved structure, or other disclosed distinguishing feature. Thus, the claims are drawn to a genus of “ GLP-1 variants fused to IL-1 Ra fragments fused to an Fc or fragment thereof” for treating any metabolic disease.
The specification on pg. 23, lines 8+, describes that a “functional derivative” encompasses any derivative of leptin, analogue or fused protein which may be prepared from the functional groups, and which is substantially similar to the activity of leptin and do not confer toxic properties. Further, the specification on lines 21+, describes, “fragment” of a leptin, analogue, fused protein, or functional derivative as any fragment or precursors of the polypeptide chain alone or linked with other residues.
The specification at pg. 3 describes the structure of G1-210B1 (GLP-1 - IgG4 Fc-IL1-Ra) fusion protein. The specification at pg. 8, Table 1 disclosed 3 variants of GLP-1 but no variant of IL-1 Ra or an Fc. The specification discloses that the fusion protein GLP-1-an Fc-IL-1 Ra can be without or with a linker. The specification fails to disclose sufficient number of variants of GLP-1 or IL-1 Ra or an Fc that represents a genus of variants represented in the claimed fusion protein. To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. Some of the factual considerations that are weighed when determining a written description include the level of skill and knowledge in the art, the disclosure of complete or partial structures, the disclosure of physical and or chemical properties, adequate disclosure of the functional characteristics, the correlation between structure and function, and disclosure of methods of making.
The problem of predicting protein structure from sequence data and in turn utilizing predicted structural determinants to ascertain functional aspects of the protein is extremely complex. While it is known that many amino acid substitutions are generally possible in any given protein the positions within the protein’s sequence where such amino acid substitutions can be made with a reasonable success are limited. Certain positions in the sequence are critical to the protein’s structure/function relationship, such as various sites or regions directly involved in binding, activity and in providing the correct three-dimensional spatial orientation of binding and active sites. These regions can tolerate only relatively conservative substitutions or no substitution (see IDS, Bowie et al., 1990, Science 247: 1306-1310, page. 1306, column 2, paragraph2; IDS, Wells, 1990, Biochemistry 29:8509-8517).
The specification at pg. 3 describes the structure of G1-210B1 (GLP-1-IgG4 Fc-IL1-Ra) fusion protein and the specification at pg. 8, Table 1 discloses 3 variants of GLP-1 but no variant of IL-1 Ra or an Fc. The specification fails to disclose enough representative of GLP-1 variants, IL-1 Ra variants or an Fc region variants as being instantly claimed genus of variants. The general knowledge and level of skill in the art do not supplement the omitted description because specific, not general, guidance is what is needed.
Applicant is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112, 1 "Written Description" Requirement, Federal Register, Vol. 66, No. 4, pages 1099-1111, Friday January 5, 2001.
Vas-Cath Inc. V. Mahurka, 19 USPQ2d 1111, states that applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention, for purposes of the written description inquiry, is whatever is now claimed (see page 1117). The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (see Vas-Cath at page 1116).
A description of a genus may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California v. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California v. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B (1), the court states an adequate written description of a DNA ... requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention.
As discussed above, the skilled artisan cannot envision the detailed variants of the genus “a fusion protein comprising any variant of GLP-1, any fragment of IL-1 Ra and an Fc”, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of making a mutation. The compound itself is required. See Fiers v.Revel, 25USPQ2d 1601 at 1606 (CAFC 1993) and Amgen v.Baird, 30 Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 148 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class.
Therefore, only a fusion protein comprising GLP-1 comprising amino acid sequence of SEQ ID NO: 2, an IL-1 receptor agonist of SEQ ID NO: 8, and an immunoglobulin Fc region (e.g., GLP-1-Fc region-IL-1 Ra, or IL-1 Ra – Fc- GLP-1), but not the full breadth of the claim meets the written description provision of 35 U.S.C. §112, first paragraph.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. 112 is severable from its enablement provision (see page 1115).
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.
Claim(s) 2, 4-13 and 17-20 are rejected under 35 U.S.C. 103 as being unpatentable over Qin et al. (US 9,745,359) in view of Osei et al. (US 9,161,953).
The instantly claimed invention is broadly drawn to A fusion protein comprising:GLP-1 or a variant thereof; an interleukin-1 receptor antagonist (IL-1 receptor antagonist) or a fragment thereof, and an immunoglobulin Fc region, wherein the variant of GLP-1 has the amino acid sequence of any one of SEQ ID NOs: 2 to 4 (claim 4), wherein the IL-1 receptor antagonist has the amino acid sequence of SEQ ID NO: 8 (claim 5), wherein the fusion protein consists of the following structural formula (I) or (II):N'-X-[linker (1)]n-Fc region fragment or variant thereof-[linker (2)]m-Y-C' (I) N'-Y-[linker (1)]n-Fc region fragment or variant thereof-[linker (2)]m-X-C' (II) in the structural formulae (I) and (II),N' is the N-terminus of the fusion protein, C' is the C-terminus of the fusion protein, X is GLP-1 or a variant thereof, Y is an IL-1 receptor antagonist or a fragment thereof, the linker (1) and the linker (2) are peptide linkers, and n and m are each independently 0 or 1 (claim 6), wherein the Fc region of the fusion protein is derived from human IgG4 (claim 7), wherein the fusion protein is a dimer (claim 8), a polynucleotide encoding the fusion protein of claim 2 (claim 9). An expression vector comprising the polynucleotide of claim 9 (claim 10) and a transformed cell comprising the same (claim 11) and a method of making a fusion protein dimer using the transformed cell of claim 11 (claim 12). A pharmaceutical composition comprising the fusion protein dimer of claim 8 and a method of treating a metabolic disease using the pharmaceutical composition of claim 8 or 13 (claims 17-20).
Regarding claim 2, Qin et al teach a fusion protein comprising a GLP-1 and interleukin 1 receptor antagonist or an analog thereof, wherein the fusion protein further comprises an immunoglobulin Fc region (see col. 5, lines 22+, col. 42, lines 4+). Regarding claim 5, Qin et al teaches an IL-1 Ra of SEQ ID NO: 218 (or SEQ ID NO: 52) which is identical to the instantly claimed amino acid sequence of SEQ ID NO: 8 (see sequence result #1 in PE2E, us 18-004-872-8.rai date 12/15/25 (83 identical sequences). Regarding claims 6-7, they teach that the Fc region is from human IgG4 and they teach using a linker to conjugate a GLP-1 agonist with the Fc (see col. 48, lines 6+), wherein the linkers are independently 0 or 1 (see col. 48, line2 28+). Regarding claim 8, they teach that the fusion protein is a dimeric fusion protein (col. 48, lines 30+). They teach cloning and construction of expression sequences using an expression vector (col. 142, lines 52+). They teach transformation of vector DNA into a host cell (col. 145, lines14+). They teach lysing cells and preparing proteins (col.145, lines46+). They teach that the fusion protein is for treating diabetes and using in a lower doses (abstract). Qin et al do not teach that the GLP-1 variant comprises amino acid sequence of SEQ ID NO: 2.
Osei et al. teach glucagon-like peptide 1 (GLP-1) having amino acid sequence of SEQ ID NO: 29 that is 100% identical to the instantly claimed GLP-1 of SEQ ID NO: 2 (see sequence alignment). They teach making a fusion protein of GLP-1 peptide for treating patients with diabetes (abstract).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use a GLP-1 agonist having amino acid sequence 100% identical to the instantly claimed sequence of SEQ ID NO: 2 as taught by Osei et al to make a fusion protein comprising a GLP-1 agonist, an interleukin-1 receptor antagonist and an Fc molecule for treating diabetes as taught by Qin et al. Additionally, one would have been motivated to do so because Osei et al teach that a GLP-1 agonist having 100% identity to the instantly claimed SEQ ID NO: 2 can be used for making a fusion protein for treating diabetes. Further, one would have a reasonable expectation of success in using a GLP-1 agonist of amino acid sequence of SEQ ID NO: 2 as taught by Osei et al for treating diabetes. Therefore, the instantly claimed invention would have been obvious over the combined teachings of the prior art.
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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 2, 4-13 and 17-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-9 of copending Application No. 18/727,662 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because a pharmaceutical composition comprising a fusion protein comprising a GLP-1, an interleukin-1 receptor antagonist and an Fc for treating a subject in need thereof, wherein the pharmaceutical composition comprising the fusion protein comprises Formula (I) or (II) are taught in claims 1-9 of US Application No. 18/727,662.
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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/GYAN CHANDRA/Primary Examiner, Art Unit 1674